# Heroin-Induced genomic regulation of Ventral Pallidum neuron subtypes

> **NIH NIH U01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2022 · $593,255

## Abstract

PROJECT SUMMARY/ABSTRACT
Opioid use, dependence, and addiction have dramatically increased to epidemic proportions in recent years,
leading to substantial financial and societal health burdens, as well as an increasing number of overdoses. To
combat this epidemic, it is imperative that we understand the neurobiological underpinnings that lead to opioid
use disorder. We must identify disrupted neuron subtypes in the brain in opioid use disorders and dysregulated
molecules within these neurons that underlie cellular, circuit, and ultimately behavioral adaptations. Use of rat
drug self-administration (SA) and relapse assays, which are considered the best available animal models of
addiction, will allow a more complete understanding of the molecular mechanisms underlying the genomic,
epigenetic, and transcriptional-induced cellular plasticity that drives the long-lasting drug seeking and propensity
for heroin relapse.
We will perform genome-wide transcriptome and open-chromatin profiling of ventral pallidum (VP) projection
neuron subtypes in rat heroin SA, both acutely following drug cessation and after prolonged periods of drug
abstinence. Here, we focus on the VP as a critical node in the brain’s reward circuit. Our studies will profile VP
neurons that project to the nucleus accumbens, ventral tegmental area, medial dorsal thalamus, and lateral
habenula. We will then integrate the transcriptomic and epigenomic data with complementary transcriptomic and
epigenomic datasets, including multimodal data from the BRAIN Initiative describing cell type diversity in the VP
and its output circuits. We will reconstruct cell type-specific gene co-expression and open chromatin networks
and identify hub genes predicted to have central roles in immediate and prolonged abstinence from heroin, which
could underlie subsequent relapse behavior. This collection of datasets and models will be made available
through a biologist-friendly web portal based on our BRAIN Initiative-funded Neuroscience Multi-Omic Analytics
platform.
Using the data generated we will develop rat gene loci-specific CRISPR epigenomic targeting tools to determine
the functional significance of key hub genes that are regulated in VP projection neuron subtypes. To achieve this
goal, we will employ rat models of relapse in combination with advanced CRISPRa and CRISPRi AAV tools to
enhance or reduce transcription of key hub genes during heroin SA or abstinence from heroin SA followed by
cue-induced reinstatement. The studies proposed in this grant application will, for the first time, identify the
distinct heroin-induced gene network adaptations occurring temporally in a cell-type-specific manner within a
novel neurobiological circuit.

## Key facts

- **NIH application ID:** 10404982
- **Project number:** 5U01DA051947-03
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Seth Abrams Ament
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $593,255
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404982

## Citation

> US National Institutes of Health, RePORTER application 10404982, Heroin-Induced genomic regulation of Ventral Pallidum neuron subtypes (5U01DA051947-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10404982. Licensed CC0.

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