David L Walker
Emory University
Project start date: 2010-04-23
Project end date: 2015-01-31
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Grants awarded to David L Walker
NEURAL SUBSTRATES OF PHASIC VERSUS SUSTAINED FEAR
David L Walker, Assistant Professor
Emory University, 1599 Clifton Road, 4th Floor, Atlanta, Ga 30322
Grant 1R01MH080330-01A2 from National Institute Of Mental Health
Abstract: Pavlovian fear conditioning has been widely used to reproduce anxiety-like states in laboratory animals and explore their neural substrates. Based largely on the results from these types of studies, a neural circuit model has been developed and widely adopted. Most often, these paradigms involve pairing brief stimuli such as lights or tones with footshock. Over the last several years, however, I have amassed evidence that when rats are trained and tested using longer duration stimuli (i.e., minutes as opposed to seconds), the current model is inadequate. On the basis of those data, I proposed an expanded model that focuses attention on the bed nucleus of the stria terminalis (BNST) and the stress-related peptide corticotropin releasing factor (CRF). Very briefly, the model posits that glutamatergic projections from the amygdala to the BNST are critically involved in sustained but not short-duration fear responses, and that neural transmission in these pathways is gated by CRF. A series of experiments are proposed which test specific predictions derived from this model. Experiments in Aim 1 evaluate the contribution to long- vs. short-duration fear of amygdala-to-BNST projections. Experiments in Aim 2 evaluate the contribution of CRF receptors to long- vs. short- duration fear. Experiments in Aim 3 evaluate the effect of CRF and sustained threat cues on glutamate release in the BNST, and the dependency of this release on the amygdala. The major techniques used are intra-cerebral drug infusion, permanent and reversible inactivation of selected brain regions, and the measurement of extracellular glutamate in different brain areas using microdialysis and high-pressure liquid chromatography (HPLC). The results from these studies will contribute to a more complete understanding of the neural bases of fear, which is a key step in developing new and more effective treatments for anxiety disorders such as PTSD and GAD. Moreover, as the BNST and CRF have been increasingly implicated in several other mental health and behavioral problems such as depression, drug craving, withdrawal-induced anxiety, and the emotional consequences of chronic pain, the data derived from these studies will likely be relevant to a broad range of clinically important phenomena. Persistent fear and anxiety responses are a significant clinical problem. Recent studies indicate that the neural substrates of short-duration fear responses may be different from those of more sustained fear responses. The experiments proposed herein are meant to further explore these differences
Keywords: 3(2H)-Isoxazolone, 5-(aminomethyl)-; ACTH-Releasing Factor; Accounting; Adopted; Affect; Agarin; Agonist; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Animals, Laboratory; Anxiety; Anxiety Disorders; Area; Attention; Aversive Stimulus; Bed Nucleus of Stria Terminalis; Brain; Brain Stem; Brain region; Brainstem; CRF receptor type 1; CRF-41; CRF-R1; CRF1 receptor; CRH; CRH-1; Cell Communication and Signaling; Cell Nucleus; Cell Signaling; Cerebrum; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Circulatory Collapse; Clinical; Common Rat Strains; Communication; Contralateral; Corticoliberin; Corticotropin Releasing-Factor Receptors; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Corticotropin-Releasing Hormone-41; Crh1 receptor; Cues; Data; Dependency; Dependency (Psychology); Depression; Drugs; EAA Antagonists; Elements; Emotional; Encephalon; Encephalons; Excitatory Amino Acid Antagonists; Fear; Figs; Figs - dietary; Fright; Glutamate Antagonists; Glutamate Receptor; Glutamate Receptor Antagonists; Glutamates; Goals; HPLC; High Pressure Liquid Chromatography; Individual; Infusion; Infusion procedures; Injection of therapeutic agent; Injections; Intracellular Communication and Signaling; Ipsilateral; L-Glutamate; Laboratory Animals; Lateral; Lesion; Mammals, Rats; Measurement; Medial; Mediating; Medication; Mental Depression; Mental Health; Mental Hygiene; Methods and Techniques; Methods, Other; Microdialysis; Modeling; Muscimol; Nerve Cells; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neural Transmission; Neurocyte; Neurons; Neuroses, Post-Traumatic; Neuroses, Posttraumatic; Nucleus; PTSD; Pantherine; Pathway interactions; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Play; Post-Traumatic Stress Disorders; Problem behavior; Procedures; Psychological Health; Rat; Rattus; Receptors, CRF; Receptors, CRH; Receptors, Corticotropin-Releasing Hormone; Research Design; Role; Sensory; Series; Shock; Signal Transduction; Signal Transduction Systems; Signaling; Stimulus; Stress; Stress Disorders, Post-Traumatic; Stress Disorders, Posttraumatic; Stria Terminalis Nucleus; Structure of terminal stria nuclei of preoptic region; Strychnidin-10-one; Strychnine; Study Type; Synaptic Transmission; Techniques; Testing; Training; Transmission; Withdrawal; amygdaloid nuclear complex; base; behavioral problem; biological signal transduction; chronic pain; chronic painful condition; circulatory shock; conditioned fear; corticotropin releasing hormone; corticotropin-releasing factor receptor 1; design; designing; drug craving; drug/agent; effective therapy; emotional dependency; experiment; experimental research; experimental study; extracellular; fear conditioning; neural; neural circuit; neural circuitry; neural model; neuronal; pathway; public health relevance; relating to nervous system; research study; response; social role; study design; success; transmission process; traumatic neurosis
Relevance: Persistent fear and anxiety responses are a significant clinical problem. Recent studies indicate that the neural substrates of short-duration fear responses may be different from those of more sustained fear responses. The experiments proposed herein are meant to further explore these differences
Project start date: 2010-04-23
Project end date: 2015-01-31
Budget start date: 23-APR-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
1R01MH080330-01A2 (2010): $396000