Fall 2008 Seminar Series in Neuroscience

Dr. David Morilak, Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio

Title:"The good, the bad and the ugly: Brain norepinephrine and stress"

Abstract: Norepinephrine (NE) exerts a widespread modulatory influence in the brain, altering the operating characteristics of many primary response circuits innervated by noradrenergic afferents. NE has long been implicated in acute stress, and in the behavioral state of arousal, but it has not been clear how its cellular modulatory effect might define a role in either stress or arousal. NE has also been implicated in depression and anxiety, and is a target of many drugs that are effective in the treatment of these disorders, but again with no clear idea how or why.
Our research addresses these three questions: What does NE do in the context of acute stress? How is the acute modulatory function of NE dysregulated by chronic stress, contributing to the cognitive, emotional, behavioral, and physiologic symptoms of depression and anxiety disorders? How is NE function also altered by chronic treatment with NE reuptake blockers that are effective in the treatment of these disorders, contributing to their beneficial clinical effects?
Our studies indicate that phasic activation of NE release in hypothalamic and limbic forebrain regions facilitates acute neuroendocrine and behavioral responses mediated in those regions and evoked by acute stress, thus enhancing stress adaptation and coping. On the other hand, elevating tonic noradrenergic transmission in medial prefrontal cortex facilitates cognitive performance on a behavioral test that assesses cognitive flexibility and attentional set shifting, executive functions mediated in mPFC and compromised in depression. Chronic stress sensitizes acute noradrenergic facilitation of behavioral and neuroendocrine stress reactivity, but paradoxically, chronic stress also induces a cognitive deficit indicating reduced noradrenergic tone in mPFC. By contrast, chronic treatment with desipramine, a selective NE reuptake blocker and effective antidepressant, attenuates acute stress reactivity and enhances cognitive performance. Thus, we hypothesize that by “clamping” noradrenergic activity at a tonically elevated, but less phasically excitable level, chronic NE reuptake blockade can alleviate both the “inhibitory” symptoms of depression related to loss of arousal and cognitive deficit, and also the more “activated” symptoms related to anxiety, thereby restoring emotional homeostasis.

Dr. Stephen Davies, Department of Neurosurgery, University of Colorado, Denver

Title: " Making Gains without Pain: New Technologies for Repairing Spinal Cord Injuries"

Abstract: The traumatically injured spinal cord often reacts to inflammation and the loss of glia at sites of injury by rapidly forming a meshwork of dense, fibrous scar tissue containing a variety of molecules that are actively inhibitory to axon growth. Although white matter pathways beyond sites of injury are also thought to present an inhibitory environment to axon growth, our research has clearly demonstrated that scar tissue presents the greatest impediment to axon regeneration in the injured adult CNS. My research team is therefore developing two complementary approaches to promoting axon regeneration and functional recovery after spinal cord injury. One line of research is focused on promoting axon regeneration by overcoming scar tissue and the multiple axon growth inhibitors within the environment of the injured spinal cord with a naturally occurring molecule called Decorin. Our other line of research is focused on generating the right kinds of astrocytes from embryonic glial restricted precursors (GRPs) for “bridging” spinal cord injuries and promoting functional recovery. In addition to their effects on spinal repair, I will be discussing some of the unexpected new insights our work with GRP-derived astrocytes (GDAs) has given on the cell biology of allodynia after spinal cord injury.

Dr. Hubert Yin Department of Chemistry and Biochemistry, University of Colorado

Title: "Chemical Biology Studies of Protein-Protein Interactions in Membranes"

Abstract: Protein transmembrane domains regulate many pivotal biological processes in the cell. But molecular recognition in the cellular membrane is little understood due to the lack of available probes with high affinity and specificity. Conventional tools such as antibodies are unable to bind to the transmembrane regions of membrane proteins in intact cells. Exogenous agents that specifically target transmembrane domains are needed to complements the antibody-based probing techniques restricted to water-soluble regions. Previous thought has that transmembrane regions do not provide enough distinguishable features for recognition by small-molecule or peptide agents. Recent findings suggested that we can use naturally-occurring protein complex structures as a seed to design such transmembrane domain probing peptides. We have successfully developed Computed Anti-Helical Membrane Protein (CHAMP), the first computational method to design de novo peptide antagonists of protein-protein interactions in the membrane. This is potentially a generally applicable tool to provide agents that can specifically recognize a target transmembrane sequence and study protein-protein interactions in the membrane.

Dr. Anthony Wagner, Department of Psychology and Neuroscience, Stanford University

Title: "The Cognitive Neuroscience of Remembering"

Abstract: Declarative memory permits an organism to bridge the past with the present, providing information from the past that serves to inform present decisions and action. Declarative memory critically depends on the medial temporal lobe (MTL) –– the hippocampal formation and surrounding entorhinal, perirhinal, and parahippocampal cortices –– as well as on interactions between the MTL and other cortical and subcortical structures. In this talk, I will discuss functional neuroimaging data that advance understanding of how the MTL subserves declarative memory. These data support four central conclusions. First, item recognition and event recollection both vary in a continuous manner. Second, a functional gradient exists within the MTL circuit, wherein variability in memory for items and for item-context conjunctions differentially correlates with activation in perirhinal cortex and hippocampus, respectively. Third, the hippocampus interacts with midbrain structures to encode across-event conjunctions, enabling the building of an integrated episodic history that supports generalization. Fourth, such integrative encoding emerges from the circuitry of the hippocampus, which enables it to detect conjunctive prediction errors the have feedback consequences for learning. Collectively, these data indicate that the MTL supports multiple forms of declarative learning, with MTL mechanisms not only empowering us to learn from the past to predict the present, but also to differentially learn from the present when our predictions are violated.

Dr. Rock Levinson, University of Colorado School of Medicine, Denver

Title: "Changes in Sodium Channel Expression In Chronic Pain"

Abstract:Nearly every human will experience severe chronic pain at some point in their lives. Current medications and treatments for this condition have limited effectiveness, and thus chronic pain severely impacts the lives of a substantial number of patients. While the subject of pain is highly complex, our group focuses on the initial mechanisms by which pain is detected and transmitted from the site of injury in the peripheral nervous system (“nociception”). In particular, we study the role that sodium channels play in generating electrical impulses that encode pain. My talk will focus on two major findings, namely that only certain kinds of sodium channels (known as “isoforms”) are specifically involved in normal nociception, and that the expression of these isoforms changes in the peripheral nervous system in chronic pain states. I will describe our studies in both animal models and in human disease.

Dr. Sharon Thompson-Schill, Center for Cognitive Neuroscience, University of Pennsylvania

Title: “Tuning the Language Organ: A New Perspective on the Role of Broca’s Area in Language Processing”

Abstract: For over a century, the relationship between left prefrontal cortex and language processing has been accepted, yet the precise characterization of this link remains elusive. Recent advances in both the psycholinguistic study of language processing and the neuroscientific study of frontal lobe function have converged on an intriguing possibility: The demands to resolve competition between incompatible characterizations of a linguistic stimulus may recruit top-down cognitive control processes mediated by prefrontal cortex. Under this account, the brain region traditionally known as “Broca’s area” – one of the principle language centers in classical models of language dysfunction – may be better described in attentional than linguistic terms. This hypothesis draws on a large body of research into the function of prefrontal cortex, and contrasts with other more domain-specific accounts of the function of Broca’s area. I will present both functional neuroimaging data from young, healthy volunteers and lesion-deficit analyses of patients with focal brain damage that jointly provide support for the regulatory hypothesis of left prefrontal cortex involvement in language processing. I will emphasize studies of single word production, but I will also discuss parallel findings beyond the domain of speech. Evidence of shared regulatory mechanisms across domains has implications for the psychological and neural architecture of language and may broadly inform the study of both linguistic and nonlinguistic cognitive processes. For reprints and more information, see http://www.psych.upenn.edu/stslab.