# Dissecting the role of the gut microbiome on striatal chromatin conformation and drug-seeking behavior

> **NIH NIH F99** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $45,436

## Abstract

Project Summary Pathological substance use disorders are devastating psychiatric illnesses characterized by
patterns of escalating and out of control drug use. These disorders account for profound disability, morbidity
and mortality among patients, while also inflicting incalculable costs on their loved ones and society at large.
Pathological use of stimulants, including cocaine, accounts for a significant proportion of morbidity and fatal
overdose nationwide. Despite tremendous advances in elucidating the molecular changes underlying stimulant
use disorders, there are no FDA-approved pharmacotherapies for their treatment. The largest obstacle to
overcome in treating patients with psychostimulant use disorder is preventing relapse. In recent years, there
has been a growing understanding that the resident population of bacteria in the gastrointestinal tract –
collectively referred to as the gut microbiome – plays a critical role in regulating brain function and behavior.
Extensive research now demonstrates that changes to the gut microbiome can support healthy brain function
and also drive the development of pathological states. In our own lab, we have previously published that acute
depletion of the microbiome can enhance the rewarding effects of cocaine and alter gene expression changes
in the brain. In this proposal, I will investigate how antibiotic-induced depletion of the microbiome affects the
persistence of drug-seeking behaviors in a mouse model of relapse, taking an integrative multi-level approach
to examine changes in striatal reward centers at the epigenetic, transcriptional, and circuit levels. Preliminary
data in Aim 1 (F99) demonstrate that microbiome-depleted mice exhibit increased cocaine-seeking behaviors
following a period of prolonged abstinence. Full transcriptomic RNA-sequencing analysis from the nucleus
accumbens demonstrates that these animals exhibit marked changes in gene expression in important gene
networks known to affect DNA binding, synaptic plasticity, and behavior. Additional analyses demonstrate
decreased permissive histone acetylation in microbiome-depleted mice following cocaine administration,
suggesting that the microbiome affects chromatin structure. Aim 2 (F99) will delve more deeply into the
microbial regulation of the epigenome in response to drugs of abuse by examining chromatin conformation in
specific populations of striatal neurons. This will be accomplished via training in and application of Fluorescent-
Activated Nuclear Sorting (FANS) and Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq).
These studies will be coupled with behavioral analyses to provide mechanistic insight into epigenetic
remodeling underlying drug-seeking behaviors. For Aim 3 (K00) I will identify a postdoctoral mentor to support
my professional development as well as my research examining the effects of the microbiome on firing activity
in striatal neuronal subpopulations using in vivo calcium imaging techniques. T...

## Key facts

- **NIH application ID:** 10319289
- **Project number:** 1F99NS124187-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Katherine Meckel
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $45,436
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319289

## Citation

> US National Institutes of Health, RePORTER application 10319289, Dissecting the role of the gut microbiome on striatal chromatin conformation and drug-seeking behavior (1F99NS124187-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10319289. Licensed CC0.

---

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