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The Gill Center for Biomolecular Science

Gill Seminars

Previous Speakers

Upcoming 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.

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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.

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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.

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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.
 

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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.

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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.

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November 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.

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April 4, 2016
David A. Lewis, M.D.

University of Pittsburgh

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

Title: Pending

Abstract: Pending

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April 18, 2016
Rodney Samaco, Ph.D.

Baylor College of Medicine

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

Title: Pending

Abstract: Pending

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