# Sex Differences in Neural Circuit Mechanisms of Aggression

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $637,718

## Abstract

PROJECT SUMMARY – SEX DIFFERENCES IN NEURAL CIRCUIT MECHANISMS OF AGGRESSION
Aggression is a necessary, adaptive component of social behavior; however, it can become escalated and may
threaten lives, increase the risk of developing psychiatric disease in victims, and incur tremendous economic
burdens on society. Even though aggression can have such dramatic effects on the health and well-being of our
society, we have very few treatments, owing to our still limited understanding of the neural circuit mechanisms
driving aggression. In this application we first take an unbiased computational approach to identify novel circuit
mechanisms of aggression. Using an iDISCO+ tissue clearing method, we broadly assessed cFos expression—
an immediate early gene (IEG) induced by neural activity—across the entire brain to identify brain regions
differentially activated following aggressive versus non-aggressive social interaction. We assessed cFos in ~500
brain regions—registered to the Allen brain atlas—simultaneously and examined interactions across brain
regions by generating co-expression networks with weighted correlation network analysis (WCNA), a widely
used data mining method for studying biological networks based on pairwise correlations between variables. In
this case we examined correlations between cFos expression in brain regions and ranked the correlations based
on the strength of the correlation and the number of total connections. One of the most strongly interconnected
networks was within the amygdala, which is made up of a highly heterogenous cluster of brain regions and cell
types that perform a diverse range of functions from controlling anxiety and fear to social behavior and reward.
Using advanced Ca2+ imaging and chemogenetics, we found that activation of Esr1 glutamatergic neurons in the
COAp of males during aggression was necessary for aggressive behavior. Chemogenetic inhibition of these
cells increased pro-social investigation during the resident intruder (RI) test, however, it did not occlude pro-
social reward/reinforcement behavior. For example, we found that previously aggressive mice will actively lever
press for an intruder mouse; not to attack to the intruder, but to engage in pro-social interactions with them.
Conversely, in females we find that activation of COAp neurons is necessary for pro-social encounters during
the RI test. Thus, our data suggests that the COAp may serve as an important switch in both sexes—though in
sexually dimorphic ways—to control the motivation to engage in pro- versus aggressive-social behavior. Based
on our strong pilot data, we have designed a series of studies to better understand this phenomenon and fully
characterize the role of COAp circuitry in mediating aggression and pro-social behavior. We will use
chemogenetics/optogenetics, electrophysiology and in vivo Ca2+ imaging to dissect the role of COAp and
downstream circuits in mediating aggression and pro-social behavior in both male and femal...

## Key facts

- **NIH application ID:** 10932971
- **Project number:** 5R01MH133299-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SCOTT JAMES RUSSO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $637,718
- **Award type:** 5
- **Project period:** 2023-09-21 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932971

## Citation

> US National Institutes of Health, RePORTER application 10932971, Sex Differences in Neural Circuit Mechanisms of Aggression (5R01MH133299-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10932971. Licensed CC0.

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