# Photopharmacological interrogation of presynaptic neuromodulation of cortico-amygdalar circuits

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $611,295

## Abstract

PROJECT SUMMARY
The basolateral amygdala (BLA) serves as a neural hub for the integration of various inputs from across the
brain to, in turn, control fear and anxiety-related behaviors and the response to chronic stress. Given this central
role in neuropsychiatric disease-relevant emotional processing, neuromodulatory G protein-coupled receptors
(GPCRs) that can control BLA function have been proposed as targets for the treatment of anxiety disorders and
post-traumatic stress disorder. However, due to the complexity of BLA circuits and the lack of tools for
spatiotemporally and genetically precise manipulation of GPCRs in vivo, it remains difficult to understand how
specific receptors in defined cell types or projections mediate their effects on BLA circuit function and behavior.
 Here we will focus on an understanding of how metabotropic glutamate receptor 2 (mGluR2) modulates
anxiety and fear-related behaviors using recently developed genetically-targeted photopharmacology in
conjunction with slice electrophysiology, behavior, fiber photometry and RNA sequencing. mGluR2 is a critical
presynaptic G protein-coupled receptor (GPCR) which mediates both rapid synaptic inhibition and the induction
of long-term depression (LTD), although connecting these dynamic synaptic processes to behavioral modulation
has been challenging. Our preliminary mapping studies using a Grm2-Cre mouse have shown that mGluR2 is
enriched in projections from the ventromedial prefrontal cortex (vmPFC) and posterior insular cortex (pIC) to the
BLA, motivating our comparative analysis of these two projection classes. We will define the ability of mGluR2
in each projection to control the synaptic strength of cortical connection to BLA pyramidal neurons and
interneurons and use our photopharmacological toolset to link presynaptic modulation to behavioral changes
across a battery of measures of avoidance to aversive stimuli and auditory fear conditioning (aim 1, aim 2). We
hypothesize that depending on the nature of the aversive stimulus (spatial, somatosensory, social) either inputs
from the vmPFC or pIC will play primary roles in behavioral control. In aim 3, we will use a dual optogenetic and
projection-targeted RNA sequencing approach to define the synaptic and molecular adaptations that occur in
each pathway in response to chronic unpredictable stress. Such analysis should inform future studies of novel
projection-defined drug targets that can have desired effects on different aspects of fear and anxiety. Together
this project will introduce a novel approach to mapping the synaptic and circuit mechanisms of behavioral control
by neuromodulatory GPCRs while providing new insights into neuromodulatory control of the BLA by presynaptic
mGluR2.

## Key facts

- **NIH application ID:** 10422437
- **Project number:** 1R01MH129693-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Joshua Levitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $611,295
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10422437

## Citation

> US National Institutes of Health, RePORTER application 10422437, Photopharmacological interrogation of presynaptic neuromodulation of cortico-amygdalar circuits (1R01MH129693-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10422437. Licensed CC0.

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