Gill Speakers

Upcoming Speakers:

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

Research Areas: (from McCarthy's website)

STEROID MODULATION OF PROSTAGLANDINS IN THE BRAIN

A few years ago we made the surpising discovery that prostaglandins, in particular PGE2, are regulated in the brain by gonadal steroids and have a major impact on the masculinization of a particular region called the preoptic area. Prostaglandins are of enormous interest since their synthesis is the target of the most prevalent over the counter and prescribed drugs on the market today, the NSAIDs, or COX inhibitors. These include aspirin, Aleve, Vioxx, Coxib and many many more. We are now extending our initial findings to other brain regions and other functional outcomes.

RELEVANCE OF SEX DIFFERENCES IN THE BRAIN TO MENTAL HEALTH DISORDERS

An individuals gender is a major predictive factor of relative risk to develop specific neurologic or mental health disorders. The incidence of autism, attention deficit disorder, Tourettes and early on-set schizophrenia are all significantly greater in males. Conversely, the frequency of major depressive disorder, general anxiety disorder, obsessive compulsive disorder and disorders of eating are all greater in females. An important distinction between these two cohorts of disorders is that those which are male biased tend to occur early in development, whereas those that are more prevalent in females generally do not occur until after puberty. By understanding the basic mechanisms establishing sex differences in the brain, we hope to provide novel insight into the etiology of these devastating conditions.

SEX DIFFERENCES IN PEDIATRIC BRAIN DAMAGE

A major source of brain damage to both premature and full-term babies is stroke, and males tend to fare worse outcomes than females to the same injury. We have found that the gonadal steroid, estradiol, is a potent regulator of the response to injury in the developing brain, being neuroprotective under circumstances and actually exacerbating injury under others. We use calcium imaging of cultured neurons to investigate the detailed cellular mechanisms by which these changes occur.

STEROID MODULATION OF GLIA

We have found that the morphology of a subclass of glia, known as astrocytes, is markedly influenced by the hormonal milieu of the developing brain. Changes in the morphology of these cells has important consequences for the synaptic patterns established on the developing neurons. Astrocyte-to-neuron communication has emerged as a major regulatory feature of the establishment of sex differences in the brain.

Previous Speakers:

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

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

Jae Young Seong, Ph.D., October 25, 2006
Korea University College of Medicine
"Orphan G-Protein Coupled Receptors: Emerging Targets for Drug Development”
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.

Kenneth Mackie, M.D., October 26, 2005
Professor, University of Washington
"Cannabis, cannabinoids, and THC: What’s all the buzz about?"
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.

David Van Vactor, Ph.D., June 2, 2005
Associate Professor, Department of Cell Biology, Program in Neuroscience
DFCI/Harvard Cancer Center, Harvard Center for Neurodegeneration and Repair, Harvard Medical School
"Signaling Mechanisms that Control Axon Guidance Decisions."
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.

Laurence F. Abbott, Ph.D., March 2, 2005
Professor of Biology, Brandeis University
"Multi-Timescale Dynamics in Neural Systems."
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.

Steven Paul, M.D., February 18, 2005
Executive VP, Science and Technology and President of Lilly Research Laboratories, Eli Lilly and Company
"Alzheimer's Disease: From Genes to New Drugs."

Phil Skolnick, Ph.D., D.Sc (hon), February 4, 2005
Senior VP, Research and Chief Scientific Officer, DOV Pharmaceutical, Inc.
"Anxiety: Of Molecules, Mice, and Men."
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.

J. Troy Littleton , Ph.D., M.D., October 21, 2004
Associate Professor of Neurobiology, The Picower Center for Learning and Memory, Massachusetts Institute of Technology
"Bidirectional Communication at Synapses:  A Genetic Dissection of Synaptic Plasticity in Drosophila."
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.