# Regulation of Gene Expression in the Human Habenula in Comorbid Opioid Addiction and Depression

> **NIH NIH R01** · LIEBER INSTITUTE, INC. · 2022 · $667,421

## Abstract

PROJECT SUMMARY/ABSTRACT
Drug addiction is highly comorbid with neuropsychiatric disorders, especially major depressive disorder (MDD).
Both conditions are moderately heritable and exacerbated by environmental factors, particularly stressful life
events, suggesting combined genetic and epigenetic liability. Furthermore, both illnesses feature dysregulation
of dopaminergic (DA) and serotonergic (5HT) systems modulating motivation and cognitive function. The
habenula (Hb) is one of the few brain regions controlling both DA and 5HT systems and is a highly organized
central node for reward circuits governing motivated behavior and affective states. Hb dysfunction is
associated with impaired mood regulation and substance use disorder (SUD), but the genetic and epigenetic
mechanisms mediating this dysfunction are unknown. Given the close relationship between brain structure
and function, assigning gene expression to functionally distinct anatomical subdivisions and cell populations
within the human Hb would significantly advance our understanding of how Hb dysregulation contributes to
neuropsychiatric disorders and SUD. Towards this end, we propose to employ 10x Genomics Multi-ome and
Visium technologies to generate corresponding single cell and spatial molecular reference maps of human Hb
to identify genetically-defined and topographically-organized cell types across medial and lateral subdivisions
of this brain region. We will also generate transcriptomic data from homogenate human Hb in patients with
MDD and comorbid MDD/opioid use disorder (OUD), and contrast these gene expression patterns to those
derived from matched neurotypical controls. We will integrate complimentary topographic and cell type-
specific reference maps with homogenate data from patients with depression and addiction to implicate
specific Hb cell populations and subregions in illness state and genetic risk for these highly comorbid
conditions. By generating the first molecular neuroanatomical atlas of the human habenula, we will facilitate
refined annotation of cell types with brain architecture in a key integration hub of brain reward circuitry that can
be targeted for prevention and treatment of debilitating neuropsychiatric and substance use disorders.

## Key facts

- **NIH application ID:** 10422281
- **Project number:** 1R01DA055823-01
- **Recipient organization:** LIEBER INSTITUTE, INC.
- **Principal Investigator:** Kristen Rose Maynard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $667,421
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10422281

## Citation

> US National Institutes of Health, RePORTER application 10422281, Regulation of Gene Expression in the Human Habenula in Comorbid Opioid Addiction and Depression (1R01DA055823-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10422281. Licensed CC0.

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