# Neural circuit and brain system alterations underlying social recognition memory deficits

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $423,126

## Abstract

Abstract
 Social deficits are a hallmark feature of several psychiatric and neurodevelopmental disorders and are a core
symptom of autism spectrum disorder. To date, behavioral therapies are the first line of intervention for treating
impaired social behaviors, whereas pharmacological treatments have been ineffective at addressing this
symptom domain. To inform treatment targets, there is an urgent need to understand the pathophysiology
underlying social deficits. Several neural circuits and hormones involved in social behaviors have been identified
and are conserved across species, e.g., the hypothalamic paraventricular nucleus and the release of the oxytocin
peptide. Despite the wealth of behavioral and pharmacological studies implicating the paraventricular nucleus
and oxytocin in social behavior, little is known about the effect of autism-associated mutations on the oxytocin
system and whether malfunction in this system underlies social deficits in autism.
 Oxytocin is primarily synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus
and is released peripherally to regulate physiological functions and centrally to modulate social behavior.
Glutamatergic signaling is involved in the process of oxytocin release. Notably, mutations in the Shank3 gene, a
high-risk gene for autism, perturb glutamatergic signaling in the hippocampus and striatum. However, the effect
of Shank3 mutations on glutamatergic signaling and oxytocin release in the paraventricular nucleus has never
been studied before. In this proposal, we study the effect of Shank3 mutations on the oxytocin system to ask
how a Shank3 mutation in rats affect the activity of oxytocin neurons, glutamatergic signaling in the
paraventricular nucleus, and the release of oxytocin at brain regions of social behavior. We also investigate
whether the effect of Shank3 mutations on the oxytocin system underlies social behavior deficits. Our central
hypothesis is that Shank3 mutations impair oxytocin release within the paraventricular nucleus and at brain
regions of the social recognition circuit (Aim 1) by interfering with glutamatergic signaling and neural activity of
oxytocin neurons in the paraventricular nucleus (Aim 2), leading to social recognition deficits (Aim 3). To this
end, we will utilize a rat model with a Shank3 mutation and employ molecular, behavioral, and in vivo imaging
experiments to capture alterations in neural activity of oxytocin neurons and identify impairments in oxytocin
release during behavior. We will also employ viral-based approaches and chemo-genetic tools for neural-specific
manipulations to determine causality between alteration in the oxytocin system and deficits in social behavior,
caused by a Shank3 mutation. This study will lead to a clearer understanding of Shank3 function in the
hypothalamic oxytocin system, which is part of a larger social brain circuit that could be targeted
pharmacologically, genetically, or via circuit-specific...

## Key facts

- **NIH application ID:** 10176596
- **Project number:** 5R01MH116108-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Hala Harony-Nicolas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,126
- **Award type:** 5
- **Project period:** 2019-08-09 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176596

## Citation

> US National Institutes of Health, RePORTER application 10176596, Neural circuit and brain system alterations underlying social recognition memory deficits (5R01MH116108-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10176596. Licensed CC0.

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