# Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $427,962

## Abstract

PROJECT SUMMARY / ABSTRACT
Cannabis use continues to be high among adolescents and is increasing in young adults. This is a significant
public health issue as heavy cannabis use during this period is linked to an increased risk for developing
affective, addictive, or psychotic disorders later in life. Adolescence and early adulthood are also when the
prefrontal cortex (PFC), which plays a key role in executive function and working memory, is maturing.
Interestingly, psychiatric disorders seen following early cannabis use often involve the PFC and deficits in
executive function are common in these disorders. This suggests that adolescent cannabis use disrupts PFC
maturation, impairing working memory/executive function and increasing risk for later psychiatric disorders.
This hypothesis is supported by functional imaging studies of individuals who heavily used cannabis during
adolescence that have identified defects in functional connectivity between PFC and several brain regions.
Thus, cannabis use may cause miswiring of PFC circuits, increasing the risk for psychiatric disorders.
To better understand the consequences and mechanisms of cannabis use during adolescence and early
adulthood, we model this process in rodents by adolescent administration of Δ-9-tetrahydrocannabinol (THC),
the primary intoxicating component of cannabis. These studies robustly demonstrate enduring deficits in PFC-
mediated behaviors following adolescent THC that are lacking if similar doses of THC are given to adults,
emphasizing a specific window of vulnerability. Our preliminary data investigating potential mechanisms have
identified three, likely-interrelated processes. The first is that adolescent THC treatment decreases projections
from the mediodorsal thalamus to the medial PFC (mPFC). The second is that adolescent THC treatment
causes neuroinflammation, including increased IL-6 and activated microglia. The third is that co-treatment with
cannabidiol prevents the behavioral and neuroinflammatory effects of adolescent THC. In the proposed
studies we will investigate the mechanisms underlying these findings and evaluate mechanism-based potential
therapies to reverse the behavioral and cognitive abnormalities caused by adolescent THC.
We propose to develop a mechanistic understanding of the consequences of adolescent cannabis use by
combining molecular, anatomical, electrophysiological, and behavioral approaches to complete three aims:
Aim 1. Test the hypothesis that CB1 receptors are required for the detrimental effects of adolescent
THC on working memory and evaluate potential therapies to reverse these deficits.
Aim 2. Test the hypothesis that adolescent THC exposure reduces MD thalamus/mPFC connectivity to
impair working memory.
Aim 3. Test the hypothesis that adolescent THC activates microglia to excessively prune mPFC inputs
from the MD thalamus to impair working memory.

## Key facts

- **NIH application ID:** 10795045
- **Project number:** 5R01DA053746-03
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** HUI-CHEN LU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,962
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795045

## Citation

> US National Institutes of Health, RePORTER application 10795045, Mechanisms and treatment of adolescent phytocannabinoid impairment of prefrontal cortex function (5R01DA053746-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10795045. Licensed CC0.

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