# Functional Implications of Sex Differences in Hippocampal Endocannabinoid Signaling

> **NIH NIH R15** · RAMAPO COLLEGE OF NEW JERSEY · 2022 · $308,000

## Abstract

Endocannabinoids (eCBs) are neuromodulators that affect behavioral phenomena such as cognition, learning,
memory, eating and sex. eCBs are involved in emotional processing and are heavily implicated in regulating
stress and anxiety. There is growing evidence supporting sex differences in the eCB system, whereby females
possess lower levels of the CB1 receptor in several cortical structures compared to males. In previous studies,
we demonstrated that exposure to chronic mild stress 1) differentially altered CB1 receptor levels in the
hippocampus of male and female rats and 2) increased GABAergic CB1 function in males. This suggests that
sex differences in the eCB system may underlie sex differences in response to stress and etiologies of stress-related disorders. For example, there is a 2:1 incidence rate of women diagnosed with stress-related disorders
such as Major Depressive Disorder and Post-Traumatic-Stress-Disorder than men. Importantly, this disparity
in mental disorders is not apparent until adolescence, when maturation of corticolimbic circuitry is critical for
development of appropriate emotional processing and adaptive responses to stress. However, there is
currently a dearth of data regarding the functional (neural plasticity and behavioral) significance of eCB sex
differences. These omissions preclude a complete understanding of both normal eCB function and its role in
the etiology and pathophysiology of neurobehavioral disorders. Our published data show a robust sex
difference of CB1 function at hippocampal dendritic GABAergic synapses whereby female CB1 displays a
higher sensitivity to exogenous activation compared to males. Exploring the mechanisms underlying this
difference, we observe a mixture of constitutive CB1 activity, tonic eCB production and estrogen-mediated eCB
production at adolescent female dendritic synapses. This is consistent with the literature on perisomatic eCB
signaling in females. Importantly, these effects are not reported in similar studies of eCB signaling in males.
We hypothesize that these sex differences across the somatodendritic axis in adolescent hippocampal
pyramidal cells A) translate into functional differences in eCB-mediated synaptic plasticity and B) underlie sex
differences in emotional learning and behavior. Synaptic plasticity experiments involving extracellular field and
whole-cell patch clamp recordings will be performed in CA1 dendritic and perisomatic layers, respectively from
adolescent male and female animals. Emotional behavior will be assessed using a hippocampal-dependent
contextual fear conditioning. These investigations will provide further elucidation of eCB neural and behavioral
function in both sexes. The results may provide insight into the mechanisms of sex differences in emotional
processing and may have implications for understanding the pathophysiology of sex-biased neurobehavioral
disorders.

## Key facts

- **NIH application ID:** 10436407
- **Project number:** 1R15MH129932-01
- **Recipient organization:** RAMAPO COLLEGE OF NEW JERSEY
- **Principal Investigator:** CHRISTIAN G REICH
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $308,000
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436407

## Citation

> US National Institutes of Health, RePORTER application 10436407, Functional Implications of Sex Differences in Hippocampal Endocannabinoid Signaling (1R15MH129932-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10436407. Licensed CC0.

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