# 2-Arachidonoylglycerol signaling in anxiety, depression, and stress adaptation

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $628,506

## Abstract

PROJECT SUMMARY Stress is a major risk factor for the development of mood and anxiety disorders and the
causative agent in posttraumatic stress disorder (PTSD). Development of stress-related psychopathology is
variable among individuals and involves complex interactions between susceptibility mechanisms favoring
development of psychopathology and resiliency mechanisms protecting against the development of mental
illness in the face of adversity. Understanding the molecular, cellular, and circuit-level mechanisms by which
stress exposure is translated into affective pathology could have broad implications for understanding the
pathophysiology of stress-related psychiatric disorders and for the development of novel treatment approaches.
We propose to test the overarching hypothesis that the endogenous cannabinoid 2-Arachidonoylglycerol (2-AG)
is a critical regulator of stress adaptation and propose to elucidate the synaptic and cellular mechanisms by
which 2-AG signaling serves to mitigate pathological responses to stress exposure. We will first test the
hypothesis that 2-AG signaling inhibits bi-directional excitatory coupling between the amygdala and ventral
hippocampus, a neural circuit critical for mediating innate danger avoidance and generalization of learned fear
responses. We will test the hypothesis that stress causes a functional collapse of 2-AG signaling within this
circuit leading to synaptic strengthening, the generation of increased avoidance, and fear generalization. We will
also test the hypothesis that stress exposure leads to increases in 2-AG release within distinct amygdala circuits
in a neural activity-dependent manner using a novel virally encoded GPCR-based endocannabinoid biosensor.
These studies will reveal, for the first time, the temporal dynamics and activity-dependent mechanisms mediating
stress-induced endocannabinoid mobilization within amygdala circuits. Lastly, we will use in vivo single-cell
calcium imaging approaches to test the hypothesis that 2-AG is required for the dynamic changes in neuronal
ensemble representations to threat predictive cues that occur during fear learning, expression, generalization,
and extinction. Taken together, these data will provide new mechanistic insight into how 2-AG signaling regulates
stress-related biobehavioral processes relevant to neuropsychiatric disorders including PTSD and could reveal
novel pathophysiological mechanisms contributing to the translation of stress exposure into affective pathology.

## Key facts

- **NIH application ID:** 10223545
- **Project number:** 2R01MH107435-06
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Sachin Patel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $628,506
- **Award type:** 2
- **Project period:** 2016-06-15 → 2022-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223545

## Citation

> US National Institutes of Health, RePORTER application 10223545, 2-Arachidonoylglycerol signaling in anxiety, depression, and stress adaptation (2R01MH107435-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10223545. Licensed CC0.

---

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