# The Impact of Early Life Adversity on mGluR5-driven Endocannabinoid Signaling and Behavioral Adaptability

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $45,563

## Abstract

PROJECT SUMMARY
 In the United States, early-life adversity (ELA) is frequently reported and is strongly linked to later-life repercussions.
Research highlights a significant association between neuropsychiatric disorders and adverse or traumatic events during
early life, indicating ELA as a potential common root cause. This association has been identified as a precursor to various
neuropsychiatric disorders, including anxiety, depression, and addiction. These conditions are of considerable global
concern, as they not only diminish overall quality of life but also have adverse effects on societal functioning.
 A pivotal aspect of ELA involves stress and the processing of sensory signals during early stressful events. These signals
undergo decoding by cortical layers in the brain, subsequently being transmitted to midbrain regions responsible for
regulating behavioral responses. The dorsal striatum plays a central role in this process by processing cortical inputs and
establishing connections with key brain regions that influence behavioral adaptability. Our recent research has unveiled
functional impairments in corticostriatal synapses in adult mice following ELA. Specifically, we observed a decrease in
glutamate release from the anterior cingulate cortex to the dorsomedial striatum in male ELA mice, contrasting with an
increase in females. Furthermore, males exposed to ELA displayed behavioral inflexibility, while females exhibited no
impairments. This represents the first direct functional evidence of the impact of ELA on this brain circuit. The current
proposal will focus on this circuit and evaluate the potential mechanism underlying ELA.
 Previous findings revealed increased metabotropic glutamate receptor 5 (mGluR5) expression after ELA, however, their
role in ELA-induced effects on corticostriatal synapses and behavioral adaptability remains unknown. Our pilot study
revealed that ELA disrupts mGluR5-mediated synaptic transmission (i.e., depolarization-induced suppression of excitation,
DSE). Based on our published and pilot work, our central hypothesis is that ELA elevates mGluR5 activity and expression,
disrupting dorsomedial striatum (DMS)-mediated functions. We aim to demonstrate this by investigating mGluR5's impact
on ELA-induced impairments and its potential rescue through mGluR5 inactivation. Understanding these ELA-induced
effects on corticostriatal synapses is crucial, as it sheds light on the potential development or progression of psychiatric
disorders. The contrast in glutamate release and behavioral responses between genders emphasizes the need to further study
this brain circuit to intervene effectively and mitigate the risk of psychiatric disorders. The proposed studies will address
critical gaps in understanding ELA-induced impairments, offering potential targets for treatment.

## Key facts

- **NIH application ID:** 10996963
- **Project number:** 1F31MH138115-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Gregory de Carvalho
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,563
- **Award type:** 1
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996963

## Citation

> US National Institutes of Health, RePORTER application 10996963, The Impact of Early Life Adversity on mGluR5-driven Endocannabinoid Signaling and Behavioral Adaptability (1F31MH138115-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10996963. Licensed CC0.

---

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