Moriel Zelikowsky, Ph.D. - US grants

Fear is a powerful emotion and under normal conditions this works to the advantage of every species on this planet. One of the most poignant examples of this is post-traumatic stress disorder (PTSD). This project maps the neural circuit underlying the extinction of PTSD by combining molecular genetic tools with in depth behavioral analyses. Using a rodent model of PTSD adapted for use in the mouse, it extinguishes specific symptoms of PTSD such as enhanced fear, increased aggression and disruptions in sexual behavior, by genetically identifying and optogenetically targeting specific subsets of neurons known to be involved in fear inhibition. This project is comprised of three aims. Aim 1 determines whether extinction under the optogenetic activation of a population of cells in the lateral division of the central nucleus of the amygdala known to be involved in fear inhibition (PKC-d+ neurons) can subsequently reduce PTSD-induced enhancements in fear, increased aggression, and alterations in sexual behavior. Aim 2 determines whether optogenetic silencing of a distinct but intermingled population of neurons (CRH+ neurons) in the same brain region can produce the same reduction in PTSD symptomology. Aim 3 examines whether similar effects can be obtained using selective silencing or activation of prefrontal cortex projections to the amygdala.

This project has significant intellectual merit in its cross-disciplinary approach. Namely, it combines cutting-edgemolecular biology and genetic tools with well-designed behavioral paradigms. The application of such molecular techniques with solid
behavioral design and analyses are intellectually important in terms of the extent to which these tools can be applied to behavioral neuroscience, taught, and shared with the public.

Broader Impacts: The dissection of PTSD extinction circuitry has the powerful potential to provide a highly targeted, translational approach for the treatment of anxiety disorders and phobias. In addition, this project encourages the teaching, learning and training of optogenetics and applications of molecular biology to questions within psychological science from within the publically accessible and motivated framework of PTSD treatment.

Project Summary/Abstract Fear is imperative to survival. As such, the brain has developed powerful and highly effective neural circuits that are capable of rapidly and flexibly organizing fear behaviors in response to threat. For this reason, when fears are formed inappropriately or expressed excessively, the consequences can be highly detrimental. This is exemplified by anxiety disorders such as post- traumatic stress disorder (PTSD), wherein following an extremely traumatic event, animals become highly sensitized and susceptible to the development and expression of a number of maladaptive behaviors. In contrast to adaptive associative fear memories or even specific phobias, the neural mechanisms underlying non-associative fear sensitization are poorly understood. In the research proposed here, we aim to investigate the neural circuits underlying trauma as well as trauma-induced enhancements in fear learning, elevated aggression, and disrupted sexual behavior. Aim 1 will combine cell-type specific functional manipulations with in depth behavioral analyses to examine the role of the dorsal bed nucleus of the stria terminalis (dBNST) in trauma. Genetically defined and anatomically restricted access to the dBNST will be obtained using Tac2-Cre mice and Cre-dependent viruses encoding optogenetic and chemogenetic effectors. Aim 2 will further dissect the unique microcircuits that control each trauma-induced behavioral phenotype by selectively manipulating and recording from downstream structures receiving Tac2+ dBNST input using optogenetics, CLARITY and fiber photometry. Building upon the tools and information obtained from Aims 1 and 2, Aim 3 will turn upstream, investigating the role of medial prefrontal cortex inputs onto dBNST Tac2+ cells and the ability for these inputs to exert top-down control of trauma and associated behaviors. Collectively, these aims will help to elucidate the neural circuitry that controls the fear-sensitized brain.