# Cell-Type Selective Transcriptional and Mitochondrial Control of Drug Seeking

> **NIH NIH K01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $169,474

## Abstract

Substance use disorders comprise chronic cycles of drug use, abstinence, and relapse driven by drug-induced
transcriptional and circuit adaptations in the brain. Despite consistent evidence that epigenetic chromatin
modifications drive these long-term neuronal adaptations, successful druggable treatment targets have not
emerged, and further understanding of mechanistic pathways from the epigenome to altered behavior are
needed for novel substance use disorder therapies. This proposal examines the link between epigenetic
processes, including histone deacetylase (HDAC) function and chromatin accessibility, and mitochondrial
morphology and function in the context of nicotine reinforcement learning to bridge this gap. Use of nicotine, the
primary psychoactive component of both tobacco and e-cigarettes, alters brain reward pathways, including inputs
to spiny projection neurons (SPNs) of the nucleus accumbens (NAc). The subsequent transcriptional and
morphological changes in these SPNs support electrophysiological activity driving cue-induced craving and drug-
seeking behaviors that make smoking cessation difficult and contribute to nicotine use disorder. Understanding
how drugs such as nicotine induce lasting molecular adaptations and alter the functioning of NAc SPNs is critical
in untangling the local mechanisms promoting persistent drug use and relapse. SPN mitochondria stand out as
an unexplored but likely regulator of NAc SPN adaptations to nicotine, mediating plasticity downstream of
epigenetic genome modifications. This proposal uses cutting edge cell-type selective techniques to examine how
both nicotine and HDAC inhibitors alter mitochondrial morphology and function, as well as individual SPN gene
expression and chromatin accessibility, to provide a new mechanistic understanding of nicotine-reward. Using a
mouse model of nicotine intravenous self-administration (IVSA) and drug seeking, I will measure NAc
mitochondrial respiratory capacity then will assess dendritic, spine, and mitochondrial morphology in the two
main SPN populations in NAc (D1- and D2-dopamine receptor containing SPNs). I will also examine these end
points after inhibition of multiple classes of HDACs, determining if nicotine’s effects on mitochondria are related
to nicotine’s function as an HDAC inhibitor. Parallel single nuclei RNA and ATAC sequencing will identify
molecular adaptations in individual NAc cell types after nicotine IVSA. Finally, after identifying and validating
molecular targets regulating transcriptional programs within in SPN cell types, I will disrupt the endogenous
mitochondria adaptations to IVSA nicotine with cell-type selective CRISPR activation or interference (CRISPRa/i)
manipulations. These studies will inform the relationship between drug-induced epigenetic modifications and
downstream mitochondrial functioning, a potential intermediary to morphological and electrophysiological
plasticity in response to rewarding drugs. In addition to providing tr...

## Key facts

- **NIH application ID:** 10948415
- **Project number:** 1K01DA061048-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Cali Ann Calarco
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,474
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948415

## Citation

> US National Institutes of Health, RePORTER application 10948415, Cell-Type Selective Transcriptional and Mitochondrial Control of Drug Seeking (1K01DA061048-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10948415. Licensed CC0.

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