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

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $45,998

## Abstract

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.

## Key facts

- **NIH application ID:** 10598940
- **Project number:** 3R01MH117421-04S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** TODD Erryl ANTHONY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $45,998
- **Award type:** 3
- **Project period:** 2022-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598940

## Citation

> US National Institutes of Health, RePORTER application 10598940, Genetic dissection of lateral septal circuitry that controls stress-induced persistent anxiety states-Diversity Supplement (3R01MH117421-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10598940. Licensed CC0.

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