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

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $582,922

## Abstract

Project Summary
We are investigating the neural circuits that control persistent elevations of defensive behaviors following
uncontrollable stress. This has potential human health benefits relevant to the mission of the NIH. In particular,
exposure to uncontrollable 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 stressful experiences normally engage specific neural circuits to increase anxiety and
defensive behaviors, as well as how abormal engagement of these circuits leads to mental illness.
Corticotropin releasing factor receptors (CRFR) 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 anxious states via the type 2
CRFR (CRFR2) 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 CRFR2-dependent changes in anxiety and
defensive behaviors via specific LS circuits, and the potential roles of hippocampal inputs, have not been
determined. Here, we focus on filling this gap in knowledge by addressing two fundamentally important issues
concerning LS connectivity and function in the mouse, a model organism whose brain shares high structural
and molecular similarity to the human brain.
 In Aim 1, we will determine how activity of CRFR2-expressing neurons in LS changes following a stressful
experience, and how these changes are related to the severity of stress-induced anxious behavior. As
particular patterns of neural activity may promote resilience or susceptibility to stress, this aim has the potential
to inform new approaches to prevent or treat stress-related disorders. We will also determine how the CRFR2
receptor alters activity of LS neurons. This is important as efforts to treat stress-related mental illnesses by
administering drugs that act on CRF receptors have shown some promise but have had limited success. An
improved understanding of how CRF receptors control brain activity may therefore result in development of
more effective therapies.
 In Aim 2, we will determine how a specific input from the hippocampus is connected to the LS, responds to
threat, and influences anxiety and fear-related behaviors.

## Key facts

- **NIH application ID:** 9881350
- **Project number:** 5R01MH117421-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** TODD Erryl ANTHONY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,922
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881350

## Citation

> US National Institutes of Health, RePORTER application 9881350, Genetic dissection of lateral septal circuitry that controls stress-induced persistent anxiety states (5R01MH117421-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881350. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*