Fall 2007 Seminar Series in Neuroscience [Updated 9-14-07]

Dr. Mike Tamkun Department of Biochemistry & Molecular Biology, Colorado State University

Title:"Kv2.1 membrane corrals: Novel regulators of K+ channel function and trafficking"

Abstract: Rapid modulation of ion channel surface expression is likely to represent a central mechanism in the regulation of neuronal excitability. The Kv2.1 delayed-rectifier K+ channel targets to unique cell surface clusters in hippocampal neurons. Since these structures are regulated in vivo by stimuli associated with neuronal injury, i.e. hypoxia, ischemia, and excess neurotransmitter release, they are likely to participate in the neuro-protective response during such insults. Our overall hypothesis is that the Kv2.1 surface clusters are central in the regulation of both Kv2.1 trafficking and function. A better understanding of Kv2.1 cluster regulation and function will improve our ability to manage stroke–related issues. We use a multidisciplinary approach utilizing techniques ranging from voltage-clamp to single quantum dot tracking. The Kv2.1 surface clusters are formed by corralling mobile channels behind a cytoskeletal-based fence. The clusters serve as a platform for trafficking vesicle-based insertion and retrieval at the cell surface, making the regulation of trafficking more efficient than if the channel is homogenously distributed over the cell surface. However, our most recent data suggest that channels within the surface clusters do not transport K+ until released from these cell surface domains, suggesting that K+ current density is controlled by more than transport to the cell surface.

Dr. Jerry Stitzel, Department of Integrative Physiology, University of Colorado at Boulder

Title: "Nic at night: The Chronopharmacology of nicotine"

Abstract: Despite the fact that smoking kills about 450,000 people in the United States per year, greater than 20% of the population continues to smoke. Curiously however, even the heaviest, most nicotine dependent smokers typically abstain from smoking during the normal sleep cycle. The ability to abstain from smoking may relate to the fact that the effects of most drugs varies over the course of the day. In fact, recent studies in rodents have shown that sensitivity to several effects of cocaine differs depending upon the time of day. In short, rodents are more sensitive to the effects of cocaine during the light phase of the light/dark cycle. Furthermore, the reduced sensitivity to cocaine during the dark phase of the light cycle appears to be dependent upon melatonin. Pinealized rats or mouse strains that do not exhibit diurnal variations in melatonin synthesis also do not show daily variations in sensitivity to cocaine. To examine whether this same phenomenon occurs for nicotine, we have measured acute sensitivity to nicotine across the 24 hr daily cycle in two mouse strains that differ in their ability to produce melatonin and in mice melatonin lacking melatonin receptors. Like other drugs of abuse, sensitivity to the locomotor and hypothermic effects of nicotine is significantly reduced during the dark phase of the light dark cycle. Moreover, a single injection of melatonin was found to reduce sensitivity to nicotine. However, unlike prior studies with cocaine, our studies indicate that the daily variation in nicotine sensitivity is not dependent upon melatonin. Consequently, the mechanism responsible for the daily variations in sensitivity to nicotine appears to be distinct from that of cocaine. Understanding the mechanism responsible for the daily variations in nicotine sensitivity should lead to a greater appreciation of why nicotine dependent individuals can abstain from smoking during the sleep cycle. Such information may be useful in the design of more effective smoking cessation aids.

Dr. Steve Maier Department of Psychology, University of Colorado

Title: "The role of the ventral medial prefrontal cortex in mediating resilience to adverse events"

Abstract: There are large differences in how individuals are impacted by adverse life events. Many of the factors determining vulnerability and resilience revolve around coping factors. Perceived ability to exert behavioral control over the adverse event is central to coping, and the neural mechanisms that mediate this process are the focus of this presentation, as studied in an animal model. Uncontrollable, relative to physically equal controllable stressors, produce a constellation of behaviors that have been called learned helplessness and behavioral depression. Research will be reviewed which indicates that these occur because uncontrollable, relative to controllable stressors, activate serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN), thereby leading to their sensitization. However, the DRN itself has neither the “processing power” nor the required somatosensory inputs to determine whether a stressor is or is not under behavior control. A variety of experiments will indicate that the DRN is simply “driven” by the presence of stressors per se, and that controllability is detected by ventral regions of the medial prefrontal cortex (mPFCv). When control is present, glutamatergic output neurons from the mPFCv are activated, and these mPFCv neurons synapse preferentially on GABAergic interneurons within the DRN that inhibit the 5-HT cells. Thus, the presence of control leads the mPFCv to actively inhibit the activation of DRN 5-HT neurons that is produced by stressors. Furthermore, experiments will be reviewed which indicate that there is plasticity in this process within the mPFCv so that an initial exposure to control alters the mPFCv in such a way that later exposures to even uncontrollable stressors will activate mPFCv inhibitory control over the DRN, thereby rendering the organism resilient in the face of uncontrollable stressors. This activation of mPFCv inhibitory modulation by behavioral control extends to stress-responsive structures other than the DRN, and the amygdala will be a focus. Finally, research that explores factors other than behavioral control that activate mPFCv inhibition of stress-responsive structures will be described, with a focus on “learned safety”. Implications for clinical issues will be discussed.

Dr. Serge Campeau Dept of Psychology & Center for Neuroscience, University of Colorado at Boulder

Title: "Habituation to repeated audiogenic stress in rats"

Abstract: Whereas emotional stress responses provide many important physiological mechanisms to help cope with daily challenges and hassles, the prolonged or repeated exposure to stress is frequently associated with several psychopathologies and physical disorders. Under many conditions, however, repeated encounters with the same challenging situation will lead to reduced stress responses, namely, habituation, which is an important adaptive mechanism serving to reduce the overall impact of stress. It is conceivable that disruption or failure of this important, but underappreciated and ill-defined, process could partly account for the development of physical and mental disorders. I will discuss our laboratory's efforts to better define the neural structures and mechanisms associated with habituation to repeated stress using loud noise, in rats.

Dr. Anthony Grace, Dept of Neuroscience, Univ of Pittsburgh

Title: "Limbic System Modulation of Dopamine Neuron Activity and the Pathophysiology of Schizophrenia"

Abstract:Schizophrenia is a debilitating disorder that affects people in late adolescence and early adulthood. A primary feature of schizophrenia are the positive symptoms - the hallucinations and delusions that are the hallmark of the disorder, and that appear to be due to a hyperdopaminergic condition. In our studies of developmental animal models of schizophrenia, we found evidence for hyperactivity within the hippocampus; a characteristic that is consistent with recent human imaging data. Outflow from this structure appears to cause the hyperdopaminergic state, as well as disrupting the frontal cortical-limbic system balance in the brain. This provides new insights into the etiology and pathophysiology of schizophrenia, and opens up new avenues for treatment of this disorder.

Dr. Michael Rugg, Dept. of Neurobiology & Behavior, University of California – Irvine

Title: “Episodic memory encoding and retrieval: a cognitive neuroscience perspective”

Abstract: Encoding and retrieval are often treated as if they are independent memory functions. Evidence from experimental psychology, however, suggests that they are interdependent. This evidence fits well with current ideas about the neurobiological basis of episodic memory, and the two frameworks come together to make predictions about the relationship between encoding- and retrieval-related neural activity that can be tested in humans using functional neuroimaging. The talk will describe recent studies motivated by these predictions, and will argue that encoding and retrieval are interdependent at both the psychological and the neural level.