Genetic dissection of lateral septal circuitry that controls stress-induced persistent anxiety states-Diversity Supplement

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Project Summary We are investigating the neural circuits that flexibly modulate defensive behavior to be appropriate to an individual’s current circumstances, based on environmental conditions and prior aversive experience. This has potential human health benefits relevant to the mission of the NIH. In particular, prolonged exposure to uncontrollable behavioral challenge (i.e. stress) is thought to contribute to or directly trigger the onset of multiple psychiatric disorders for which existing therapies are inadequate. Improved treatments for such disorders will require an understanding of how aversive experiences modulate specific neural circuits to alter defensive behavior, as well as how abnormal modulation of these circuits leads to mental illness. Corticotropin releasing hormone receptors (CRHR) control behavioral and physiological responses to stress and are implicated in trauma-related mental illnesses, but the neural circuit-level mechanisms by which they act have not been clearly defined. One critically important region is the lateral septum (LS), which is potently activated by uncontrollable stressors and regulates severity of stress-induced defensive states via the type 2 CRHR (CRHR2) in rodent models. Moreover, neuroimaging studies of patients with stress-related disorders have consistently detected abnormalities in the hippocampus, a structure that is strongly connected with the LS. However, the precise means by which stress induces persistent CRHR2-dependent changes in defensive behavior via specific LS circuits, and the potential roles of hippocampal inputs, have not been determined. A key first step taken to address this question has been to define the in vivo neural activity patterns of LSCrhr2 neurons in standard assays for defensive behavior (Aim 1, parent grant). These recordings revealed unexpected functional diversity of LSCrhr2 neurons, with multiple activity profiles indicative of distinct functions. Moreover, multiple threat-related signals observed in the LSCrhr2 population were not detected in our recordings from hippocampal neurons that project to LS (Aim 2, parent award). To address these issues, Dionnet Bhatti is pursuing two aims that are highly relevant to but distinct from those described in the parent grant: In Aim 1, To define the variables encoded in the activity of individual LSCrhr2 neurons, Dionnet Bhatti is performing cellular resolution in vivo calcium imaging during a complex, trial-based instrumental defensive behavioral task. Further, he is using functional manipulations to test the causal role of these activity patterns in defensive behavior. In Aim 2, Dionnet will test the hypothesis that hypothalamic projections to the LS encode detection of salient threat stimuli and are required for defensive behavior.