Mitochondrial regulation of structural plasticity in ventral hippocampus-nucleus accumbens projection neurons and cocaine seeking after prolonged abstinence from self-administration

The National Institute on Drug Abuse awarded the University of Maryland, Baltimore $153,560 under the Drug Use and Addiction Research Programs (CFDA 93.279) on November 30, 2026, as a Project Grant (F32DA066191).

The award funds research investigating how mitochondrial regulation influences structural plasticity and cocaine-seeking behavior in ventral hippocampus-nucleus accumbens projection neurons following prolonged abstinence from intravenous cocaine self-administration. The research addresses relapse vulnerability in cocaine use disorder by examining mitochondrial dynamics—the balance of fission and fusion processes—in upstream brain regions projecting to the nucleus accumbens and their contribution to long-lasting neuronal adaptations and drug-seeking behavior after extended periods of abstinence.

Performance occurs in Baltimore, Maryland, with a period of performance through May 31, 2029.

Abstract

Cocaine use disorder is a chronic, relapsing condition that imposes significant personal and societal costs. A central challenge in treating this disorder is the enduring risk of relapse, which can persist even after extended periods of abstinence. Relapse is often triggered by environmental cues associated with prior drug use. These behavioral vulnerabilities are driven by long-lasting changes in brain circuits involved in memory, motivation, and reward. The ventral hippocampus (vhippo), which provides excitatory input to the nucleus accumbens (NAC), plays a crucial role in linking contextual memories to drug-seeking behavior. Evidence suggests that mitochondrial health and function in reward brain regions are essential for neuronal adaptations associated with substance use disorders, among other psychiatric illnesses. Mitochondria are highly adaptable organelles that respond to cellular needs by undergoing continuous cycles of fission and fusion. Recent evidence suggests that mitochondrial dynamics, the balance of fission and fusion processes, regulate synaptic plasticity in the NAC dopamine receptor 1 medium spiny neurons (D1-msns) after repeated cocaine exposure, and increase drug- seeking behavior after an acute period of abstinence. Yet, whether and how mitochondrial adaptations in upstream regions that project to the NAC contribute to vulnerability remains unknown. This proposal aims to determine how mitochondrial machinery in vhippo-NAC projection neurons influences structural plasticity and cocaine seeking following prolonged abstinence from intravenous self-administration. A wide body of literature demonstrates altered glutamatergic excitatory transmission into the NAC. Circuit-based studies uncovered altered plasticity at vhippo-NAC D1-MSN synapses. However, how mitochondrial mechanisms occurring in vhippo-NAC projection neurons influence long-lasting plasticity adaptations and drug seeking after prolonged abstinence is unknown. I hypothesize that prolonged abstinence from cocaine intravenous self- administration alters mitochondrial morphology and gene expression in the vhippo-NAC projection neurons, leading to enduring plasticity that drives cocaine-seeking behavior. To test this hypothesis, aim 1 will use a projection-specific viral approach to visualize and manipulate mitochondrial fission by knocking down its regulator, DRP1, and examining the effects on mitochondrial morphology, dendritic spine structure, and cocaine-induced reinstatement. Using a ribotag system, aim 2 will employ cell-type-specific RNA sequencing to identify transcriptomic changes in mitochondrial genes within vhippo-NAC projection neurons following reinstatement. Together, these studies will define how cocaine alters mitochondrial structure, function, and gene expression in a relapse-relevant circuit and may identify novel targets for the treatment of substance use disorders.