# Infralimbic circuit control over a sex-dependent switch in threat responding

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2022 · $490,159

## Abstract

Project Summary
Sex differences in the development and prevalence of mental illnesses are widespread, suggesting that the
factors that promote disease risk and resilience may be distinct in men and women. The neurobiological
mechanisms underlying this possibility are poorly understood, however, because the vast majority of pre-
clinical animal research has been conducted in males. In addition, the behavioral outcome measures used to
understand learned fear have focused predominantly on passive, or freezing behavior. We recently identified
an active, escape-like conditioned fear response in rats (“darting”) that occurred almost exclusively in females
and was predictive of improved extinction retention. A better understanding of potentially sexually dimorphic
mechanisms that drive this behavior could open new avenues for treatment of disorders that are more
prevalent in women, like PTSD. We propose here to define the neural circuitry that drives the selection of
conditioned darting vs. freezing, and how that integrates with known extinction circuits to promote extinction
retention. Our preliminary data implicate the infralimbic cortex (IL) in this role, and we will use pharmacological,
chemogenetic, and viral techniques to probe how descending IL projections to the dorsal and ventral
periaqueductal gray (PAG) may mediate a strategic switch between active and passive responding and drive
long-term behavioral flexibility through putative collaterals in the amygdala. We will then use sophisticated
machine vision and machine learning-based tools to define the broader behavioral repertoires within which
darting exists, thereby identifying a multifaceted phenotype that could provide insight into the mechanisms
underlying individual differences in stress resilience and vulnerability.

## Key facts

- **NIH application ID:** 10425352
- **Project number:** 5R01MH123803-03
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** REBECCA M SHANSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $490,159
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425352

## Citation

> US National Institutes of Health, RePORTER application 10425352, Infralimbic circuit control over a sex-dependent switch in threat responding (5R01MH123803-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10425352. Licensed CC0.

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