# Dissecting PFC Endocannabinoid-THC -regulated circuits in movement behavior

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2022 · $42,459

## Abstract

SUMMARY: Cannabis use in the U.S. has been dramatically increasing from 8.9% in 2016, to 17.5% in 2019,
of U.S. citizens (age 12+) having used Cannabis in the last year. As Cannabis use increases, it is critical that we
understand the biological activity of unwanted effects such as hypolocomotion that inhibit a patient’s ability to
move and function normally. ∆9-Tetrahydrocannabinol (THC), the primary psychoactive compound in THC, acts
as a partial agonist at the endocannabinoid (eCB) receptor, CB1R, to induce motor impairments in mice such as
hypolocomotion and catalepsy. Beyond this, the neural-circuit basis of hypolocomotive responses to THC, and
other CB1R agonists, remains largely unexplored. Using a novel eCB sensor GRAB-eCB2.0, in the prelimbic
cortex (PrL), we observed a correlation between spontaneous movement events and eCB activity transients.
These eCB transients, and replicated GCaMP6f calcium transients, are time-locked to the initiation of movement
and were significantly greater in THC-treated mice compared to vehicle-treated mice. The central hypothesis of
this proposal is that THC activates CB1R’s on select PrL GABAergic interneuron subpopulations, which
disinhibits the glutamatergic activity within the PrL to modulate spontaneous movement. Aim 1 will determine if
select GABAergic subpopulations modulate THC dependent PrL-mediated spontaneous movement. I will utilize
in situ hybridization to probe differential expression patterns of GABAergic interneurons (GABA-IN’s). Combining
GABA-IN-Cre lines with viral techniques and optogenetic electrophysiology, I will investigate the physiological
changes induced by THC. We will measure THC-dependent changes in IPSCs as well as use cutting-edge
techniques to probe the cannabinoid-dependent depolarized suppression of excitation/inhibition (DSE/DSI) in
layers 2/3 to layers 5/6 contralaterally. Aim 2 will utilize fiber photometry of GABA-IN-Cre and VGLUT-Cre
animals expressing cre-dependent GCaMP6f or eCB2.0 to record the specific neuronal activity and eCB levels
of inhibitory and excitatory neurons during spontaneous movement of mice treated with THC and/or one of a
series of pharmacological agents. We will also virally express a CRISPR-CB1R construct to eliminate CB1R from
GABA-IN’s and glutamatergic neurons to determine if THC is able to produce the same changes in neuronal
activity. We hypothesize that select subpopulations of GABA-IN’s mediate the THC-dependent increase in PrL
activity associated with spontaneous movement. To determine the sufficiency of PrL activity in THC treated mice,
GABA-IN’s and glutamatergic neurons will be optogenetically stimulated or inhibited to mediate movement. The
goal of this proposal is to train me to become an independent investigator focused on the neuropharmacology
of neuromodulation, leveraging training in novel approaches to decipher the mechanisms by which THC
modulates prelimbic cortical activity during movement while inducing robust hypolocomotion...

## Key facts

- **NIH application ID:** 10386291
- **Project number:** 1F31DA055448-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Anthony Edward English
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,459
- **Award type:** 1
- **Project period:** 2022-03-16 → 2025-03-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386291

## Citation

> US National Institutes of Health, RePORTER application 10386291, Dissecting PFC Endocannabinoid-THC -regulated circuits in movement behavior (1F31DA055448-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10386291. Licensed CC0.

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