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The Gill Center for Biomolecular Science

Gill Seminars

Upcoming Speakers

Previous Speakers

September 30, 2015
George F. Koob, Ph.D. Director

National Institute on Alcohol Abuse and Alcoholism, Washington, DC, USA

Seminar will take place in the Indiana Memorial Union, Whittenberger Auditorium during the 2015 Gill Symposium

Title: Neuroplasticity in the brain stress systems in addiction

Abstract: Addiction to alcohol and drugs has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Multiple sources of reinforcement contribute to the motivation to compulsively seek drugs including core elements of positive reinforcement (binge/intoxication stage) and negative reinforcement (withdrawal/negative affect stage) and conditioned reinforcement (preoccupation-anticipation stage). The construct of negative reinforcement can be defined here as drug taking that alleviates a negative emotional state created by drug abstinence. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical circuits that form the brain stress systems within the extended amygdala, basal ganglia and frontal cortex. Specific neuroplasticity in these circuits includes not only recruitment of the classic hormonal stress axis mediated by corticotropin-releasing factor (CRF) in the hypothalamus, but also extrahypothalamic CRF in the extended amygdala and frontal cortex. Recruitment of dynorphin-k opioid aversive systems in the ventral striatum and extended amygdala represents another dynamic neuroplasticity of the brain stress systems. In animal models, acute withdrawal from all major drugs of abuse increases reward thresholds, increases anxiety-like responses, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block anxiety-like responses associated with withdrawal, the increases in reward thresholds produced by withdrawal from drugs of abuse, and compulsive-like drug taking during extended access. Excessive drug taking also engages activation of CRF in the medial prefrontal cortex and is accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding and relapse. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-k opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Antagonism of the k opioid system can also block anxiety-like effects and reward deficits associated with withdrawal from drugs of abuse and can block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, compelling evidence exists to argue that plasticity in the brain stress systems, a heretofore largely neglected component of dependence and addiction, is triggered by acute excessive drug intake, is sensitized during repeated withdrawal, persists into protracted abstinence, and contributes to the development and persistence of addiction. The neuroplasticity of the brain stress systems in addiction not only provides understanding of the neurobiology of negative reinforcement mechanisms in addiction, but also provides key insights into how the brain processes negative emotions.


September 30, 2015
Garret D. Stuber, Ph.D.

University of North Carolina, at Chapel Hill

Seminar will take place in the Indiana Memorial Union, Whittenberger Auditorium during the 2015 Gill Symposium

Title: Dissecting the neural circuits that mediate motivated behavior

Abstract: In order to survive and effectively navigate an ever-changing and unpredictable environment, organisms must readily adapt their behavior to seek out needed resources, while simultaneously avoiding life-threatening situations. These opposing processes are controlled by neural circuitry that is readily engaged by both environmental and physiological factors to promote behavioral output. The work of my lab studies the precise neural circuits that control both reward and aversive-related behavioral responses. By utilizing optogenetic and other circuit mapping tools, we aim to delineate the precise functional synaptic connections between molecularly distinct neuronal populations that are critical for the generation of these critical behavioral states. A holistic understanding of the interconnected neural circuit elements that mediate diverse motivational behaviors will likely provide important insight into a variety of complex neurological and neuropsychiatric illnesses such as drug and alcohol addiction, anxiety, depression, and eating disorders.


September 30, 2015
Mary Kay Lobo, Ph.D.

University of Maryland School of Medicine

Seminar will take place in the Indiana Memorial Union, Whittenberger Auditorium during the 2015 Gill Symposium

Title: Divergent roles of nucleus accumbens projection neuron subtypes in motivational behaviors

Abstract: The complex cellular heterogeneity of the nucleus accumbens (NAc) has been a major challenge in understanding how specific cell subtypes in the NAc mediate motivational behaviors including drug abuse and stress induced behaviors. To provide insight into this we are examining the two NAc projection medium spiny neuron (MSN) subtypes and their circuits in maladaptive motivational states. We have employed genetic tools to profile and manipulate transcriptional machinery and optogenetic or chemogenetic tools to alter activity in the two NAc MSN subtypes. Through these studies we have uncovered distinct and divergent roles for these MSNs in behavioral outcomes to cocaine and social defeat stress induced behaviors. Overall our studies provide a comprehensive understanding into the distinct roles of the NAc MSN subtypes in dysfunctional motivational behaviors.


September 30, 2015
Loren H. Parsons, Ph.D.

The Scripps Research Institute

Seminar will take place in the Indiana Memorial Union, Whittenberger Auditorium during the 2015 Gill Symposium

Title: Losing Balance: Impaired Endocannabinoid Signaling in Stress and Addiction

Abstract: The endogenous cannabinoid system participates in important regulatory mechanisms involved in physiological homeostasis. Brain endocannabinoid signaling, predominantly mediated by 2-arachidonoylglycerol (2-AG) and anandamide (AEA), is recruited by stress exposure and plays an important role in the homeostatic constraint of physiological and affective responses to stress.  We have found that various addictive drugs increase brain endocannabinoid levels in components of the extended amygdala, and that prolonged drug exposure dysregulates endocannabinoid signaling in these regions in a manner that persists well into protracted abstinence.  In particular, chronic alcohol exposure results in blunted 2-AG signaling in the central nucleus of the amygdala, and this contributes to dependence-related negative affective states and impaired control over alcohol consumption.  The effects of chronic alcohol on amygdalar AEA signaling are similar, but less robust and more transient than observed for 2-AG. Pre-existing genetic disruptions in endocannabinoid signaling also contribute to emotional distress and may confer increased susceptibility to pathological drug use.  In contrast to the consequences of chronic alcohol exposure in outbred rats, we find greater dysregulation of AEA vs. 2-AG signaling in the central amygdala of selectively bred rats that exhibit innate binge-like patterns of alcohol consumption and enhanced stress-reactivity known to be a vulnerability factor for alcohol dependence. Aberrant AEA signaling in these animals results from excessive CRF signaling that confers increased activity of the AEA hydrolytic enzyme FAAH.  These findings provide convergent evidence that dysregulated endocannabinoid signaling in the central amygdala contributes to dependence-related behaviors in outbred animals, and innate behaviors that are risk factors for development of problematic alcohol use in a genetic model of dependence vulnerability.  However, within the models evaluated there appear to be distinctions between the endocannabinoid disruptions conferring vulnerability to dependence vs. those resulting from prolonged alcohol exposure.  This may be relevant for the design of endocannabinoid-based therapeutic strategies for alcohol use disorder and alcoholism.

Dr. Parsons is a Professor in the Committee on the Neurobiology of Addictive Disorders at The Scripps Research Institute (TSRI) in La Jolla, California.  He received a Ph.D. in Chemistry from Emory University where he trained with Dr. Joseph B. Justice, Jr.  He subsequently enjoyed a postdoctoral fellowship in behavioral pharmacology under the mentorship of Dr. George F. Koob at TSRI.  In 1998 he established an independent research laboratory at TSRI, and his work has focused on the neurochemical bases of motivation, drug reward and addiction.


September 30, 2015
Marina E. Wolf, Ph.D.

Rosalind Franklin University of Medicine and Science

Seminar will take place in the Indiana Memorial Union, Whittenberger Auditorium during the 2015 Gill Symposium

Title: Synaptic mechanisms maintaining persistent cocaine craving

Abstract: Cue-induced cocaine craving remains a significant cause of relapse even after prolonged periods of abstinence. In a rat model of this phenomenon, cue-induced cocaine craving progressively intensifies (“incubates”) during the first months of withdrawal from extended-access cocaine self-administration. We showed previously that incubation of cocaine craving is mediated by strengthening of AMPAR transmission in the nucleus accumbens (NAc) due to the accumulation, after 3-4 weeks of withdrawal, of Ca2+-permeable AMPARs (CP-AMPARs). Thus, removing CP-AMPARs from NAc synapses should reduce craving. Our recent work has shown that this can be accomplished via mGluR1 stimulation. In the NAc of drug-naïve rats, group I mGluR activation results in an mGluR5-dependent synaptic depression that is expressed presynaptically. After incubation, this is abolished, and a novel form of LTD emerges that is mGluR1-dependent and expressed postsynaptically via CP-AMPAR removal. To understand its relevance for incubation of craving, we first conducted biotinylation studies after varying periods of cocaine withdrawal to test the relationship between the levels of mGluR1 and CP-AMPAR transmission. We found that decreased mGluR1 surface expression in the NAc precedes and enables CP-AMPAR accumulation. Thus, restoring mGluR1 tone by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. Next, we conducted studies after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high. In slice recordings, we demonstrated that mGluR1 stimulation removes CP-AMPARs from NAc synapses. We further demonstrated that systemic administration of an mGluR1 PAM similarly reduced CP-AMPAR transmission and thereby reduced cue-induced cocaine craving. These results demonstrate a strategy whereby recovering cocaine addicts could use a systemically active compound to protect against cue-induced relapse. Recently, we found that inhibition of protein translation in NAc slices (~1 h incubation with anisomycin, cycloheximide, or rapamycin) restored synaptic transmission to the state observed in drug-naïve rats, i.e., CP-AMPAR levels were decreased, mGluR1-LTD was eliminated, and mGluR5-mediated synaptic depression was restored. These results suggest that aberrant protein translation in the NAc is critical for sustaining synaptic adaptations that are directly linked to persistent enhancement of cocaine craving. We are currently testing this hypothesis by characterizing the regulation of dendritic protein translation in the NAc of drug-naïve rats and “incubated rats”. We are also exploring similarities between synaptic mechanisms underlying incubation of cocaine craving and methamphetamine craving.   Support: DA009621 and DA015835.


October 2, 2016
Hsiao-Huei Chen, Ph.D.

University of Ottawa, Department of Medicine

Seminar will be held in MSBII, Gill Conference Room 102 at 12:00 p.m.

Title: A novel therapeutic target for anxiety and metabolic syndrome

Abstract: A global survey of 17 studies including over 85,000 participants revealed a 20% increased risk of anxiety mood disorders with diabetes.  A review in Nature Reviews, Endocrinology noted that “Intervention studies for anxiety or diabetes-specific emotional distress are currently lacking, and further research that can help to optimize antidepressant treatment is also urgently needed”. Our studies revealed a common link shared by anxiety disorders and metabolic syndrome: unopposed activity of the tyrosine phosphatase PTP1B. We found that LMO4 is an endogenous inhibitor of PTP1B that maintains hypothalamic leptin and insulin signalling to control peripheral metabolism. Chronic high fat diet or saturated fatty acid treatment reduces palmitoylation and inhibition of LMO4 on PTP1B activity, leading to obesity and type 2 diabetes. In addition, we demonstrated that either stress or stress hormone corticosterone reduces palmitoylation and inhibition of LMO4 on PTP1B activity, leading to dephosphorylation of glutamate receptor mGluR5 and collapse of endocannabinoid (eCB) signaling in the amygdala. Collectively, these data reveal a stress-responsive corticosterone-LMO4-PTP1B-mGluR5 cascade that impairs amygdalar eCB signaling and contributes to the development of anxiety. Importantly, our preclinical studies in mice demonstrate the efficacy of using a PTP1B-selective inhibitor, Trodusquemine, a natural Squalamine compound isolated from dogfish liver, to treat anxiety and metabolic syndrome.


May 1, 2015
Mark Zylka, Ph.D.

University of North Carolina

Seminar will take place at noon in MSBII, Room 102

Title: Gene length matters in autism

Abstract: Dr. Zylka will discuss his research on Ube3a, transcriptional regulators linked to autism, and his labs search for environmental risk factors for autism.


April 13, 2015
Charles E. Schroeder, Ph.D.

Nathan Kline Institute, Department of Psychiatry, Columbia University College of Physicians and Surgeons

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Neuronal Mechanisms of Temporal Prediction in Active Sensing

Abstract: Neuronal oscillations reflecting synchronous, rhythmic fluctuation of neuron ensembles between high and low excitability states, dominate ambient activity in the sensory pathways. Because excitability determines the probability that neurons will respond to input, a top-down process like attention can use oscillations as “instruments” to amplify or suppress the brain’s representation of external events. That is, by tuning the frequency and phase of its rhythms to those of behaviorally and/or cognitively-relevant event streams, the brain can use its rhythms to parse event streams and to form internal representations of them. In doing this, the brain is making temporal predictions. I will discuss findings from parallel experiments in humans and non-human primates that outline specific structural and functional components of this temporal prediction mechanism. I will also discuss its possible generalization across temporal scales, as well as motor system contributions to sensory systems’ dynamics.


April 6, 2015
Cheryl Conrad, Ph.D.

Arizona State University

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Consequences of chronic stress on the brain and behavior: Mechanisms for resilience

Abstract: Chronic or persistent stress is a known risk factor for a multitude of neuropsychiatric conditions that include, but not limited to, post-traumatic stress disorder, major depression, anxiety disorders, and drug addiction/relapse. Moreover, the neurocircuitries and mediators underlying the stress system overlap with brain regions involved in many neuro-psychiatric conditions. Consequently, work using chronic stress in rodent models can provide insight into understanding mechanisms that underlie the vulnerabilities and resilience for brain health. I will describe some of my team’s past research on chronic stress effects on the hippocampus, a brain region that displays great sensitivity and functional plasticity in response to chronic stress. This is the same brain structure that has received attention for its role in guiding navigation, or spatial ability, with Drs. O’Keefe, Moser, and Moser receiving the 2014 Nobel Prize in Physiology or Medicine on their work in this structure. My team’s work has centered on how chronic stress disrupts this navigational (or “spatial”) memory and produces hippocampal dendritic retraction, which compromises neuronal communication. A novel feature of these chronic stress-induced alterations in spatial memory and dendritic morphology is that they can recover in the following weeks after the chronic stress paradigm has ended. I will discuss some new research that unveils some of the mechanisms underlying the recovery process following the termination of chronic stress. Time permitting, additional findings will be discussed that reveal sex differences in how chronic stress influences the brain and behavior, as well as some other work investigating the prefrontal cortex and amygdalar brain regions.


March 30, 2015
Susan G. Amara, Ph.D.

Director of the Division of Intramural Research Programs, National Institute of Mental Health

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Dynamic regulation of signaling pathways in dopamine neurons: the intracellular actions of amphetamines

Abstract: Neurotransmitter transporters present at the plasma membrane contribute to the clearance and recycling of neurotransmitters and have a profound impact on the extent of receptor activation during neuronal signaling. These carriers also are the primary targets for psychostimulant drugs of abuse, antidepressant medications, and drugs such as methylphenidate and amphetamines, which are used to treat attention deficit disorders. This lecture will highlight several of the major signaling pathways that regulate dopamine transporter function, and will also consider recent work showing that amphetamine-like drugs can directly activate intracellular signaling pathways in dopamine neurons to trigger changes in membrane protein trafficking and other cellular activities. Although several steps in the process remain undefined, the intracellular actions of amphetamine modulate both dopaminergic and glutamatergic signaling and can contribute to the acute behavioral effects of amphetamine-like drugs.


February 23, 2015
Michael R. Bruchas, Ph.D.

Washington University School of Medicine, St. Louis

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Dissecting Neural Circuits and GPCR Signaling in Stress Behavior

Abstract: Stress responses are largely controlled by specific neurotransmitters and their receptors in the central nervous system.  Many of these signals are conveyed through activation of both neuropeptide (i.e. CRF and Opioid) and monoamine (norepinephrine, dopamine, serotonin) receptor systems.  These receptors are seven transmembrane spanning G-protein coupled receptors (GPCR) and they can stimulate a variety of signaling cascades following neurotransmitter/neuropeptide release.  Neuropeptide and monoamine circuits are engaged by stress, and elicit a complex array of behavioral responses relevant to anxiety, addiction, and depression. Two neuropeptide systems of  major interest in stress responsivity include dynorphin opioid peptides and CRF. These systems and circuits have classically been studied using pharmacological approaches, in vivo and in vitro electrophysiology and biochemical methods.  Here we will describe recent advances in optogenetic technology including development and implementation of cellular scale wireless optogenetic devices for in vivo behavioral measures.  In addition, we report divergence of behavioral responses using optical control of discrete brain region subnucleai containing dynorphin expressing neurons.  We find that optical control of this neuropeptide system in select regions results in differences in reward and aversion behavior.  Finally, we will also discuss recent advances in controlling various monoamine and peptide GPCR signaling pathways with optogenetic strategies and how these technologies reveal novel insights into neuromodulator function in stress-induced affective behavior.


CANCELLED due to adverse weather conditions in Chicago.

Rescheduled for November 2, 2015

February 2, 2015
A. Vania Apkarian, Ph.D.

Northwestern University School of Medicine

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Transition to chronic pain: Predictors and consequences

Abstract: 1) I will review accumulating evidence regarding brain reorganization with chronic pain. Both human brain imaging studies as well as animal model studies specifically interrogating the role of supraspinal plasticity will be emphasized. The primary take home message is that the grey matter of the neocortex dynamically changes with chronic pain and this reorganization is pain type specific.

2) It is common clinical knowledge that although a very large patient population presents with similar injuries that give rise to pain, only a small minority of them develop chronic pain. Thus the critical question in the field of pain research is: what characteristics differentiate between those that develop chronic pain and the ones who properly recover from their injury into health. I will review the results from the only existing longitudinal brain-imaging based study, where brain anatomical and functional properties were studied as subjects transitioned from acute to chronic pain. One hundred and twenty sub-acute back pain patients (SBP, no back pain for at least one year and persistence of back pain for 4-12 weeks of an intensity of 5/10) were recruited and followed over one year, where repeated brain imaging and pain questionnaire outcomes were collected. Sixty-eight subjects completed the study. Different subgroups of these subjects were analyzed at various phases of the study to examine 1) brain grey matter reorganization and related functional properties, 2) brain white matter properties as predictors of pain chronification, 3) changes in brain activity reflecting back pain in the transition to chronic pain, 4) relationship between smoking and chronic pain. The primary result of these analyses is the important observation that very simple brain parameters accurately predict who will develop chronic pain and who will not. Both anatomical and functional properties seem critical.
 If time permits I will present an overall mechanistic model of the transition to chronic pain that summarizes the results presented in both lectures.

Overall we envision four distinct phases for transition from acute to chronic pain:

  1. Predisposition
  2. Injury or inciting event
  3. Transition
  4. Maintenance

Mechanisms underlying each of these phases are distinct. Phase 2 is primarily determined by nociceptive processes, while phase 1 seems mainly brain dependent,  for chronic back pain.

Reference papers:
Corticostriatal functional connectivity predicts transition to chronic back pain.
Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, Fields HL, Apkarian AV.
Nat Neurosci. 2012 Jul 1;15(8):1117-9.

A dynamic network perspective of chronic pain.
Farmer MA, Baliki MN, Apkarian AV.
Neurosci Lett. 2012 Jun 29;520(2):197-203.


January 26, 2015
Zuoxin Wang, Ph.D.

Florida State University

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: The Monogamous Brain

Abstract: The socially monogamous prairie vole (Microtus ochrogaster) displays mating-induced pair bonding, demonstrated by a preference for a familiar partner versus a conspecific stranger (partner preference) and aggression toward strangers (selective aggression), and thus provides an opportunity to study the neurochemical mechanisms underlying pair bonding.  Accumulating evidence has implicated a variety of neurochemicals including dopamine and oxytocin in the regulation of pair bonding behavior. In this talk, I will focus on dopamine in the nucleus accumbens (NAcc) to illustrate its role in the formation and maintenance of pair bonding.  Thereafter, I will discuss the data from our recent studies demonstrating that neurochemical oxytocin that is involved in pair bonding also plays a role in mediating social buffering effects on the stress response as well as in restoring social bonding impaired by drug exposure.  Taken together, our data support the notion that multiple neurochemicals in a circuitry might represent important targets for the treatment of social deficits.  (Supported by NIH grants DAR01-019627 and MHR01-058616).


October 20, 2014
Norbert Fortin, Ph.D.

University of California, Irvine

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: The neurobiology of the memory for sequences of events: a synergistic approach in rats and humans

Abstract: It is well established that the ability to temporally organize information is fundamental to many perceptual, cognitive, and motor processes. Temporal organization is also critical to memory. In fact, since many of our memories have overlapping elements, including specific items and locations, our capacity to distinguish individual memories critically depends on remembering their unique temporal context. Unfortunately, while our understanding of how the brain processes the spatial context of memories has advanced considerably in recent years, our understanding of their temporal organization lags far behind. The overall objective of our research is to understand the fundamental neurobiological mechanisms underlying the memory for sequences of events and the memory for elapsed time. In this seminar, I will primarily focus on our recent work in rodents in which we used localized brain inactivations and single-cell recordings to help elucidate the contributions of the hippocampus and prefrontal cortex. I will also present recent findings from our parallel work in human subjects, which suggests that rats and humans use similar strategies, cognitive processes and neural circuits to remember sequences of items. I will conclude by discussing the importance of developing integrated, cross-species approaches to advance basic and clinical memory research. 


October 15, 2014
Matthias H. Tschöp, M.D.

Helmholtz Diabetes Center and Technische Universität München

Seminar will take place at 3:30 p.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2014 Gill Symposium

Title: The Metabolic Syndrome: A Brain Disease? 

Abstract: All metabolic processes, from single cell substrate oxidation to complex behaviors, are under the control of specific CNS circuits, aiming to maintain homeostasis. Afferent signals include gut hormones, adipokines and nutrient components, while efferent information primarily originates from the hypothalamic nuclei and involves components of the autonomic nervous system as well as the classic endocrine axes. We recently observed that diet-induced metabolic diseases, such as obesity and type 2 diabetes, are associated with (and preceded by) pathological processes in these hypothalamic control centers. Such pathophysiology concerns the hypothalamic cell matrix beyond key neuronal populations and includes astrocytosis, microgliosis, hypervascularisation as well as increased presence of pro-inflammatory cytokines. Specific targeting of such “hypothalamic inflammation” using novel gut-peptide based delivery of glucocorticoids to key metabolic disease regions improved both local pathophysiology and systemic metabolic health. Such a novel unimolecular dual agonism and steroid delivery approach may not only offer superior therapeutic option for at least some patient subpopulations, but also suggests a pathogenetic relevance for this novel hypothalamic syndrome.


October 15, 2014
Scott Sternson, Ph.D.

HHMI, Janelia Farm Research Campus

Seminar will take place at 11:40 a.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2014 Gill Symposium

Title: The Neurobiology of Need

Abstract: Neural circuits essential for survival, such as those that mediate hunger, are shaped by selective pressure but involve flexible goal-directed actions. This is exemplified by starvation-sensitive AGRP neurons that are sufficient to rapidly coordinate voracious food seeking and consumption behaviors. We have used cell-type-specific techniques for neural circuit manipulation to examine the structural organization and motivational properties of AGRP neuron hunger circuits. We find that AGRP neuron circuits coordinate multiple processes controlling appetite through distinct circuit projections. In addition, AGRP neurons transmit a signal with negative valence that can serve a negative reinforcement teaching signal for food-seeking behavior. Similar characteristics are also found for a separate neuron population that controls thirst. Therefore, these homeostatic neurons provide a link between physiology and the emotional and motivational qualities of need states.


October 15, 2014
Sabrina Diano, Ph.D.

Yale University School of Medicine

Seminar will take place at 10:30 a.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2014 Gill Symposium

Title: Free radicals in the central regulation of metabolism

Abstract: Reactive oxygen species (ROS) are important regulators of cellular functions. While most attention regarding ROS is paid to DNA damage, degenerative processes and aging, free radicals also serve as critical signaling molecules in physiological processes.  For example, we showed that ROS activates POMC neurons, inhibits NPY/AgRP cells, and, they reduce feeding.  On the other hand, suppression of ROS diminishes POMC cell activation and promotes the activity of NPY/AgRP neurons leading to increased feeding. The levels of ROS in POMC neurons positively correlate with circulating leptin levels in lean and ob/ob mice, a relationship that is diminished in diet-induced obesity (DIO). High fat feeding in DIO lead to alteration of ROS levels and feeding via control of peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA levels and related proliferation of peroxisomes. Central administration of ROS alone increased c-fos and leptin sensitivity in POMC neurons and reduced feeding of DIO mice. Taken together, our data unmasked a crucial physiological role for ROS in central regulation of energy metabolism.


October 15, 2014
Tony K. T. Lam, Ph.D.

University of Toronto

Seminar will take place at 9:10 a.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2014 Gill Symposium

Title: CNS control of hepatic lipid and glucose metabolism

Abstract: Our main focus has been to elucidate nutrient and hormone sensing mechanisms in the gut and the brain that regulate hepatic glucose production, hepatic VLDL-TG secretion and food intake to maintain glucose, lipid and energy homeostasis. We have discovered nutrient sensing in the duodenum triggers hormonal signaling and a gut-brain-liver axis to inhibit glucose production and lower plasma glucose levels. We have identified jejunual nutrient sensing is necessary for duodenal-jejunal bypasss to rapidly lower glucose levels in uncontrolled diabetes. Lastly, we have unveiled novel insulin, glucagon and nutrient signaling pathways in the brain that regulate hepatic glucose production, VLDL-TG secretion and food intake. In summary, our discoveries reveal molecular targets in the brain and the gut that may carry therapeutic potential to lower blood glucose and lipid levels and body weight in diabetes and obesity.


October 15, 2014
Randy Seeley, Ph.D.

University of Michigan

Seminar will take place at 2:10 p.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2014 Gill Symposium

Title: Bariatric Surgery:  It’s not what you think it is. Molecular targets for the effects of surgery on behavior and metabolism.

Abstract: While various bariatric surgeries provide both the largest and most durable weight loss of any currently available therapy, there remain great uncertainties around the mechanisms that produce such weight loss.  At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia.  These weight and metabolic successes put a premium on understanding how these surgeries exert their effects.  We have been using a variety of mouse models to test specific hypotheses about key molecular targets that mediate the benefits of bariatric surgery.  Bariatric surgery produces changes in a number of brain-gut signaling systems that result in profound changes in food intake and food selection.  In addition to typical gut hormones, bariatric surgery results in changes in bile acids and bile acid signaling that are crucial for many of the behavioral and metabolic effects of the surgery.  ______________________________________________________________________________

April 23, 2014
Grace Zhai, Ph.D.

University of Miami, Miller School of Medicine

Seminar will be held in MSBII, Room 102 at 4:00 p.m.

Title: A balancing act: how to regulate the neuroprotective and NAD synthetic role of NMNAT

Abstract: Dr. Grace Zhai's research is focused on the mechanisms of neurodegeneration and protection, with an emphasis on the endogenous maintenance programs in the nervous system that can be enhanced to offer neuroprotection. Her group identified and characterized a novel neuronal maintenance and protective function of NMNAT (nicotinamide mononucleotide adenylyltransferase), a highly conserved enzyme in the NAD synthesis pathway. NMNAT is an effective and versatile neuroprotective factor, and its overexpression protects against several neurodegenerative conditions in fly and mouse models, including excitotoxicity-, spinocerebellar ataxia 1 (SCA1)- and tau- induced neurodegeneration. In this talk, she will discuss how neurons partition NMNAT into two distinct functions, i.e. NAD synthesis and neuroprotection, and how such partitioning is regulated under normal and adverse conditions to achieve neuroprotection.


April 9, 2014
Matthew Hill, Ph.D.

University of Calgary

Seminar will be held in MSBII, Room 102 at 4:00 p.m.

Title: Mechanisms of endocannabinoid regulation of anxiety

Abstract: Accumulating evidence has demonstrated that the endocannabinoid system is an important regulatory system over activation of the HPA axis in response to stress and emotional behaviour. The central locus of these effects has yet to be fully elucidated, but given the integral role of the amygdala in the processing of aversive stimuli and the generation of anxiety-like responses, it seems likely that this structure is involved. In response to acute stress, tissue levels of the endocannabinoid, anandamide, are found to rapidly decline within the amygdala; a phenomenon which appears to be due to a rapid induction of anandamide hydrolysis by the enzyme fatty acid amide hydrolase (FAAH). Following chronic stress, this induction of FAAH and suppression of anandamide within the amygdala persists beyond the period of stress exposure, producing steady-state reductions in anandamide signaling within the amygdala. Under conditions of acute stress, local administration of a FAAH inhibitor into the basolateral amygdala attenuates activation of the HPA axis suggesting that this loss of anandamide signaling contributes to activation of the HPA axis. Furthermore, following exposure to chronic stress, mice deficient in FAAH do not develop the increased anxiety-like behavioural responses seen in wildtype mice, demonstrating that induction of FAAH by stress is a necessary step in the modulation of emotionality by stress. Collectively, these data indicate that stress produces a rapid and sustained suppression of anandamide signaling within the amygdala which contributes to both activation of the HPA axis and the generation of anxiety-like responses, possibly through a disinhibition of excitatory afferents to the basolateral amygdala and a consequential increase in the intrinsic excitability of the amygdala. These findings may help to provide a framework by which we may understand the central mechanism by which FAAH inhibitors exhibit anxiolytic actions.


April 4, 2014
Catherine Woolley, Ph.D.

Northwestern University

Seminar will be held in Myers Hall, Room 130 at 4:00 p.m.

Title: Acute Estrogen Modulation of Synapses in the Hippocampus

Abstract: That steroids such as estrogens can modulate brain function within minutes has been known for decades, but the last ~40 years of research into mechanisms of steroid actions in the brain have been dominated by transcription-related genomic effects.  Recently, however, interest in acute nongenomic estrogen actions has grown, in parallel with recognition that estrogens may be produced as neurosteroids in the brains of both males and females.  I will discuss our recent work investigating how estrogens acutely modulate synaptic transmission in the hippocampus and how this modulation may be related to neurological disorders such as epilepsy.


March 5, 2014
Rebecca Craft, Ph.D.

Washington State University

Seminar will be held in MSBII, Room 102 at 4:00 p.m.

Title: Sex Differences in Cannabinoid Analgesia

Abstract: Sex differences in various effects of cannabinoids – including analgesic, motoric, cognition-impairing, and reinforcing effects – have been reported in rodents, with females typically being more sensitive than males.   The Craft lab has focused on characterizing sex differences in cannabinoid-induced antinociception in rats.  THC and other cannabinoid agonists are more potent and in some cases more efficacious in females than in males against acute thermal and mechanical pain, and THC is more effective in females than in males in a model of persistent inflammatory pain.  Sex differences in cannabinoid-induced sedation likely contribute to sex differences in their antinociceptive effects, but do not fully explain them, as sex differences in antinociception persist when THC is administered peripherally.  Sex differences in THC-induced antinociception can be attributed largely to estradiol, which increases females’ sensitivity to THC.  Sex differences in THC’s behavioral effects (and perhaps estradiol enhancement of THC sensitivity) can be attributed to both pharmacokinetic and pharmacodynamic mechanisms.  For example, females produce more 11-OH-THC – a potent active metabolite of THC -- than males do, and females may have more CB receptors than males do, in pain-related areas of brain and in the periphery.  Given that women suffer more types of chronic pain and more frequent and severe pain than do men, the greater pain-relieving potential of cannabinoids in females may offer a clinically important alternative to traditional analgesics.


November 20, 2013
Melanie Kelly, Ph.D.

Dalhousie University

Seminar will be held in MSBII, Room 102 at 4:00 p.m.

Title: The Ocular Endocannabinoid System: Therapeutic Prospects For Cannabinoid Drugs

Abstract: A number of well-described ocular effects are produced in humans following ingestion of Cannabis sativa or individual constituent phytocannabinoids, such as D9-THC (THC). These include: a reduction in intraocular pressure (IOP), and vasodilation (Green 1975, Hepler 1971). To-date, cumulative evidence  has determined that THC and other cannabinoids mediate these, and other actions locally via the ocular endocannabinoid system. The presence of endocannabinoids, including anandamide (N-arachidonoyl ethanolamine; AEA) and 2-arachidonoyl glycine (2-AG), along with their biosynthetic and metabolic enzymes and receptors, has now been demonstrated in anterior and posterior ocular tissues, including the retina. In addition, alterations in endocannabinoids have been detected in ocular tissue in human pathology.  Our work is using both in vitro cell models and in vivo animal models, including genetic models, to examine the elements of the endocannabinoid system that give rise to the ocular pharmacological effects of cannabinoids. Specifically, we are exploring the potential for the development of cannabinoid-based therapeutics for the treatment of blinding eye diseases, including glaucoma, uveitis and proliferative vitreoretinopathy.


November 5, 2013
Michael Courtney, Ph.D.

University of Eastern Finland, Kuopio Campus

Seminar will be held in MSBII, Room 102 at 1:30 p.m.

Title: Signalling Downstream of the NMDA receptor - pathways contributing to neurodegeneration

Abstract: Our lab aims to understand the function and regulation of signalling pathways associated with neuronal damage and disease. Excitotoxicity is considered to be a mechanism common to many neurodegenerative conditions, resulting from excess influx of calcium through NMDA receptors. After decades of failed stroke trials, a successful trial reported in 2012 used a competitor of the NMDA receptor interaction with PSD95 signalling complexes, which renewed optimism about targeting excitotoxicity. To better understand NMDA receptor signalling mechanisms, in particular those mediated by PSD95 in excitotoxicity, we have investigated the activation of p38 MAP kinase by nNOS in response to NMDA. Our earlier studies reported constructs that could reduce excitotoxic p38MAPK activation and cell death by competing with the interaction between nNOS and PSD95, confirming this interaction is required and targetable. Further investigation revealed an additional requirement, a protein binding pocket of nNOS which is distinct from the PSD95 interacting loop. We found that excitotoxic stimulus induces the recruitment of NOS1AP to this pocket of nNOS, that NOS1AP also binds the p38MAPK activator MKK3, and that the recruitment event is necessary for p38MAPK activation and ensuing cell death, which can be reduced by RNAi knockdown of NOS1AP and MKK3. On the basis of these findings we developed a cell-permeable peptide inhibitor of the interaction between NOS1AP and the nNOS and found it to be neuroprotective both in cortical neuron cultures and to double the amount of surviving brain tissue in a rodent model of neonatal hypoxia-ischemia, a major cause of neonatal death and paediatric disability. We propose that the highly unusual sequence specificity of the nNOS-NOS1AP interaction and its involvement in excitotoxic signalling may provide future opportunities for generation of neuroprotectants with high specificity.


September 25, 2013
Bruce L. McNaughton, Ph.D.

The University of Lethbridge

Seminar will take place from 1:30PM-2:30PM in the Indiana Memorial Union, Whittenberger Auditorium

Title: Doughnuts in the Brain: A Toroidal Attractor Theory of the Cognitive Map

Abstract: The hippocampal formation of the mammalian brain is crucial to the storage and consolidation of 'episodic' memories: memories for experiences that unfold in space and time. It accomplishes its role in memory using so-called 'place-cells', which provide a unique code reflecting the spatio-temporal context of experiences.  This code serves as a tag or 'index' that links together sub-components of a given experience which are stored in distributed form throughout the neocortex. The index code is generated by complex interactions of cellular and network mechanisms whose understanding has been greatly facilitated by technologies that enable monitoring cellular activity from large numbers of neurons in the brains of behaving animals. These interactions enable integration of self-motion information to keep track of spatial location, and append information about external and internal events onto the resulting internal spatial coordinate system, thus generating a 'cognitive map'. Networks in thalamus and midbrain ('head-direction cells') compute relative head orientation (azimuth) as animals rotate their heads; cells in medial entorhinal cortex ('grid cells') fire in a regular, 2-D periodic, spatial pattern (‘grid field’) when an animal moves about its world.  Head-direction and grid cells can be explained by a theory in which pre-wired synaptic matrices determine ring (1-D) or toroidal (2-D; ‘doughnut-like’) manifolds of allowed states (‘attractors’) of network activity. The speed by which the neuronal state is updated relative to the animal’s physical motion in space sets the scale of the 2-D grid field, and there are multiple such grid cell modules, each with a different movement gain, and thus each expressing a different spatial scale. Next, hippocampal place cells, which receive grid field information at multiple spatial scales, provide unique codes for spatial location, possibly by a Fourier synthesis-like summation on their inputs.   Finally, inputs from other brain regions, representing features and events in the world, or internal states such as goals, modulate the rate (but not relative location) of place cell firing, thus generating a unique, conjunctive code for ‘what’ happened ‘where’.  Although they exhibit a high degree of experience-dependent plasticity, these networks appear to be wired up by a self-organizing process in early post-natal development in a manner that is independent of experience (a priori).  Thus, in a sense, Immanuel Kant was correct: "Space… originates from the mind's nature in accord with a stable law as a scheme, as it were, for coordinating everything sensed externally".


September 25, 2013
Loren M. Frank, Ph.D.

University of California, San Francisco

Seminar will take place from 3:00PM-4:00PM in the Indiana Memorial Union, Whittenberger Auditorium

Title: Neural Substrates of Memory and Decision-Making

Abstract: The hippocampus is a brain structure known to be critical for forming and retrieving memories for the experiences of daily life. How, exactly, it does so has remained a mystery for some time, but recent progress indicates that specific patterns of neural activity can be linked to specific memory functions.  In this talk I will discuss work from my laboratory that provides such a link. We have shown that hippocampal replay events can reactivate patterns of brain activity from a previous experience in awake animals and that disrupting these events interferes with learning and memory-guided decision-making.  Further, we have found that the intensity of replay activity is predictive of whether an upcoming choice will be correct or incorrect. Our results suggest that the awake replay of place cell sequences plays a central role in deliberative processes that underlie memory-guided decision making. 


September 25, 2013
Joshua Dubnau, Ph.D.

Cold Spring Harbor Laboratory

Seminar will take place from 10:50AM-11:30AM in the Indiana Memorial Union, Whittenberger Auditorium

Title: Micro-RNA 276a and the Zombie Fruit Fly

Abstract: The ability to form olfactory associative memories requires circuit mechanisms to integrate accurate and specific odor representations with aversive or appetitive unconditioned stimuli (USs). The US signal can include information about valence, intensity and quality of the stimulus, all of which may modulate the arousal state of the animal. I will describe a micro-RNA::dopamine receptor genetic regulatory module that plays distinct and separable roles in olfactory arousal on the one hand and on odor-US association on the other. MicroRNA genes do not code for proteins, but instead generate small noncoding RNAs that regulate expression of specific target mRNAs with complementary target motifs. Although a growing number of studies demonstrate that micro-RNA function broadly speaking plays an important role in the brain, there still are few examples where function of individual micro-RNAs have been connected through neural circuits to behavior. We demonstrate that normal olfactory behavior in Drosophila requires the micro-RNA dme- miR276a in two different neuronal cell types: mushroom body Kenyon cells and ellipsoid body R4 central complex neurons. In both circuits, miR276a targets a DA1 type dopamine receptor. But this regulatory relationship serves different aspects of olfactory behavior in mushroom body versus central complex. This miR276a-Dopamine receptor interaction in mushroom body neurons plays a role in long-term olfactory associative memory per se and in ellipsoid body neurons the same regulatory interaction modulates olfactory arousal.


September 25, 2013
Ivan Soltesz, Ph.D.

University of California, Irvine

Seminar will take place from 9:40AM-10:20AM in the Indiana Memorial Union, Whittenberger Auditorium

Title: Organization and Control of Hippocampal Chronocircuits

Abstract: Distinct interneuronal subtypes have evolved in hippocampal neuronal circuits to deliver GABA to specific spatial domains of principal cells at particular times during behaviorally relevant network oscillations. The precise spatiotemporal control of populations of principal cells by the GABAergic system is a critically important yet incompletely understood process that is compromised in several other major neurological and psychiatric disorders. We will discuss recent results from awake mice that demonstrate a novel frequency-independent temporal ordering of interneuronal discharges during network oscillations in the hippocampus. In addition, we will show how on-demand, closed-loop optogenetic strategies can be used to control chronocircuit dysfunctions in epilepsy in a spatially, temporally and cell-type specific manner. Finally, we will discuss how the close integration of experimental findings with large-scale, data-driven computational simulations of hippocampal networks offers a powerful tool towards the identification of key circuit parameters that may be particularly effective in controlling chronocircuit behavior. These closely integrated experimental and computational approaches allow a better understanding of the mechanisms underlying neuronal oscillatory circuit functions in control animals and chronocircuit dysfunction in neurological and psychiatric disorders.


April 10, 2013
Betty Bei Yao
, Ph.D.
Abbott Laboratories
Seminar will be held in Multidisciplinary Building II (MSBII), Gill Conference Room 102 at 4:00 p.m.

Title: Principles in Drug Discovery    

Abstract: The process of developing new therapeutic drugs has become extraordinarily lengthy and expensive, motivating the search for ways to improve the process.  A particular problematic (and costly) issue is moving a potential drug to human trials, only to have it fail through lack of efficacy or unacceptable side effects.  One way to address failure during clinical trials is to better understand the actions of the candidate drug earlier in its development as well as early target validation.  In her talk, Dr. Yao will discuss her experience with this process, emphasizing the approach of investing in early target validation in order to increase the probability of clinical success.

About the speaker:  Dr. Yao is an Associate Director at Abbvie (formerly Abbott Laboratories) where she has more than 15 years of experience in developing neuroscience-related therapeutic targets.


March 27, 2013
Joseph F. Cheer, Ph.D.

University of Maryland School of Medicine

Seminar will be held in Multidisciplinary Building II (MSBII), Gill Conference Room 102 at 4:00 p.m.

Title: Endogenous cannabinoids and the pursuit of reward

Abstract: Endocannabinoids (eCBs) may provide animals with an adaptive advantage by promoting behaviors that maximize reward while minimizing punishment and fear. The mesolimbic dopamine system, which is thought to generate a teaching signal involved in the selection of advantageous behavioral repertoires, is under control of eCBs and; therefore, may contribute to the ability of eCBs to not only strengthen responses leading to the procurement of reward but also those leading to the reduction of harm. We previously demonstrated that disrupting eCB signaling uniformly decreases dopaminergic encoding of reward-predictive cues and reward directed behavior. Here, we investigate whether eCBs also modulate dopaminergic encoding of cues predicting either the avoidance of punishment or aversive outcomes. We first used fast-scan cyclic voltammetry to investigate whether disrupting eCB signaling alters dopaminergic encoding of cues predicting the avoidance of punishment during behavior maintained in a signaled shock avoidance procedure. In this task, a stimulus light was presented as a warning signal for 2-s prior to the delivery of recurring foot shocks. During this 2s warning period, a response lever was extended into the testing chamber which, if pressed, produced a 20s safety period signaled by a tone. Animals could initiate an avoidance response by pressing the lever within the 2s warning period, entirely preventing shock. Alternately, once shocks commenced, animals could initiate an escape response by pressing the lever during this punishment period, terminating shock. Disrupting eCB signaling by treating animals with rimonabant dose-dependently decreased concentrations of dopamine release in the nucleus accumbens that were time-locked to the warning signal while simultaneously weakening shock avoidance behavior, effectively shifting the behavioral outcome from avoidance to escape. We next assessed the effects of disrupting eCB signaling on dopaminergic encoding of cues predicting aversive outcomes using a fear-conditioning model. As previously reported, rimonabant treated rats were resistant to the extinction of fear memories induced by a fear-associated cue when presentations occurred 24hr after conditioning. Impaired fear memory extinction was accompanied by diminished dopaminergic encoding of the fear-associated cue in the nucleus accumbens. In vehicle treated rats we observed a decrease in accumbal dopamine release events during presentation of the fear-associated cue, an effect that was attenuated by rimonabant pretreatment. Together these data suggest that eCBs might modify distinct behavioral responses related to aversive stimuli by modulating conditioned mesolimbic dopamine release events. 


March 6, 2013
Michael Beierlein, Ph.D.

University of Texas Medical School

Seminar will be held in Multidisciplinary Building II (MSBII), Gill Conference Room 102 at 4:00 p.m.

Title: Cholinergic synaptic signaling in the thalamus

Abstract: Cholinergic neurons in the basal forebrain and the brain stem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular acetylcholine (ACh) levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Our studies demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that the synaptic release of ACh release leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic α4β2 nicotinic (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. ACh can also bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, brief trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our work highlights the presence of fast and precise cholinergic synaptic signaling, suggesting novel computational mechanisms for the control of neuronal activity in thalamic circuits.


February 27, 2013
Linda R. Watkins, Ph.D.

University of Colorado at Boulder

Seminar will be held in Multidisciplinary Building II (MSBII), Gill Conference Room 102 at 4:00 p.m.

Title: "Listening” and “Talking” to Neurons: Clinical implications of glial dysregulation of pain, opioid actions & drugs of abuse 

Abstract: Work over the past 18 years has challenged classical views of pain & opioid actions. Glia (microglia & astrocytes) in the central nervous system are now recognized as key players in: pain amplification, including pathological pain such as neuropathic pain; compromising the ability of opioids, such as morphine, for suppressing pain; causing chronic morphine to lose effect, contributing to opioid tolerance; driving morphine dependence/withdrawal; driving morphine reward, linked to drug craving & drug abuse; & even driving negative side effects such as respiratory depression.  Glial activation arises under conditions of chronic pain from neuron-to-glia signaling.  Intriguingly, the glial activation receptor that creates neuroinflammation under conditions of chronic pain is one and the same receptor that is activated by opioids. Atop this, what is both fascinating & fundamentally important for drug development is that opioid effects on glia that create neuroinflammation are via the activation of a non-classical, non-stereoselective opioid receptor distinct from the receptor expressed by neurons that suppresses pain. This implies that the effects of opioids on glia & neurons should be pharmacologically separable so to lead to new drugs for the control of chronic pain & to increase the clinical efficacy of pain therapeutics. Indeed, drugs in development that target either glia activation generally or this glial activation receptor in particular have shown remarkable efficacy as stand alone treatments for neuropathic pain, by blocking neuron-to-glia signaling, plus blocking unwanted side effects of opioids, as well as other drugs of abuse


February 6, 2013
Robert W. Gereau, Ph.D.

Washington University School of Medicine in St. Louis

Seminar will be held in Psychology Building, Room PY101 at 4:00 p.m.

Title: Translational pain research: targeting central sensitization

Abstract: Work in my lab focuses on identification of molecular mechanisms of plasticity in pain pathways that lead to the development of pathological pain.  Central sensitization is a term that describes a form of plasticity wherein CNS circuits involved in pain transmission are hyper-excitable, leading to enhanced pain in response to noxious or even innocuous stimuli.  This seminar will describe studies that we have conducted over the past 15 years that identify a G protein-coupled metabotropic glutamate receptor as a critical mediator of central sensitization in preclinical models of chronic pain.  I will also describe our current efforts to determine whether similar mechanisms mediate central sensitization in humans.  


January 30, 2013
Alfred I. Geller, Ph.D.

Harvard Medical School

Seminar will be held in Psychology Building, Room PY101 at 4:00 p.m.

Title:HSV-1 vectors for neural gene therapy and cognitive learning mechanisms

Abstract: We are developing gene therapies for neurological diseases and studying the cellular and molecular foundations of an advanced cognitive function, visual object discrimination learning. 
     We reported the first gene transfer into neurons, via any virus vector, and we pioneered helper virus-free Herpes Simplex Virus (HSV-1) plasmid vectors. 
     We corrected a rat model of Parkinsonʼs disease by expressing tyrosine hydroxylase in the partially denervated striatum, the first example of correcting an animal model of a neurological disease by direct gene transfer.  Further, coexpressing four dopamine biosynthetic and transporter enzymes supports regulated release of dopamine and high-level biochemical and behavioral correction of a rat model of Parkinsonʼs disease.  
     We are examining the cellular and molecular foundations of an advanced cognitive function, visual object discrimination learning.  The strategy targets some of the essential information for this learning to an identified neocortical circuit, thereby enabling examination of the role of identified neurons, within the essential circuit, in learning.  Delivery of a constitutively active protein kinase C (PKC) into several hundred spatially-grouped glutamatergic and GABAergic neurons in rat postrhinal (POR) cortex activated PKC pathways, increased activation-dependent neurotransmitter release, and supported both faster learning and improved steady state accuracy for subsequent visual shape discriminations.  Further, the genetically-modified circuit encodes some of the essential information for performance; after gene transfer and learning, small neurochemical lesions, centered on the gene transfer site, caused deficits selectively for discriminations learned after gene transfer.  Activity-dependent gene imaging showed the essential circuit contains ~500 neurons and is sparse-coded.  Further, the activity of the genetically-modified neurons is required for both the learning and subsequent performance, as shown by coexpressing this PKC and an siRNA that blocks fast neurotransmitter release.  This system can support studies on the molecular and cellular mechanisms that encode essential information for an advanced cognitive function.


January 23, 2013
Volker Neugebauer, M.D., Ph.D.

University of Texas Medical Branch

Seminar will be held in Psychology Building, Room PY101 at 4:00 p.m.

Title: Amygdala interactions with medial prefrontal cortex in pain

Abstract: The amygdala is generally considered a brain center for emotions. Synaptic plasticity in the amygdala network of lateral-basolateral nuclei (LA-BLA) and central nucleus (CeA) has emerged as an important contributor to the emotional-affective aspects of pain (Neugebauer et al. 2004 Neuroscientist; 2009 Brain Res Rev). The laterocapsular division of the central nucleus (CeLC) receives nociceptive-specific information from spinal cord and brainstem as well as highly processed multimodal, including nociceptive, information from thalamus and cortex through the LA-BLA network. Pain-related neuroplasticity is associated with increased responsiveness and output of neurons in the CeLC and BLA. CeLC activity drives amygdala-dependent pain behaviors such as emotional-affective responses and anxiety. Abnormally enhanced BLA output inhibits processing in the medial prefrontal cortex (mPFC), resulting in cognitive deficits (Ji et al. 2010 J Neurosci; Sun and Neugebauer 2011 J Neurophysiol). A consequence of impaired mPFC function in pain is the loss of cortical control of amygdala processing, allowing the persistence of pain and its emotional-affective state. Pain-related amygdala plasticity and strategies to restore cortical control (Ji and Neugebauer 2012 Mol Brain; Takaki et al. 2012 Neuropharmacology) will be discussed.


January 16, 2013
Anis Contractor, Ph.D.

Northwestern University Feinberg School of Medicine

Seminar will be held in Psychology Building, Room PY101 at 4:00 p.m.

Title: Life without kainate receptors; insights from kainate receptor knockout mice

Abstract: Kainate receptors are glutamate-gated ion channel receptors that have a surprisingly diverse array of cellular signaling roles, and contribute to synaptic and circuit function in unexpected ways. Despite it being over two decades since the first reported cloning of a kainate receptor subunit, we still do not fully understand how these synaptically localized receptors contribute to circuit function and ultimately effect behavior. My laboratory have been untangling the connection between synaptic kainate receptor function and their influence on circuits and behavior by studying kainate receptor knockout mice. I will present our latest work that has demonstrated a strong link between kainate receptor function and affective behaviors.


December 12, 2012
Marina Picciotto, Ph.D.

Yale School of Medicine

Seminar will be held in Psychology Building, Room PY101 at 4:00 p.m.

Title: Role of nicotinic acetylcholine receptors in circuits underlying complex behaviors in brain

Abstract: Nicotinic acetylcholine receptors (nAChRs) are critical mediators of the effects of ACh in the brain. Although we know a lot about the role of nAChRs in circuits underlying reward and addiction, nAChRs are expressed throughout the brain and are important for many behavioral processes, including those related to affect and appetite. Importantly, there are differences in the nicotinic receptor subtypes, the role of receptor activation and inactivation and the brain areas responsible for distinct behavioral functions of nAChRs. For example, both activation and desensitization of high affinity alpha4/beta2* nAChRs and activation of presynaptic alpha7 nAChRs in the ventral tegmental area is necessary for nicotine reward. In contrast, inhibition of acetylcholine signaling through beta2* nAChRs appears to be antidepressant-like and activation of beta4* nAChRs in the arcuate nucleus of the hypothalamus can decrease food intake and body weight. Overall, the identification of these diverse central effects of nAChRs provides new avenues for understanding the role of these receptors in brain function, and may contribute to the development of novel medications for addiction, depression and obesity.


October 24, 2012
Kurt Haas, Ph.D.

University of British Columbia

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Direct imaging of structural and functional plasticity and metaplasticity in the awake developimg brain

Abstract: Natural sensory input shapes both structure and function of developing brain neurons, but how early experience-driven morphological and physiological plasticity are interrelated remains unclear. Using rapid time-lapse two-photon calcium imaging of network activity and single-neuron growth within the unanesthetized developing brain, we demonstrate that visual stimulation induces coordinated changes to neuronal responses and dendritogenesis. Further, we identify the transcription factor MEF2 as a major regulator of neuronal response to plasticity inducing stimuli directing both structural and functional changes. Our results demonstrate how sensory experience acting through altered levels of the transcription factor MEF2 fine-tunes the plasticity thresholds of brain neurons during neural circuit formation.


October 2, 2012
Hugo Bellen, D.V.M., Ph.D.

Howard Hughes Medical Institute, Baylor College of Medicine

Seminar will take place at 3:00 p.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2012 Gill Symposium

Title: Molecular mechanisms underlying Lou Gehrig’s disease (ALS)

Abstract: Neurodegenerative disorders cause a progressive decline in function and morphology of neurons.  Emerging evidence indicates that impaired mitochondria may play an important pathogenic role in numerous neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), Charcot-Marie-Tooth (CMT), Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases. Mitochondria provide energy and are highly dynamic organelles that can form interconnected intracellular networks under specific conditions. They are actively transported along the cytoskeleton and continuously undergo fusion and fission, collectively termed mitochondrial dynamics. Drosophila offers a unique model system in which to study these diseases as it has a short life span, its genetics is well documented and it is easy to manipulate. In addition its genes and molecular processes are highly similar to their human homologs.

VAP proteins contain an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to membrane receptors and induces oocyte maturation. The MSP domains of VAP proteins are cleaved and secreted ligands that bind to Eph receptors, Lar-like protein-tyrosine phosphatases as well as Roundabout growth cone guidance receptors that are expressed on the muscle surface. A point mutation (P56S) in the MSP domain of human VAPB is associated with ALS, but the mechanisms underlying the pathogenesis are poorly understood. In Drosophila neurons, the equivalent point mutation in fly VAP leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. The binding of the MSP domain to muscle membranes promotes Arp2/3-dependent actin remodeling and mitochondrial morphology, as VAPB mutant muscles display mitochondrial localization, morphology, mobility, and fission/fusion defects. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics in muscles. We propose that neurons secrete MSP to promote muscle energy production and metabolism, in part through the regulation of mitochondrial dynamics. The loss of mitochondrial function in muscles impairs the secretion of a BMP like hormone, which in turn leads to a reduction of the size of the presynaptic boutons, and a dysfunctional neuromuscular junction. The defects in neurons and muscles that we observe provide a molecular pathway to better understand the pathogenesis that underlies ALS, especially since the VAPB proteins is also lost in numerous sporadic cases of ALS.


October 2, 2012
Guoping Feng, Ph.D.

Massachusetts Institute of Technology

Seminar will take place at 11:15 a.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2012 Gill Symposium

Title: Probing synaptic and circuitry mechanisms of psychiatric disorders

Abstract: Recent human genetic and genomic studies have identified a large number of candidate genes for obsessive-compulsive disorder (OCD), autism spectrum disorders (ASDs), and schizophrenia, many of which encode postsynaptic scaffolding proteins including MAGUK, SAPAP, and SHANK families of proteins. These groups of multidomain proteins form a key scaffold, orchestrating the assembly of the macromolecular postsynaptic complex at excitatory synapses. This complex has been proposed to play key roles in targeting, anchoring, and dynamically regulating synaptic localization of neurotransmitter receptors and signaling molecules. Using genetically modified mice as a model system, we explore how mutations in these genes lead to synaptic dysfunction and abnormal behaviors relevant to OCD and ASDs. We find that both SAPAP3 and SHANK3 proteins are highly expressed at cortico-striatal synapses, part of the neural circuit strongly implicated as being dysfunctional in OCD and ASDs. Genetic deletion of SAPAP3 or SHANK3 leads to repetitive/compulsive behaviors in mice. Furthermore, SHANK3 mutant mice display profound social deficits. Morphological, biochemical, and electrophysiological studies all point to defects at the glutamatergic cortico-striatal synapses. Our findings suggest a common synaptic and circuitry mechanism for some of the abnormal behaviors relevant to OCD and ASDs. 


October 2, 2012
Ulrike Heberlein, Ph.D.

HHMI, Janelia Farm Research Campus

Seminar will take place at 9:40 a.m. in indiana Memorial Union, Whittenberger Auditorium during the 2012 Gill Symposium

Title: Flies, sex and alcohol: How social experience affects ethanol consumption

Abstract: Natural rewards and abused drugs affect the function of the brain’s reward systems, and abnormal function of these brain regions is associated with addictive behavior. Some aspects of drug reward can be modeled in the genetically tractable fruit fly Drosophila melanogaster. Flies exhibit complex addiction-like behaviors, including a lasting attraction for a cue that predicts ethanol intoxication and a preference for consuming ethanol-containing food, even if made unpalatable. In addition to genetic factors, social experience can affect drug addiction. We therefore investigated the relationship between sexual experience and alcohol preference in Drosophila. In males, mating increased Neuropeptide F (NPF) levels, whereas sexual deprivation reduced NPF. Moreover, activation or inhibition of the NPF system reduced or enhanced ethanol preference, respectively. These results thus link sexual experience, NPF system activity, and ethanol consumption. In addition, artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF/NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly.


October 2, 2012
Craig Montell, Ph.D.

The Johns Hopkins University

Seminar will take place at 1:45 p.m. in the Indiana Memorial Union, Whittenberger Auditorium during the 2012 Gill Symposium

Title: Control of animal behavior and decision making through TRP channels

Abstract: Sensory input through our classical senses of touch, hearing, vision, taste and smell, drive many animal behaviors, ranging from aggression, courtship and mating, flight, feeding behavior and sleep patterns. The sensory stimuli that initiate these behaviors activate signaling through quite different time-scales and mechanisms. Nevertheless, a unifying theme is that so many of our senses and sensory driven behaviors rely on TRP channels. TRP channels share the common features of six transmembrane domains and permeabilities to cations. However, TRP channels are unusual in displaying extraordinary diversities in activation mechanisms and specific cationic selectivities.

We cloned the gene encoding the archetypal TRP channel in the 1980s through studying visual transduction in the fruit fly, Drosophila melanogaster. The fly visual cascade is initiated by light activation of rhodopsin, which engages a trimeric G-protein and a phospholipase C. Visual transduction culminates with the opening of the TRP and TRPL channels. In 1995 we found that TRPs comprise a family of cation channels that are conserved from worms to humans. We now know that in one animal or another TRP channels contribute to virtually every sensory modality, and control a daunting array of behaviors. Flies encode 13 TRPs, most of which are expressed and function in sensory neurons, and impact behaviors ranging from phototaxis to thermotaxis, the avoidance of noxious chemicals and proprioception.

In this presentation, I will describe recent work from my laboratory demonstrating how Drosophila TRP channels impact on animal behavior and decision making, including the ability to sense very small differences in temperature in the comfortable range. Animals from worms to humans are capable of detecting temperatures differences of 1°C or less, and use this ability to choose their favorite environmental temperature. In the fruit fly, we found that this exquisite sensitivity depends on a TRP channel called TRPA1. Instead of direct activation of TRPA1 by small changes in temperature, TRPA1 is activated through a thermosensory signaling cascade, which allows the animals to amplify small differences in temperature. Surprisingly, this thermosensory signaling cascade depends on rhodopsin. This was unexpected since rhodopsins were formerly thought to function exclusively in light sensation. I will also describe how similar TRPA1-dependent signaling cascades allow flies to sense insect repellents and noxious tastants. Once again, these signaling cascades depend on rhodopsins, underscoring the concept that rhodopsins are not strictly light sensors, but represent a new class of polymodal sensory receptors.

Many diseases result from defects in TRP channels, including the childhood neurodegenerative disease, MLIV, which results from mutations in TRPML1. Based on insights from a fly model for this disease, I will describe a concept to treat this devastating disease.


April 20, 2012
Michelle Glass, Ph.D.

The University of Auckland

Seminar will be held in MSBII, Room 102 at 12 p.m.

Title: Trafficking of the cannabinoid CB2 receptor

Abstract: Recent work by Atwood et al suggested that the cannabinoid CB2 receptor undergoes receptor internalisation in an agonist selective manner, internalising in response to the classical cannabinoid CP55,940 but not in response to the atypical cannabinoid WIN55,212.  Recent data from my lab is not consistent with this finding and instead suggests that all agonists result in internalisation of the CB2 receptor.  In this seminar I will present our data that I believe explains how methodological differences can complicate interpretation of the internalisation data, and demonstrate a novel and unusual trafficking phenotype of the CB2 receptor.


April 18, 2012
John A. Dani, Ph.D.

Baylor College of Medicine

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Nicotinic Cholinergic & Dopaminergic Mechanisms in the CNS

Abstract: Nicotinic acetylcholine receptors (nAChRs) and dopaminergic receptors (DARs) are co-expressed broadly in the CNS, where they have diverse roles. We have examined the effects of long-range vs. local manipulation of nicotinic cholinergic and dopaminergic receptors on in vivo synaptic plasticity of the perforant path to the dentate gyrus of awake, freely-moving mice. This kind of plasticity underlies learning environmentally driven associations to develop successful behaviors.
            Both local nicotinic influence within the hippocampus and long range influences over dopamine centers regulated synaptic plasticity and learning. Field recordings from the hilar region of the dentate were measured in response to electrical stimulation in the medial part of the perforant path. Nicotinic receptor activation caused a long-lasting potentiation of the evoked responses. The local action of nicotinic cholinergic activity influenced hippocampal inhibitory circuits, ultimately, disinhibiting principle neurons. Simultaneously, nicotinic activity increased the firing rate and the phasic bursts by midbrain dopamine neurons. The dopamine signal lowered the threshold for synaptic plasticity and enabled learning. Blocking the dopamine signal prevented both the plasticity and learning. Together, these results suggest that dopaminergic signaling serves as a functional label of salient events by enabling synaptic plasticity that underlies associative memory. These kinds of mechanisms are usurped during the addiction process caused by nicotine from tobacco.  Supported mainly by NIH NIDA (DA09411) and NINDS (NS21229, NS048505).


February 1, 2012
Cheryl Anne Frye, Ph.D.

The University at Albany

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Steroids: The good, the bad, and the ugly

Abstract: Progesterone is typically considered to be primarily secreted by peripheral glands (gonads, placenta, adrenals) and to exert their trophic effects on reproductive tissues through nuclear progestin receptors (nPRs).  Our research focuses on novel sources (brain) and substrates other than nPRs for actions of progestogens. Progesterone and its 5α-reduced metabolite and neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP; allopregnanolone) are produced de novo in the midbrain ventral tegmental Area (VTA), hippocampus, nucleus accumbens and frontal cortex when adult rodents face acute challenges, such as engaging in social behaviors. Biosynthesis of steroids in these regions are decreased with chronic stressors, such as social isolation.  Prenatal stressors also reduce progestogen secretion, impair pregnancy outcomes, and reverse sex-typical patterns in cognitive or affective behavior of offspring.  We are currently investigating the role of pregnane xenobiotic receptors to mediate progestogen biosynthesis in the brain.  In terms of targets of progestogens actions, in the VTA, progestogens work through GABA, NMDA, and dopamine receptors, rather than nPRs.   Our recent work focuses on progestogens’ actions via cognate membrane progestin receptors.  These findings are relevant for steroid biosynthesis in brain (neurosteroidogenesis) influencing sex/gender differences in neurotypical development and/or neuroendocrinopathies associated with neurodevelopmental (autism), neuropsychiatric (anxiety, depression, post-traumatic stress disorder) and neurodegenerative (epilepsy, Alzheimer’s Disease, traumatic brain injury, cancer) disorders and aging. 


October 26, 2011
Ning Quan, Ph.D.

Ohio State University

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Integrating the neuroimmune suprasystem: finding a path

Abstract: The central nervous system (CNS) and the immune system have been viewed traditionally as separate systems.  The function of the CNS is to gather multiple diverse inputs from the periphery, integrate relevant sensory signals, and use appropriate outputs to optimize the functions of peripheral effector systems.  The function of the immune system is to recognize potential pathogens, activate cells of the immune system, eradication infectious agents, and maintain immunity.  The crosstalk between these two systems is at the heart of the new discipline—neuroimmunology.  Research in this discipline has revealed how certain mental disorders can originate from activation of the immune system, how diminished immune function can stem from depressed state of mind, how treatment strategies targeting neuroimmune communication, rather than the two systems in isolation, can benefit both systems, and how health and pathology are regulated by the integrated neuroimmune suprasystem.  This lecture will focus on our studies that have uncovered the pathways linking the CNS and the immune system and address how these pathways are physiologically designed to provide a conduit for the communication between these two systems without allowing one’s function to infringe upon the other.


October 19, 2011
Marc Caron, Ph.D.

Duke University Medical Center

2011 Gill Symposium, October 19, 2011, Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Monoaminergic neurotransmission in health and disease

Abstract: Monoamines such as dopamine, norepinephrine and serotonin are important regulatory molecules in virtually all organs of the body. The physiological effects of these signaling molecules are mediated almost exclusively through G protein coupled receptors (GPCR). Marc Caron and his colleagues have pioneered our understanding of how several genes families involved in the actions of monoamines, those coding for GPCRs, transporters and enzyme of synthesis regulate a multitude of physiological functions.
With his colleagues, they were the first to purify the prototype of these receptors, the b-adrenergic receptor and clone its gene. GPCRs, which represent one of the largest protein family, are 7-transmembrane proteins activated by signals as diverse as light to large proteins to transmit cellular signals via activation of heterotrimeric G proteins.Signaling through activated GPCRs is dampened by phosphorylation of the receptor by specific receptor kinases, followed by the interaction of the phosphorylated receptor with beta-arrestins.This event provides a mechanism not only to limit G protein-mediated signaling but also serves as a trigger for cellular recycling of competent receptors back to the plasma membrane. It is now becoming increasing appreciated that complexes of GPCRs and b-arrestins are also capable of initiating signals that are temporally and functionally distinct from conventional G protein-mediated events.
Transporters, on the other hand, are typically 12-transmembrane proteins involved in the cellular internalization or re-uptake of nutrients or signaling molecules. Monoamine transporters are mostly expressed in neuronal tissues and are responsible for recapturing monoamines following neuronal firing and in doing so play a critical role in the maintenance of monoamine homeostasis. Not surprisingly, these transporters are involved in the mechanisms of action of psychostimulants and many therapeutic agents.
Monoamine hydroxylases are a family of enzymes that catalyze the rate-limiting step in the synthesis of monoamines from amino acids and the recent discovery of naturally occurring mutations in these enzymes, suggests their potential involvement in the etiology of certain brain disorders. 
The presentation will describe how genetic manipulations of these various signal transduction components has yielded important insights not only into the mechanisms of action of monoaminergic control of neurotransmission but also how these principles might be used to develop more selective and effective therapies for central nervous system disorders. 


October 19, 2011
Leslie Vosshall, Ph.D.

The Rockefeller University

2011 Gill Symposium, October 19, 2011, Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: The Genetics of Smell Perception: Humans, Flies, & Mosquitoes

Abstract: Olfactory cues communicate information about the external world, which is detected by the olfactory system and translated into appropriate behaviors. While the neural circuitry of smell perception in insects and vertebrates is organized along similar principles, the molecular odorant receptors of insects are radically different.

Insects are both beneficial and deleterious to human health and happiness. While honeybees are the principal pollinators of our crops, mosquitoes are major vectors of human infectious diseases and a wide range of insect pests damage human agricultural products. Olfaction—the sense of smell—is an important sensory modality used by insects to find plants and animals to feed on. Recent findings suggest that insects have adopted two evolutionarily distinct family of membrane proteins to detect odor cues. The first comprises about 60 seven transmembrane domain proteins called ORs, which adopt a topology distinct from the more conventional seven transmembrane domain G protein-coupled receptors that vertebrates and nematodes use to sense odors. ORs are heteromultimeric protein complexes composed of a variable ligand binding subunit and a constant subunit called Or83b that is critical for targeting the receptor to the ciliated dendrites of olfactory sensory neurons. There is emerging evidence that these atypical receptors function as odor-gated ion channels, but the extent to which these receptors depend on G protein signaling for their function remains a topic of intense debate in the field. A second family of receptors called IRs is evolutionarily related to mammalian ionotropic glutamate receptors and appears to be specialized to detect carboxylic acids and amines, which are potent mosquito attractants. The fact that both ORs and IRs are divergent, insect-specific receptors suggests that small molecule inhibitors of these proteins have the potential to be safer and more effective insect repellents than DEET. This is of particular interest because certain mosquito species have evolved an intense attraction to humans and in doing so serve as deadly vectors of infectious disease that plague most of the developing world.

This presentation will discuss recent advances in the molecular biology of smell in humans and insects.


October 19, 2011
Justin Kumar, Ph.D.

Indiana University-Bloomington

2011 Gill Symposium, October 19, 2011, Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Birth of the Drosophila Retina from a Cauldron of Gene Regulatory Networks

Abstract: The identity of individual tissues and organs is specified during development by batteries of selector genes and signal transduction pathways that are organized into functional units called gene regulatory networks. Such networks control the development of the Drosophila eye-antennal imaginal disc, a monolayer epithelium that gives rise to the adult compound eyes, the ocelli, the antenna, maxillary palps and surrounding head cuticle. The eye-antennal disc therefore provides an opportunity to understand the mechanisms by which multiple gene regulatory networks function simultaneously within a single tissue to establish regional identities. Over the years many studies have suggested that regional identity is established by either compartmentalization of selector gene expression and activity or through a stochastic competition amongst gene regulatory networks. Results from studies in my laboratory suggest that regional identities are established through a different mechanism. We propose that gene regulatory networks simultaneously promote primary fates through waves of gene activation and inhibit alternate fates through transcriptional repression of secondary selector gene batteries. This model is based on the molecular and developmental phenotypes that we observe in the developing eye field when members of the eye specification pathway are mutated and/or when these genes are forcibly expressed within non-retinal tissues. In the former instance the repression of head capsule and antennal selector genes is alleviated within the retina and as a result the compound eyes are replaced with head capsule. In the latter case forced expression of eye specification network genes in non-retinal tissues results in the repression of endogenous gene regulatory networks and the formation of ectopic eyes. In this presentation I will describe our recent efforts to understand the mechanisms by which the retina arises from the cauldron of selector genes and signal transduction pathways that are expressed and function within the developing eye-antennal disc of Drosophila.  


October 19, 2011
Gerry Oxford, Ph.D.

Indiana University School of Medicine and Stark Neurosciences Research Institute

2011 Gill Symposium, October 19, 2011, Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Agonizing Decisions: Functional Selectivity of G-Protein Coupled Receptors

Abstract: Transduction of many external stimuli (e.g. light, odorants, neurotransmitters, hormones) by cells in all tissues occurs through activation of members of a large gene superfamily called G-protein coupled receptors (GPCRs) that couple receptor activation to complex cascades of signaling events through a vast and expanding array of intracellular and membrane bound proteins.  A common feature of the transduction process for GPCRs is the intermediation of heterotrimeric G-proteins.  Upon agonist binding to GPCRs, dissociation or rearrangement of the cognate G-protein subunits is thought to trigger stimulation or inhibition of various enzymes, ion channels, and other effector molecules.  Classical receptor theory suggests that any agonist of a specific GPCR will induce the same conformational changes and that differences in efficacy and potency among agonists reflects only the coupling efficiency and relative binding affinity. 
Recent evidence for a number of GPCRs has alternatively suggested the existence of ligand-specific conformations of a single receptor isoform that preferentially traffic receptor activation to select subsets of signaling pathways resulting in distinct signal cascades for different agonists.  In the case of the human D2 dopamine receptor, we have discovered selective activation patterns (potency and intrinsic activity) for potassium and calcium channels, adenylyl cyclase, and Erk1/2 upon exposure to a series of different agonists.  The underlying molecular mechanisms for this “functional selectivity” of agonist action on single receptors are unknown. 
In this presentation, we will explore the parameter space and possible mechanisms underlying this phenomenon and the implications for drug discovery and drug:drug interactions.


October 12, 2011
David Lovinger, Ph.D.

National Institutes of Health/NIAAA

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Endocannabinoid-Dependent Striatal Synaptic Plasticity: Roles in Learning and Memory

Abstract: The striatum is a subcortical brain region with important roles in the control and learning of actions and action sequences.  The dorsomedial and dorsolateral striatal subregions are part of "Associative" and "Sensorimotor" forebrain circuits that are thought to control goal-directed and habitual actions, respectively.  Endocannabinoid neuromodulators and the cannabinoid 1 (CB1) receptor are present in appreciable amounts in striatum, where they participate in synaptic plasticity involving retrograde postsynaptic-presynaptic signaling.  In this lecture, mechanisms involved in endocannabinoid-dependent long-term synaptic depression (LTD) at GABAergic and glutamatergic striatal synapses will be described.  Experiments combining brain slice electrophysiology, optogenetics, and neuron-specific knockout of CB1 receptors have been performed to determine the properties of LTD at different GABAergic striatal synapses.  The role of CB1 receptors in stimulus-response "habit" learning in an instrumental conditioning paradigm will also be described.  Recent experiments have examined the roles of CB1 receptors on different striatal cellular elements in this form of learning.  Findings to date indicate that endocannabinoid-dependent plasticity contributes to the physiological changes in corticostriatal circuits that underlie habitual performance of actions, with implications for many aspects of behavior and addiction.


September 21, 2011
Joseph LoTurco, Ph.D.

University of Connecticut

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Identification of Novel Pathways Underlying Brain Development and Function

Abstract: Neurodevelopmental disorders exact a tremendous toll on society. Disruptions in brain development caused by diverse genetic and environmental insults can lead to a wide range of disabilities, from relatively rare congenital disorders associated with severe disability in children to far more common disorders in learning. The diversity and specificity of different neurodevelopmental disorders suggest that they may each be associated with unique alterations in cellular and molecular pathways underlying brain circuitry and function. Identification of such pathways could lead to novel therapeutic interventions as well as to new mechanistic insights into brain function and dysfunction. In this lecture Joe LoTurco will present recent progress made in his lab towards understanding the functions of genes associated with both a rare developmental disorder, primary microcephaly, and a very common learning disorder, reading disability. Analysis of the function of a gene associated with primary microcephaly, Citron Kinase, has revealed a novel mechanism of epigenetic regulation required for normal brain growth. The kinase binds to DNA at regulatory sequences where it orchestrates a pattern of gene expression through phosphorylation of an enzyme required for histone modification. Similarly, analysis of genes associated with reading disability has revealed new cellular and neurobiological mechanisms. The gene Dyx1c1, the first dyslexia associated gene, is required in a pathway needed for the proper assembly of cellular motor proteins needed in motile cilia, and in the embryo, for appropriate left-right patterning. The gene Dcdc2, associated with reading disability and ADHD, is required for maintaining a balance of NMDA receptor activity. The loss of Dcdc2 function creates an increase in synaptic noise that degrades the precision of action potential firing rates in cerebral neocortex.


September 14, 2011
Paul E. M. Phillips, Ph.D.

University of Washington

Seminar will be held in Psychology, Room PY101 at 4:00 p.m.

Title: Coupling value to actions: dopamine and decision making

Abstract: Valuation signals in the brain offer estimates of future rewards based on the available environmental information.  These predictions of rewards can be used by the brain to guide behavior and update decision-making policies, particularly in situations where the reward yield is dependent on the agent’s actions.  One such valuation signal is represented by sub-second dopamine neurotransmission which biases actions to obtain rewards.  Therefore, alteration of dopamine by pathology and/or pharmacology can profoundly alter reward decision policies.  However, to understand the computation performed using dopamine transmission and how it might go awry in disease, we need to identify the precise nature of the valuation signal as well as the circuit-level effects of dopamine transmission.  To address these questions, we used fast-scan cyclic voltammetry at chronically-implanted carbon-fiber microelectrodes to measure dopamine release with sub-second temporal resolution in rats learning about reward predictive cues and performing a series of decision-making operant tasks.  Using this approach we tested how dopamine signals to reward-predictive cues are acquired, whether they encode objective or subjective value (utility), whether they track deprivation states and whether they valued rewards alone, or incorporate the utility of the mechanisms (cost) required to obtain them.


April 20, 2011
Michael N. Shadlen, M.D., Ph.D.

University of Washington

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Believing and time. A neural mechanism for decision making

Abstract: This lecture describes recent advances in our understanding of the neural mechanisms responsible for some forms of decision-making. The study of decisionmaking opens a window on the neural basis of many other higher cognitive capacities which also use information in a contingent fashion and in a flexible time frame — free from the immediacy of sensory events or the need to control a body in real time. I will describe neural recordings from the parietal cortex of nonhuman primates that are trained to make difficult perceptual decisions. The neural responses provide insight into how decisions are made: how accuracy and speed are traded against one another, how the brain reasons from probabilistic cues (as in predicting the weather), how prior probability affects the decision process, and how the brain assigns confidence — degree of belief —that a decision is correct.


April 13, 2011
Paul Mermelstein, Ph.D.

University of Minnesota

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Membrane Estrogen Receptors activate Metabotropic Glutamate Receptors to affect Nervous System Function

Abstract: Our understanding of estrogen signaling in the nervous system has undergone a significant shift in recent years. Estrogens were initially identified as initiators of gene expression through the activation of the ligand-gated transcription factors estrogen receptor-α (ERα) and estrogen receptor-β (ERβ). However, estradiol can also act directly at the surface membrane of cells, leading to both short- and long-term effects on cellular function. The mechanism(s) by which estrogens act at the cell surface has remained unclear. This seminar will outline recent findings describing how ERα and ERβ can be trafficked to the cell surface to initiate rapid steroid-mediated G protein-coupled receptor signaling. ERα and ERβ are themselves not GPCRs, but rather interact with traditional GPCRs to initiate cell signaling. Specifically, we find estrogen receptors to activate several classes of metabotropic glutamate receptors (mGluRs).  This ER/mGluR signaling system can explain how estradiol can activate a wide-range of intracellular pathways, as well as provides a mechanism to explain a wide-range of rapid estrogen actions in the brain.


March 9, 2011
Edwin W. McCleskey, Ph.D.

Scientific Officer, Howard Hughes Medical Institute

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Sensors for the pain of a heart attack

Abstract: We feel ischemic muscle pain when working muscle gets insufficient oxygen; examples include the pain of a heart attack and the pain of a 400 yard dash. Is the trigger for this pain the acid that gets released from anaerobic muscle? The fact is that extracellular pH, the signal to be detected by the sensory neurons that transduce the pain, only drops a few tenths of a unit during that 400 yard dash. Such modest pH changes occur throughout the body during kidney or respiratory disease, yet such patients do not suffer from ischemic pain. This seminar will address this paradox, describing a molecular mechanism by which multiple ischemic signals (acid, lactate, and extracellular ATP) are detected simultaneously by muscle sensory neurons, thereby providing a mechanism to selectively detect ischemic acidosis.


March 2, 2011
William N. Green, Ph.D.

The University of Chicago

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: The Dynamic Role of SAP97 in the Sorting of Glutamate Receptors in Neurons

Abstract: Synaptic plasticity is dependent upon the differential sorting, delivery and retention of AMPA- and NMDA- type glutamate receptors at synapses.  We have found that differential sorting of glutamate receptor subtypes begins within the endoplasmic reticulum (ER) of neurons. While AMPARs are trafficked to the plasma membrane via the conventional somatic Golgi network, NMDARs move from the somatic ER into a specialized ER sub-compartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. The retention and trafficking of NMDARs within this ER sub-compartment requires two membrane-associated guanylate kinases (MAGUKs), SAP97 and CASK, which bind together via L27 domains. SAP97, without CASK, associates with AMPARs in the ER and mediates its trafficking from the soma. Distinct conformations of SAP97 have been demonstrated but their function and what triggers changes in conformation are unclear. Using intramolecular FRET pairs fused to the SAP97 N- and C-termini, we find that SAP97 exists in two conformations in vivo: an “extended” conformation with a distance >100A between FRET pairs and a “compact” conformation with a distance of  ~70A between FRET pairs. In the extended conformation, SAP97 preferentially associates with GluN2B-containing NMDARs while in the closed conformation preferentially with GluA1-containing AMPARs. The transition from closed to extended conformation was triggered by CASK binding to SAP97. Our results reveal the dynamic nature of SAP97. Specifically, how its conformation is regulated by interactions with its L27 domain and how SAP97 conformation determines whether it associates with AMPARs or NMDARs during sorting.


February 9, 2011
Marina Wolf, Ph.D.

Rosalind Franklin University of Medicine and Science

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: AMPA receptor plasticity: A target for treating cocaine addiction

Abstract: Nucleus accumbens (NAc) medium spiny neurons are excited primarily by AMPA-type glutamate receptors. This is required for cocaine seeking in several rodent models of cocaine addiction, suggesting AMPA receptor transmission in the NAc as a key control point for cocaine-related behaviors. In rats that are drug-naïve or have had limited cocaine exposure, excitation of NAc neurons is mediated primarily by Ca2+-impermeable AMPA receptors (CI-AMPARs). After extended access cocaine self-administration and withdrawal, cue-induced cocaine craving intensifies (“incubates”). We have shown that the expression of incubated cue-induced craving is mediated by Ca2+-permeable AMPARs (CP-AMPARs), which have higher conductance than CI-AMPARs and therefore enable stronger excitation of medium spiny neurons. CP-AMPARs are added to NAc excitatory synapses during withdrawal. My presentation will focus on our recent work showing that group I metabotropic glutamate receptors, which are expressed postsynaptically in medium spiny neurons, can be targeted to remove CP-AMPARs from NAc synapses of rats that have undergone incubation of cocaine craving.


January 19, 2011
Michael Tamkun, Ph.D.

Colorado State University

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Kv2.1 membrane corrals: Novel regulators of neuronal potassium channel
localization and function

Abstract: Kv2.1 membrane corrals: Novel regulators of neuronal potassium channel localization and function The Tamkun lab uses a combination of live cell imaging, single molecule detection and diffusion analysis and voltage-clamp to study the mechanisms and functional significance of voltage-gated K+ channel localization on the cell surface. The data to be presented indicate that Kv2.1-containing surface clusters do not contain high threshold channels whose voltage-sensitivity shifts upon release; nor are they a reservoir of non-conducting channels that are activated upon release. Rather, these specialized membrane structures may represent surface domains where the plasma membrane potential is coupled to the function of intracellular systems.


November 10, 2010
Ru-Rong Ji, Ph.D.

Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Brigham & Women’s Hospital, Harvard Medical School

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Resolution of chronic pain

Abstract:Inflammatory pain, such as arthritis pain is a growing health problem. Inflammatory pain is generally treated with opioids and non-steroid anti-inflammatory drugs such as cyclooxygenase (COX) inhibitors. However, side effects limit the analgesic efficiency of current therapies. Recently, resolvins, a novel family of lipid mediators including RvE1 and RvD1, derived from omega-3 polyunsaturated fatty acid, show remarkable potency in treating diseases associated with inflammation. Dr. Ji will discuss how resolvins attenuate inflammatory pain via both peripheral and central actions. He will not only show how resolvin reduces inflammation but also demonstrate how resolvin modulates synaptic plasticity in the spinal cord.


October 20, 2010
George Uhl, M.D., Ph.D.

The Johns Hopkins University School of Medicine

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Cellular and molecular impact of elucidating brain disorders with complex genetic architectures: examples from addiction and ability to quit smoking

Abstract: “I will review evidence that common brain disorders, and the costs attributable to them, receive substantial heritable contributions. Large contributions of polygenic influences (as well as rare variants) contrast with the modest contributions from Mendelian (single gene) and oligogenic (major gene) genetic architectures. I will focus on vulnerability to develop dependence on an addictive substance and ability to quit smoking, two phenotypes that are influenced by complex genetics that we have studied using GWA in multiple samples. The substantial (and overlapping) genetic contributions to these phenotypes appear to come from polygenic variants in genes that are largely expressed in brain and likely to contribute to individual differences in its wiring, molecular biology, gene regulation and neurotransmission. I will review the challenges and opportunities provided by the vast amounts of currently available GWA data for studies that help to understand the cellular and molecular bases for brain activities and brain disorders. Translational, post GWAS studies that elucidate the ways in which such polygenic variants influence the brain and behavior provide a rich source for increasing understanding of the brain in ways that can provide direct relevance for understanding human brain disorders.”


September 8, 2010
Marc Tessier-Lavigne, Ph.D.

Genentech, Inc.

2010 Gill Symposium, September 8, 2010 at 3:30 p.m., Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Wiring the brain: the logic and mechanisms of axon guidance, regeneration and degeneration

Neuronal growth cones navigate over long distances along specific pathways to find their correct targets, guided by evolutionarily conserved attractants and repellents that act simultaneously and in coordinate fashion to direct pathfinding.  This presentation will describe some recent advances in elucidating axon growth and guidance mechanisms, including the identification of mechanisms through which growth cones switch their responsiveness to guidance cues at intermediate targets from attraction to repulsion.  When axons are damaged, they attempt to regenerate, but fail to do so in the brain and spinal cord.  This presentation will also describe advances in understanding mechanisms that limit regeneration in the adult CNS and that contribute to axonal pruning and degeneration both during development and in later life.


September 8, 2010
Karl Deisseroth, M.D., Ph.D.

University of Stanford

2010 Gill Symposium, September 8, 2010 at 11:15 a.m., Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Optogenetics: development and application

Abstract: We have been developing and applying optogenetics, a technology based on single component opsin-based regulators of transmembrane ion conductance and signaling; in this approach, opsin genes are delivered by genetically or topologically-targeted vectors, and light is delivered to the freely moving mammal by portable solid-state optical devices. In previous work (refs 1-9) we have developed a panel of optogenetic genes and related optical devices, with which cells can be turned on or off with millisecond precision and in different patterns within freely moving mammals, and we have applied this technology to probe the dynamics of cells and circuits relevant to schizophrenia, narcolepsy, Parkinson’s disease, depression, and addiction. More recently (refs 10-12), we have shown that application of molecular engineering and trafficking principles can further expand the optogenetic repertoire along several long-sought dimensions. For example, we have shown that membrane trafficking strategies now permit 1) optical regulation at the far red/infrared border; 2) increased potency of optical inhibition without increased light power requirement (chloride-mediated photocurrents beyond the nanoampere level that maintain the light sensitivity and behaviorally-significant reversible, step-like stable kinetics of earlier tools); and 3) generalizable strategies for targeting cells based not on genetic identity, but on morphology and tissue topology, to allow versatile targeting when promoters are not available. Together these results illustrate use of molecular and cellular principles to enable versatile, fast optogenetic technologies suitable for the study of circuit dynamics, mammalian behavior, and neuropsychiatric disease.
1.            Zhang F., et al. (2007).  Nature 446, 633-9.
2.            Boyden E.S., et al. (2005).  Nature Neuroscience 8, 1263-1268.
3.            Zhang F., et al. (2008). Nature Neuroscience, AOP April 23, 2008.
4.            Adamantidis A. et al. (2007) Nature, 450:420-424.
5.            Berndt A, et al. (2008) Nature Neuroscience, 12:2, 229-34.
6.            Airan R.D., et al. (2009). Nature 458(7241):1025-9.
7.            Gradinaru V., et al. (2009). Science 324(5925):354-9.
8.            Sohal V.S., et al. (2009) Nature 459(7247):698-702.
9.            Tsai H.C., et al.  (2009). Science 22;324(5930):1080-4.
10.          Gunaydin L.A., et al. (2010), Nature Neuroscience in press.
11.          Gradinaru  V.,et al. (2010), Cell in press.
12.          Lee et al., (2010), Nature in press.

September 8, 2010
Andrea G. Hohmann, Ph.D.

Indiana University-Bloomington

2010 Gill Symposium, September 8, 2010 at 10:05 a.m., Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Endocannabinoid Mechanisms of Pain Suppression

Abstract: Stress mobilizes endogenous cannabis-like substances (endocannabinoids) in the brain to suppress sensitivity to pain. This behavioral phenomenon is known as stress-induced analgesia.  However, mechanisms governing the in vivo formation of these endogenous analgesic mediators are unknown.  Here we show that activation of type 5 metabotropic glutamate receptors (mGluR5) in the dorsolateral periaqueductal gray (PAG) initiates stress-induced analgesia by mobilizing the endocannabinoid 2-arachidonoylglycerol (2-AG).  In the PAG, mGluR5 activation stimulated 2-AG formation and produced cannabinoid CB1 receptor-dependent stress-induced analgesia.  Pharmacological blockade of the putative 2-AG-synthesizing enzyme, diacylglycerol lipase (DGL), suppressed both 2-AG accumulation and stress-induced analgesia.  These effects were mimicked by virally-mediated RNA silencing of the DGL-a, but not DGL-β, isoform in the PAG.  Moreover, DGL-a colocalizes with mGluR5 at postsynaptic sites in the PAG, whereas CB1 resides at presynaptic sites, thereby identifying the molecular architecture of 2-AG signaling in the PAG.  Our studies provide definitive evidence that 2-AG formation is triggered in vivo by activation of an mGluR5-DGL-a pathway, consistent with a retrograde 2-AG signaling mechanism.  This pathway is required for endocannabinoid-mediated analgesia. 


September 8, 2010
Fletcher A. White, Ph.D.

Indiana University School of Medicine and Stark Neurosciences Research Institute

2010 Gill Symposium, September 8, 2010 at 9:20 a.m., Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: The Role of Chemokines in Chronic Pain Syndromes

Abstract: Pain normally subserves a vital role in the survival of the organism, prompting the avoidance of situations associated with tissue damage. However, the sensation of pain can become dissociated from its normal physiological role. In conditions of neuropathic pain, spontaneous or hypersensitive pain behavior occurs in the absence of the appropriate stimuli. Our incomplete understanding of the mechanisms underlying chronic pain hypersensitivity accounts for the general ineffectiveness of currently available options for the treatment of chronic pain syndromes. Despite its complex pathophysiological nature, it is clear that neuropathic pain is associated with short- and long-term changes in the excitability of sensory neurons in the dorsal root ganglia (DRG) as well as their central connections. Recent evidence suggests that the upregulated expression of inflammatory cytokines/chemokines in association with tissue damage or infection triggers the observed hyperexcitability of pain sensory neurons. The actions of inflammatory cytokines/chemokines synthesized by DRG neurons and associated glial cells, as well as by astrocytes and microglia in the spinal cord, can produce changes in the excitability of nociceptive sensory neurons. These changes include rapid alterations in the properties of ion channels expressed by these neurons, as well as longer-term changes resulting from new gene transcription. This presentation will describe advances in understanding mechanisms that contribute to chronic pain syndromes.


September 8, 2010
Val J. Watts, Ph.D.

Purdue University

2010 Gill Symposium, September 8, 2010 at 2:30 p.m., Indiana University, Whittenberger Auditorium, Indiana Memorial Union

Title: Ligand-dependent oligomerization of D2 dopamine receptors with A2A adenosine and CB1 cannabinoid receptors in living neuronal cells

Abstract: D2 dopamine receptors have been implicated in neuropsychiatric and neurologic disorders including schizophrenia, drug abuse, and Parkinson’s disease.  Acute activation of D2 dopamine receptors inhibits cyclic AMP accumulation, however, persistent activation of D2 dopamine receptors enhances subsequent drug-stimulated cyclic AMP accumulation.  This specific enhancement of adenylyl cyclase signaling, termed heterologous sensitization, occurs following persistent activation of several Gai/o-coupled receptors in vitro and in vivo.  Previous studies support a hypothesis that heterologous sensitization requires the activation of Gai/o subunits to induce sensitization through a variety of direct and indirect mechanisms.  One of these mechanisms includes a potential role for receptor oligomerization.  D2 dopamine receptors are  co-expressed with and may oligomerize with both A2A adenosine and CB1 cannabinoid receptors in the basal ganglia; an area of the brain involved in such processes as cognition, motor function, and emotional control.  Evidence for A2A and D2 receptor heteromeric complexes in the striatum has been proposed to explain their mutual antagonism of cellular signaling. Previous studies also suggest that D2 receptor interactions with the CB1 receptor promote a switch in coupling of the CB1 receptor from Gai/o to Gas, providing a unique pharmacology. Despite these examples, limited information exists on the regulation of A2A-D2 or CB1-D2 receptor dimers in living cells.  At the cellular level, the portion of receptors engaging in homo- and heteromers, as well as the effect of persistent receptor activation or antagonism on the cell oligomer repertoire are also largely unknown.  We recently employed a novel technique, multicolor bimolecular fluorescence complementation (BiFC) to examine the subcellular localization and drug modulation of A2A-D2L and CB1-D2 heterodimers in the Cath.a differentiated (CAD) neuronal cell model. The results of these studies will be the focus of this presentation.


April 14, 2010
Mark S. Shapiro, Ph.D.

University of Texas Health Science Center at San Antonio

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Regulation of and functional role of M-type (KCNQ) potassium channels in neurons

Abstract:The M-type K+ current is made by the KCNQ (Kv7) family of subunits and is thought to play dominant roles in regulating membrane excitability of neurons, cardiomyocytes and smooth muscle.  Originally named for its depression by stimulation of muscarinic acetylcholine receptors in sympathetic neurons, later work has shown M channels to be a target of a number of different receptors linked to Gq/11-type G proteins and phospholipase C.  Emerging as central to the modulation is a critical lipid messenger molecule, phosphatidylinositol 4,5-bisphosphate (PIP2), whose binding to M channels is thought to be necessary for their function.  I will present our recent advances in understanding the molecular and structural mechanisms of PIP2-mediated modulation of these critical neuronal K+ channels.  In addition, we are clarifying the functional role of KCNQ channels in regulation of action potential firing and release of neurotransmitter using a number of approaches, as well as seeking to further localize the channels to several different types of peripheral and central neurons, and to sub-cellular structures in those cells.  Our work may lead to novel modes of therapeutic intervention for a wide spectrum of nervous system, cardiovascular and psychiatric disorders.


April 7, 2010
Hui-Chen Lu, Ph.D.

Baylor College of Medicine

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: Are the Wallerian Slow and NMNAT proteins neuroprotective in a mouse model of Alzheimer's disease?

Abstract:The loss of neurons, or neurodegeneration, is one of the hallmarks of Alzheimer’s disease (AD).  Strategies to slow neurodegeneration may be effective in treating AD. Wallerian Slow (WldS) mice show reduced axonal loss in response to peripheral nerve injury and other neurodegenerative processes. These protective effects are attributed to a chimeric gene, Ube4b/Nmnat (WldS), which contains the entire coding region of Nicotinamide Mononucleotide Adenylyltransferase (NMNAT), leading to increased NMNAT expression. NMNAT is an NAD synthesizing enzyme and is broadly protective against neurodegeneration as first demonstrated in Drosophila.  In these studies we have investigated if WldS and NMNAT are protective in mouse models of AD.

A missense mutation in tau (tauP301L) induces the development of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17).  The age-related loss of neurons and cognitive dysfunction in rTg(tauP301L)4510 mice (designated Tau mice here for simplicity) closely mimics the clinical features of tauopathy.  Thus, this transgenic mouse line is a useful animal model to study therapies for both AD- and tauopathy-associated neurodegeneration.

In my talk, I will present in vivo evidence that WldS and NMNAT are neuroprotective in aged Tau mice.  Initially, we over-expressed WldS globally in the brains of Tau mice by crossing WldS mice with Tau mice to generate mice over-expressing both Tau and WldS. We next engineered recombinant adeno-associated viruses encoding WldS or only NMNAT and used them as “gene therapy” tools to over-express WldS or NMNAT in a tissue- and time-specific manner. These viral vectors allowed us to examine if WldS or NMNAT can prevent or rescue the Tau-related neurodegenerative phenotype after the onset of neurodegeneration.  The efficacy of WldS and NMNAT was evaluated with a combination of anatomical, electrophysiological, and behavioral approaches.  The neuroprotection offered by WldS and NMNAT at both the anatomical and functional level in treating the mouse model of Alzheimer’s disease will be discussed.


November 13, 2009
Edwin Rubel, Ph.D.

University of Washington

Seminar will be held in Woodburn Hall, Room 120 at 1:30 p.m.

Title: Experience and Auditory Brainstem Development: Signals, Cellular Events and Critical Periods

Abstract: Since the classic experiments of Hamburger, Levi-Montalcini, and Hubel & Wiesel, a large variety of studies have shown that manipulations of peripheral input and sensory experience can have profound influences on the development of sensory encoding pathways of the central nervous
system.  Yet, relatively little is known about the cellular mechanisms whereby changes in sensory system function influence the structure or integrity of CNS elements.  We have used the brainstem auditory pathways of birds and mammals to investigate the early cellular events underlying
deprivation- and deafferentation-induced changes in the structure and integrity of neurons and glial cells.  Our work in this area uses a variety of methodologies on /in vivo/ and /in vitro /preparations of the brainstem to address three issues related to activity-regulated development and maintenance of auditory brainstem neurons.  What is the nature of the _inter_cellular signals regulating structural integrity of postsynaptic neurons?  What are some of the _intra_cellular cascades of events underlying deprivation-induced changes in neuronal integrity? What biological mechanisms may underlie developmental differences in responses to peripheral manipulations (critical periods)?

I will briefly summarize our approach to these problems and then discuss two lines of recent and ongoing experiments.  First, using normal and transgenic mice, and microarray technology we have focused understanding the differential susceptibility of neonatal and adult sensory systems to
neuronal death due to deprivation of afferent activity (a critical period).  I will present results indicating that downstream regulators of cell death can dramatically modulate the critical period response and
that the switch from deprivation sensitive to deprivation insensitive probably involves the orchestrated changes transcription of many cell death regulatory genes.  These experiments emphasize the developmental transition from selection pressures to optimize plasticity of the growing nervous system to selection pressures emphasizing stability. Second, I will present results of a series of experiments that address the dynamic changes seen in individual dendritic arbors as a function of
the integrity and activity of excitatory synaptic input.  The symmetrical, segregated input to the dendrites of nucleus laminaris provide a unique model to investigate dynamic changes in dendritic
structure and intracellular events that may underlie local modifications of dendritic structure.

Support provided by NIDCD.


October 28, 2009
Loren H. Parsons, Ph.D.

The Scripps Research Institute

Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.

Title: An evaluation of brain endocannabinoid signaling and addiction-related behaviors

Abstract:Addictive drugs exert their behavioral and reinforcing effects through actions on multiple neurotransmitter systems including monoamines, endogenous opioids, and both excitatory and inhibitory amino acids.  A growing body of literature also points to an involvement of the endogenous cannabinoid system in the etiology of drug addiction. For example there is evidence of a significant correlation between allelic variances in the cannabinoid-1 (CB1) receptor gene and the incidence of drug dependence in humans.  Similarly, a naturally occurring single nucleotide polymorphism in the gene encoding the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) is associated with problem drug and alcohol use.  A substantial amount of preclinical data also points to a CB1 receptor influence in regulating the self-administration of alcohol, opiates and nicotine.  However, little is known of the mechanisms through which endocannabinoids modulate drug-induced behaviors and there is even less understanding of the effects of prolonged drug exposure on endocannabinoid signaling.  This lecture will provide in vivo evidence that voluntary drug intake alters extracellular endocannabinoid levels in the rodent brain in a manner that modulates the motivation for continued drug intake. Data demonstrating altered endocannabinoid function following chronic drug exposure will also be presented along with evidence that this dysfunction contributes to excessive drug intake through negative reinforcement mechanisms.

[Hosts – Ken Mackie and Heather Bradshaw]
Sponsored by the Neuroscience Training Grant, and the Gill Center


October 12, 2009
Erika Holzbaur, Ph.D.

University of Pennsylvania
School of Medicine

Seminar will be held in Jordan Hall, Room 009 at 4:00 p.m.

Title: Motor Neurons Require Motor Proteins: Molecular Motors, Axonal Transport, and Neurodegeneration

Research Description:Our laboratory is focused on the microtubule-based motor cytoplasmic dynein and its activator dynactin. Dynein and dynactin are required for vesicular trafficking, microtubule organization, mitotic spindle assembly, and development of polarity. We are interested in the mechanisms of force production and motor function, mechanisms of cargo coupling and regulation, effects of dynein and dynactin on dynamics of the cytoskeleton, and the analysis of neurodegenerative diseases resulting from impairments in dynein/dynactin function. Disruptions in dynein/dynactin function cause motor neuron degeneration and muscle atrophy, leading to motor neuron diseases similar to ALS. Approaches in the lab include in vitro motility assays for motors, microtubules and organelles, biochemical and cellular assays for binding partners, live cell microscopy, and development and characterization of transgenic mouse models for motor neuron disease.


May 20, 2009
Daniel Johnston, Ph.D.

University of Texas at Austin

2009 Gill Symposium, May 20, 2009, 3:30 p.m., Indiana Memorial Union, Whittenberger Auditorium 

Title: Active dendrites are the colorful wings of the mysterious butterflies

Santiago Ramón y Cajal referred to neurons as the “mysterious butterflies of the soul”.  The wings of these butterflies—their dendrites—were traditionally considered as passive integrators of synaptic information.  It is now widely accepted that these wings are ‘colorful’, that is, they are endowed with a mosaic of voltage-gated ion channels, with each family of neurons, or ‘butterflies’ made of distinct hues and shades.  Rapidly evolving evidence provides direct and indirect demonstrations for activity-dependent plasticity of these ion channels, pointing towards chameleonic adaptability in these hues.  We have focused our efforts on two of these channels, a fast transient potassium channel and a hyperpolarization-activated cation (h) channel.  Both are highly expressed in dendrites of hippocampal neurons and both play important roles in regulating the intrinsic excitability of these cells.  The h-channel is particularly interesting because it shows bi-directional changes in function with long-term synaptic potentiation and depression and in certain disease states.  This presentation will discuss the background of this field as well as recent work related to dendritic ion channel plasticity.


May 20, 2009
Linda Hsieh-Wilson, Ph.D.

California Institute of Technology

2009 Gill Symposium, May 20, 2009, 11:30 a.m., Indiana Memorial Union, Whittenberger Auditorium 

Title: Uncovering roles for carbohydrates in axonal growth and regeneration

The field of chemical neurobiology is rapidly evolving and providing insights into the molecules and interactions involved in brain development, neuronal communication and memory storage. We will describe the synergistic application of organic chemistry and neurobiology to explore the structure and function of chondroitin sulfate glycosaminoglycans in the nervous system and their impact on neuronal growth and spinal cord regeneration. 


May 20, 2009
Rajesh Khanna, Ph.D.

Department of Pharmacology and Toxicology and the Paul and Carole Stark Neurosciences Research Institute and, Indiana University School of Medicine.

2009 Gill Symposium, May 20, 2009, 9:15 a.m., Indiana Memorial Union, Whittenberger Auditorium 

Title: Regulation of neurite outgrowth and synaptic efficacy by calcium channel-CRMP-2 interactions

Collapsin response mediator proteins (CRMPs) specify axon/dendrite fate and axonal growth of neurons through protein-protein interactions.  Their functions in presynaptic biology remain unknown.  Here, we identify the presynaptic N-type Ca2+ channel (CaV2.2) as a CRMP-2–interacting protein.  CRMP-2 binds directly to CaV2.2.  Both proteins co-localize within presynaptic sites in hippocampal neurons.  Overexpression into hippocampal neurons of a CRMP-2 protein fused to EGFP caused a significant increase in Ca2+ channel current density along with modest changes to other biophysical properties.  Depolarization of CRMP-2–EGFP overexpressing neurons elicited a significant increase in release in glutamate compared to control neurons.  Toxin block of Ca2+ entry via CaV2.2 abolished this stimulated release.  The increased glutamate transmission was attributed to an increase in synaptic vesicle recycling by CRMP-2.  CRMP-2’s effects on axonal length and branch complexity, important for establishing synaptic connectivity, were reduced by blocking Ca2+ influx via CaV2.2. Thus, the CRMP-2–Ca2+ channel interaction represents a novel mechanism for modulation of Ca2+ influx into nerve terminals and, hence, of synaptic strength.


May 20, 2009
Christian C. Felder, Ph.D.

Neuroscience Division, Eli Lilly and Company

2009 Gill Symposium, May 20, 2009, 10:00 a.m., Indiana Memorial Union, Whittenberger Auditorium 

Title: Muscarinic acetylcholine receptors: A potential novel approach for the treatment of schizophrenia

Muscarinic receptors play a role in regulating both the dopamine and glutamate systems which are key neurotransmitter systems disrupted in schizophrenia. The five muscarinic acetylcholine (M1-M5) receptors were cloned beginning in 1986, yet development of subtype selective ligands has lagged well behind molecular characterization of both structure and function of this receptor family.  Historically, acetylcholine mimetics based on arecoline provided modest functionally selective agonists which were advanced into clinical development for symptomatic treatment of Alzheimer’s disease and schizophrenia. However, side effects linked primarily to parasympathetic drive prevented successful launch of a muscarinic agonist therapeutic. Despite these challenges, positive proof of concept data was generated in both Alzheimer’s disease and schizophrenia. Additional knowledge of muscarinic receptor subtype physiology was gleaned primarily from experiments with knockout mice bearing genetic deletion of each muscarinic receptor subtype. More recently, highly selective agonists and positive allosteric modulators have been described for the M1 and M4 receptors.  This presentation will focus on the discovery and preclinical development of a selective positive allosteric modulator for the muscarinic M4 receptor targeted for the symptomatic treatment of schizophrenia.


May 20, 2009
Aina Puce, Ph.D.

Indiana University Department of Psychological and Brain Sciences

2009 Gill Symposium, May 20, 2009, 2:30 p.m., Indiana University, Whittenberger Auditorium 

Title: The neural basis of social cognition

The study of social interactions under naturalistic and dynamic conditions is a holy grail with regard to understanding how the brain processes meaningful, but fleeting, socially relevant information.  To this end, multimodal imaging confers many advantages by capitalizing on the various strengths of the different assessment techniques. I will present data from functional MRI studies and scalp electrophysiological ERP studies that relate social cognition - the study of understanding the actions and intentions of others. Importantly, fMRI can identify the active brain structures in a social cognition task, whereas ERP studies are excellent at delineating the timing of these processes. One approach is to combine the data from both methods to give a more complete picture of the working human brain. I will contrast perceptual neural responses to socially relevant and seemingly irrelevant face and body movements from those related to higher order social and affective processing. Additionally, I will examine how important it is to control low-level stimulus variables in order to study social cognition, and how robust data can be obtained with both explicit and implicit manipulations of social cognition. Finally, I will discuss some approaches for future studies which will use single-trial neuroimaging and behavioral approaches.Supported by R01 NS049436.


April 29, 2009
Eva Anton, Ph.D.
UNC School of Medicine

4:00 p.m. in the Psychological and Brain Sciences Building, PY101  

Title: Mechanisms of neuronal placement and differentiation in the developing cerebral cortex


April 22, 2009
Klaus-Armin Nave, Ph.D.

Max Planck institute of Experimental Medicine

4:00 p.m. in the Psychological and Brain Sciences Building, PY101  

Title: Axon-glia interactions and mouse models of human myelin disease

The long-term integrity of axons is a bottleneck for the function of the nervous system, as illustrated by many several neurodegenerative diseases. Oligodendrocytes and Schwann cells myelinate long axons for rapid impulse conduction, but other important functions of these axon-associated glial cells exist that remain poorly understood. We have identified genes expressed exclusively in mature oligodendrocytes, such as Plp1 and Cnp1, that are not essential for myelination, yet required the long-term survival of axons. The role of ensheathing glia in preserving axonal integrity also involves peroxisomes that are often localized at sites of axon-glial contact. Loss of peroxisomal functions in oligodendrocytes of conditional Pex5 mutants causes axon loss in the white matter and a strong inflammatory response, with the infiltration of B and activated CD8(+) T cells. The model is discussed that oligodendrocytes provide a neuroprotective function against both axonal degeneration and neuroinflammation, which is relevant for human neurological diseases, such as multiple sclerosis.


April 15, 2009
Tibor Harkany, Ph.D.

University of Aberdeen School of Medical Sciences and the Karolinska Institutet

4:00 p.m. in the Psychological and Brain Sciences Building, PY101  

Title: Endocannabinoid signaling during brain development

Endocannabinoids (eCB) function as retrograde messengers at both excitatory and inhibitory synapses, and control various forms of synaptic plasticity in the adult brain. The molecular machinery required for specific eCB functions during maintenance of synaptic homeostasis is becoming well established. However, eCB signaling plays surprisingly fundamental roles in controlling the acquisition of neuronal identity during CNS development. Recent work suggests that selective recruitment of regulatory signaling networks to CB1 cannabinoid receptors dictates neuronal state-change decisions. In addition, the spatial localization and temporal precision of eCB action emerges as a novel organizer in developing neuronal networks. At the moment, we are far from understanding the molecular logic and chronodynamics of how eCB signaling networks specify in the embryonic brain, and how their specific neurodevelopmental functions relate to and define their retrograde control of neurotransmitter release at mature synapses. Important open questions include: where and when eCBs are produced in the developing brain; the molecular identity of eCBs and whether they represent ‘active’ signals; whether respective receptors and intracellular signal transduction cascades differ from those in the postnatal brain; how eCB signaling integrates with other regulatory systems; and how the relative power of this newly-emerging signaling entity contributes to define neurodevelopmental processes. In this talk, I will summarize contemporary discoveries establishing eCB-driven cellular identification events in the developing cerebrum, and define a unifying concept of how eCB signaling provides positional signals for excitatory and inhibitory afferents along the dendritic tree of cortical neurons, thus shaping the complexity of cortical connectivity.  


April 08, 2009
D. James Surmeier, Ph.D.

Northwestern University

4:00 p.m. in the Psychological and Brain Sciences Building, PY101

Title: To go or not to go: dopaminergic modulation of striatal synaptic plasticity    

At synapses between cortical pyramidal neurons and principal striatal medium spiny neurons (MSNs), postsynaptic D1 and D2 dopamine (DA) receptors are postulated to be necessary for the induction of long-term potentiation and depression, respectively – forms of plasticity thought to underlie associative learning. Because these receptors are restricted to two distinct MSN populations, this postulate demands that synaptic plasticity be unidirectional in each cell type. Using brain slices from DA receptor transgenic mice, we show that this is not the case. Rather, DA plays complementary roles in these two types of MSN to ensure that synaptic plasticity is bidirectional and Hebbian. In models of Parkinson’s disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms.


March 25, 2009
Jeffrey Mogil, Ph.D.

McGill University

4:00 p.m. in the Psychological and Brain Sciences Building, PY101

Title: Pain, Sex and Your Mother      

Pain researchers have now come to some consensus regarding the existence of small quantitative sex differences in the sensitivity to and tolerance of pain in humans.  Differences in the effectiveness of analgesics in men and women are also appreciated.  However, broad conclusions regarding the existence and direction of such sex differences are complicated by emerging evidence from laboratory animals that sex differences interact with genetic background.  That is, male and female mice of only certain genetic backgrounds display sex differences.  Even the direction of sex differences (male>female vs. female>male) may depend on genetic factors.  In addition to these quantitative sex differences, evidence is rapidly emerging that the sexes may differ qualitatively in their neural processing of pain and analgesia.  That is, different neural circuits, transmitters, receptors and genes may be relevant to pain modulation in males and females.  I will present data from our laboratory and others demonstrating that the specific genetic and neurochemical mediation of analgesic mechanisms in male and female mice are radically different.  More recent experiments in my laboratory pertain to the other meaning of “sex and pain.”  We are studying the effect of pain itself on sexual behavior in male and female mice using standard and “paced” mating paradigms.


October 15, 2008
Margaret M. McCarthy, Ph.D.
University of Maryland School of Medicine

4:00 p.m. in the Psychological and Brain Sciences Building, PY101

Title: Multiple Mechanisms, One Goal – Sexual Differentiation of the Brain

The Organizational / Activational Hypothesis established 50 years ago that enduring sex differences in brain and behavior are established by the actions of gonadal steroids early in life.  What has been lacking is a mechanistic understanding of how steroids permanently alter the neuronal architecture to induce sex differences in adult physiology and behavior.  Our research group has begun to make in-roads in this area and have discovered a surprising role for prostaglandins, as well as more ubiquitous neurotransmitters such as GABA and glutamate. We have also determined that cell-to-cell communication, frequently involving astrocytes and neurons, is a common principle and yet, the precise mechanism of steroid-mediated differentiation of the brain is regionally specific. The net result of divergent mechanisms of the same steroid is the creation of a wider variety of phenotypic outcomes than could be achieved by a uniform mechanism across all brain regions.  Understanding the mechanistic basis of steroid action on the developing brain will provide insight into potential sites of prevention or intervention for the many gender-biased neurological and mental health disorders with developmental origins.

October 10, 2008
Johannes W. Hell, Ph.D.
Professor, Department of Pharmacology
University of Iowa

2:30 p.m. in the Chemistry Building, CH033

Title: The role of NR2B phosphorylation by calcium/calmodulin kinase II in learning and memory

We are studying the assembly and function of signaling complexes at synapses, the contact points between neurons that mediate synaptic transmission.  A period of heightened activity leads to a permanent upregulation of synaptic transmission at individual synapses.  This physiological phenomenon known as long-term potentiation or LTP is thought to underlie learning and memory. We found earlier that the two key players in LTP induction, the NMDA-type glutamate receptor and the calcium-and calmodulin-dependent kinase CaMKII, interact with each other, strategically placing CaMKII next to the source of calcium influx that activates the kinase and also next to the postsynaptic substrates important for LTP. We identified single residues that are critical for CaMKII binding to the NMDAR. Knock-in mice with point mutations that inhibit CaMKII binding to the NMDAR show normal basal synaptic function  but reduced LTP and impaired memory formation.

September 17, 2008
Nephi Stella, Ph.D.
University of Washington School of Medicine

4:00 p.m. in the Psychological and Brain Sciences Building, PY101

Title: Targeting enzymes that hydrolyze endocannabinoids for the treatment of neurodegenerative diseases

Microglial cells, the macrophages of the brain, play a key role in the control and propagation of neuroinflammation. It is known that microglia produce endocannabinoids and express CB2 receptors, and that 2-AG stimulates microglial cell migration through CB2 receptors. Although endocannabinoid-hydrolyzing enzymes constitute a promising therapeutic target and their inhibition in microglia is likely to control neuroinflammation response and propagation, little is known about their expression in these immune cells. We have previously shown that the microglial cell line BV-2 expresses a novel, uncharacterized 2-AG-hydrolyzing enzyme. Here, in collaboration with the Cravatt laboratory, we performed an activity-dependent protein profiling of the serine hydrolase activities expressed by BV-2 cells and identified three novel 2-AG-hydrolyzing enzymes: ABHD6, ABHD12 and NTE. Using both a pharmacological approach and shRNA knockdown, we show that ABHD6 constitutes a major player in the control of 2-AG hydrolysis and bioactivity in BV-2 cells. We found that ABHD6 activity is also important in controlling 2-AG hydrolysis and bioactivity in neurons. Finally, we found a transient down-regulation of ABHD6 mRNA in the striatum of R6/2 mice, a model of Huntington’s Disease, as a function of disease progression. These results suggest that ABHD6 constitutes a novel component of the endocannabinoid signaling system and may represent a promising target for the control of neuroinflammation occurring in neurodegenerative diseases.

October 22, 2007
Cary Lai, Ph.D.
The Scripps Research Institute

Title: Neuregulin-ErbB Signaling in the Nervous System

4:00 p.m. in the Kelley School of Business, CG 1008

Abstract: Our laboratory is studying the role of the receptor tyrosine kinases, the “ErbBs” (ErbBs 1-4) and their ligands, the “neuregulins” (NRGs 1-4) in the mature and developing nervous system. NRG1 is best known as a key regulator of Schwann cell function and as a regulator of acetylcholine receptor (AChR) expression in muscle cells in vitro. Our primary focus has been the analysis of conditional knockout mice that lack ErbB4 in the nervous system and on the production of transgenic mice that permit the regulated expression of NRG1. Our studies have revealed that ErbB4 is expressed by multiple populations of tangentially migrating neuronal precursors. During development, ErbB4 marks the migrating interneuronal precursors as they move from the ganglionic eminences to the cortex and hippocampus. In mature mice, ErbB4 is expressed by cells in the rostral migratory stream (RMS), the primary site of neurogenesis in the adult rodent brain. The RMS contains interneuronal precursors that are born in the subventricular zone near the lateral ventricle and that migrate to the olfactory bulb. In both populations of cells, the loss of ErbB4 leads to a reduction in the number of interneurons and to deficits in migration. A preliminary behavioral characterization of ErbB4-deficient mice has revealed a a reduction in anxiety-like behavior. As ErbB4 is expressed at high levels in the intercalated cells of the amygdala, we are testing the hypothesis that a loss of ErbB4 function in this region may be responsible for this behavioral alteration. We are also evaluating neuregulin function by establishing lines of transgenic mice that permit the regulated expression of 3 isoforms of NRG1 (I, II and III). We have developed a system permitting expression in cholinergic neurons, through the use a bacterial artificial chromosome (BAC) encoding choline acetyltransferase. Temporal regulation is provided by the tetracycline system. These mice should allow assessing the plasticity of the myelination process, should permit testing the role of NRG1 as a regulator of AChR expression at the neuromuscular junction in vivo, and should facilitate an understanding of how NRG1 affects neuronal function in the CNS. As NRG1 has been identified as a susceptibility gene for schizophrenia, mice permitting inducible expression of NRG1 should help to assess the role of this factor in a number of pathways implicated in this process including defects in cell migration, neurotransmitter receptor expression, interneuronal function and myelination.

February 19, 2007
Wayne D. Bowen, Ph.D.
Brown University

Title: Sigma-2 Receptor-Mediated Apoptosis in Human SK-N-SH Neuroblastoma Cells

4:00 p.m. in the Psychological and Brain Sciences Building , PY101

Abstract: Sigma receptors comprise a novel family of pharmacologically-defined receptor sites that recognize several important classes of psychotropic drugs. These include typical neuroleptics such as haloperidol, the psychotomimetic agent phencyclidine (PCP), some synthetic opiates such as pentazocine, and some psychostimulants like cocaine. Sigma-1 and sigma-2 receptor subtypes are currently known. In addition to expression throughout the CNS, these receptors are found in peripheral tissues and are highly expressed in tumor cell lines of various tissue origins. We have shown that sigma-2 receptor agonists induce apoptotic cell death in both tumor cell lines and in primary neuronal cells. We have explored the signaling pathway in human SK-N-SH neuroblastoma cells in some detail. Treatment of these cells with the sigma-2 subtype selective agonist, CB-64D results in caspase-dependent cell death via a mechanism that is dependent upon mitochondrial depolarization. The Bcl 2 -family protein, Bid, is cleaved in a caspase-dependent manner. Truncated Bid (tBid) is known to promote mitochondrial depolarization. We also show that several apoptogenic factors are released from mitochondria. Apoptosis inducing factor (AIF) and endonuclease G (Endo-G) are released upon treatment with sigma-2 agonist and translocate to the nucleus. Cytochrome C is released into the cytosol. Release of these factors is dependent upon Bid cleavage and is blocked by caspase inhibitors. Taken together, the data suggest that sigma-2 receptors activate caspase-dependent Bid cleavage to depolarize mitochondria, causing release of AIF, Endo-G, and cytochrome C, which ultimately leads to cell death. Caspase activation may be related to the ability of sigma-2 agonists to increase cellular ceramide levels in these and other cells. Sigma-2 receptor-mediated apoptosis could play a role in induction of the tardive dyskinesias occurring in patients treated chronically with typical neuroleptics and may also be exploited in the development of novel antineoplastic agents effective against a wide variety of cancers.

November 29, 2006
Cary H. Lai, Ph.D.
The Scripps Research Institute

Title: The Many Wonders of Neuregulin-ErbB Signaling in the Nervous System

12:00 p.m. in the Indiana Memorial Union, State Room East

Abstract: The neuregulins (NRG1-4) are a family of polypeptide growth factors that bind to and activate members of the transmembrane protein-tyrosine kinases known as the “ErbBs” (ErbB1-4). The interest in neuregulin biology has increased as a result of the identification of the NRG1 gene as a susceptibility factor for the neuropsychiatric disorder schizophrenia. Given the significance of this association, just what does NRG1 do in the brain? The current evidence suggests that NRG1 appears to be involved in a dizzying array of processes, many of which have been implicated as factors contributing to the development of this disorder. NRG1 has been shown to serve as a key regulator of myelination in the peripheral nervous system and may also influence this process in the CNS. Neuregulin signaling through ErbB4 has been observed to alter the migration of interneuronal precursors and may modulate their function in the mature nervous system. NRG1 has also been shown to regulate the expression of neurotransmitter receptors, and hence is capable of affecting synaptic function. In addition, recent studies have provided evidence that both NRG1 and ErbB4 engage in “back-signaling”, where the cytoplasmic tails of these molecules can enter the nucleus and influence transcription. Although the other neuregulins expressed in the brain, NRG2 and NRG3, have not been linked to schizophrenia, the ability of these molecules to activate ErbB signaling suggests that we are yet to uncover additional functional roles for neuregulin-ErbB signaling in the nervous system.

October 25, 2006
Jae Young Seong, Ph.D.
Korea University College of Medicine

Title: Orphan G-Protein Coupled Receptors: Emerging Targets for Drug Development

Abstract: The superfamily of G protein-coupled receptors (GPCRs) is the largest and most diverse group of membrane-spanning proteins. It plays a variety of roles in pathophysiological processes by transmitting extracellular signals to cells via heterotrimeric G proteins. Completion of the human genome project revealed the presence of ~ 168 genes encoding established transmitter GPCRs, as well as 207 genes predicted to encode novel GPCRs for which the natural ligands remained to be identified, the so-called ‘orphan' GPCRs. Eighty-seven of these orphans have now been paired to novel or previously known molecules, and 120 remain to be deorphaned. Since known GPCRs have often been successfully used as therapeutic targets, orphan GPCRs may serve as a rich source of potential targets for drug discovery. For several years, we have attempted to elucidate the mechanism underlying the ligand-receptor interaction and signal transduction of GPCRs for many neuropeptides such as gonadotropin-releasing hormone, oxytocin/vasopressin, and neurotensin. Accumulation of this research experience allows us to develop a novel high throughput assay system to screen novel compounds acting at orphan GPCRs. Using this system, we found that orphan GPR92 responds to various lipid-derived molecules. As the mRNA and protein for GPR92 are largely expressed in the dorsal root ganglia, it is postulated that interaction of GPR92 with its ligands may be involved in sensory (particularly pain sensing) processes. The precise physiological role of GPR92 and its ligands in the sensory system, however, should be further elucidated.

October 26, 2005
Kenneth Mackie, M.D.
Professor, University of Washington

Title: Cannabis, cannabinoids, and THC: What’s all the buzz about?

Abstract: The desire to understand how cannabis produces its characteristic psychoactive effects has resulted in the discovery of a novel neuromodulatory network, the endocannabinoid system. This system is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that make and degrade endogenous cannabinoids. Neuronal cannabinoid (CB1) receptors appear to mediate the psychoactive effects of cannabis and its phytocannabinoids (such as delta-9 THC), as well as the neuronal effects of endocannabinoids. At the behavioral level, endocannabinoids are involved in processes as diverse as memory, movement, and analgesia. Emerging clinical data suggests that manipulations of the endocannabinoid system may be therapeutically beneficial. At the cellular level, endocannabinoids acting at CB1 receptors play a role in specific forms of long and short duration synaptic plasticity, and it is plausible that these cellular effects underlie the behavioral effects. The interactions of delta-9 THC with endocannabinoids likely underlie the psychoactive effects of cannabis, although emerging evidence suggests that this is not due to delta-9 THC merely “hijacking” and activating CB1 receptors.

June 2, 2005
David Van Vactor, Ph.D.
Associate Professor, Department of Cell Biology, Program in Neuroscience, DFCI/Harvard Cancer Center, Harvard Center for Neurodegeneration and Repair, Harvard Medical School

Title: Signaling Mechanisms that Control Axon Guidance Decisions

Abstract: Growth cone navigation relies upon active remodeling of actin and microtubule cytoskeletal arrays. Despite rapid progress in finding actin regulators downstream of various guidance receptors, little has been learned about signaling effectors that directly associate with microtubules. Here we identify the microtubule-associated protein Orbit/MAST as a component that cooperates with the Abelson (Abl) protein tyrosine kinase during axon guidance in the Drosophila embryo. At the midline, Orbit/MAST and Abl mutants exhibit identical phenotypes, suggesting a model where Abl acts a node to coordinate actin and microtubule dynamics downstream of Slit. Orbit/MAST displays strong genetic interactions with Slit and its Roundabout-family receptors, supporting this model. Orbit/MAST is expressed at high levels in the developing nervous system where it localizes to axons and growth cones. Higher resolution imaging of the Orbit/MAST ortholog CLASP in Xenopus growth cones suggests that this family of microtubule plus-end tracking proteins identifies a subset of dynamic microtubules that probe the actin-rich peripheral domain of the growth cone where guidance signals exert their initial influence on cytoskeletal organization.

March 2, 2005
Laurence F. Abbott, Ph.D.
Professor of Biology, Brandeis University

Title: Multi-Timescale Dynamics in Neural Systems

Abstract: Storing memories of ongoing, everyday experiences requires a high degree of plasticity, but retaining those memories demands protection against changes induced by further activity and experience. The standard model for memory storage involves switch-like transitions in the connections between neurons, induced by activity. Such a mechanism is good at storing but bad at retaining memories if the transitions are likely, and poor at storage but good at retention if they are unlikely. Statistical and mean-field calculations can quantify these effects, and they suggest that better performance can be obtained using multi-timescale dynamics. Professor Abbot presented a model based on a cascade of states governed by widely different time constants and showed that it combines high levels of memory storage with long retention times, significantly outperforming alternative models. The model accounts for previously unexplained aspects of the dynamics of learning and memory.

February 18, 2005
Steven Paul, M.D.
Executive VP, Science and Technology and President of Lilly Research Laboratories, Eli Lilly and Company

Title: Alzheimer's Disease: From Genes to New Drugs

February 4, 2005
Phil Skolnick, Ph.D., D.Sc (hon)
Senior VP, Research and Chief Scientific Officer, DOV Pharmaceutical, Inc.

Title: Anxiety: Of Molecules, Mice, and Men

Abstract: Generalized anxiety disorder is the second most commonly diagnosed psychiatric illness in primary care settings. The lifetime prevalence of generalized anxiety disorder has been estimated at 5-6%, and should thus be considered a significant public health issue. Dr. Skolnick summarized c onverging lines of evidence that the neurotransmitter GABA ( g -aminobuytric acid), by signaling through GABA A receptors, modulates anxiety as well as the action of many useful anti-anxiety agents. Three main issues were presented: 1) a review of current thinking on the assembly and operation of GABA A receptors; 2) evidence that modulation of GABA A receptors produces anxiety-like behaviors in primates, including humans; and 3) prospects for the development of novel anxiolytics acting via GABA A receptors.

October 21, 2004
J. Troy Littleton, Ph.D., M.D.
Associate Professor of Neurobiology, The Picower Center for Learning and Memory, Massachusetts Institute of Technology

Title: Bidirectional Communication at Synapses:  A Genetic Dissection of Synaptic Plasticity in Drosophila

Abstract:The computational power of the brain depends on synaptic connections that link together billions of neurons.  Dr. Littleton's laboratory is interested in the mechanisms by which neurons form synaptic connections, how synapses transmit information, and how synapses change during learning and memory. Bernard Katz and colleagues established the hypothesis that calcium influx into the presynaptic nerve terminal triggers neurotransmitter release and the initiation of synaptic communication. Dr. Littleton's research group has used genetic and electrophysiological approaches at the Drosophila embryonic neuromuscular junction to characterize the molecular mechanisms that mediate calcium sensing and synaptic vesicle fusion at synapses. In particular, this group has shown that the calcium-binding synaptic vesicle protein Synaptotagmin 1 couples calcium influx to rapid and synchronous synaptic vesicle fusion.  They have also identified a novel calcium-sensitive vesicular trafficking pathway that is present in the postsynaptic compartment that mediates retrograde signaling at synapses. This retrograde signaling pathway requires a distinct synaptotagmin isoform, Synaptotagmin 4, and mediates both plasticity induction and synaptic rewiring in response to activity.  An important tenet for research into synaptic plasticity underlying memory formation is Hebb's postulate, which proposes that a synaptic connection is potentiated when the activity of the pre- and post-synaptic neurons are correlated, leading to structural changes in synaptic growth.  Dr. Littleton and colleagues have performed a genetic dissection of synapse-specific potentiation and growth using the Drosophila glutamatergic neuromuscular junction. Their current findings indicate that calcium influx into postsynaptic cells induces secretion of retrograde signals from postsynaptic vesicles, activating a cAMP pathway in presynaptic terminals that modulates synaptic growth in a Hebbian input/output-specific manner.