Cocaine-induced mitochondrial mechanisms and molecular mediators in reward circuitry

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Project Summary: Drug abuse is a debilitating relapsing disease characterized by compulsive drug seeking and use despite negative personal consequences. Repeated exposure to drugs of abuse is accompanied by persistent alterations in molecular processes, including alterations in transcription factors that regulate altered neuronal plasticity and function, which underlie the persistent behavioral responses associated with substance use disorder. Recent work demonstrates that mitochondrial processes can play a role in neuronal plasticity mechanisms. We uncovered a role for mitochondria fission and its molecular mediator, Drp1, in mediating plasticity adaptations in nucleus accumbens (NAc) D1 expressing medium spiny neurons (D1-MSNs). Further, Drp1 and fission are necessary for cocaine seeking-behavior. Despite these initial studies there is still a large deficit in our understanding into how mitochondrial processes integrate into circuit adaptations across brain reward regions that occur with psychostimulant exposure. Moreover, there is poor understanding of the upstream transcriptional processes that regulate molecules mediating mitochondrial function in brain reward regions. Our studies will bridge this gap by investigating the impact of cocaine intravenous self-administration (IVSA) on (1) the excitatory inputs to NAc that regulate mitochondrial processes in MSN subtypes and their influence on drug seeking behavior, (2) the impact of mitochondrial fission in D1-MSNs on NAc output regions, and (3) explore mitochondrial molecules and processes, and their upstream transcriptional regulators, in NAc MSN subtypes and their input and output regions. To do these we employ AAV intersectional tools to manipulate or label NAc input and output neurons while also targeting NAc MSNs in cocaine IVSA. We use chemogenetic approaches to examine the impact of NAc excitatory inputs on mitochondrial dynamics and molecular mediators in NAc MSN subtypes. We further examine the interaction between excitatory inputs and mitochondrial fission in D1-MSNs on drug seeking behavior. We also examine the impact of mitochondrial fission in D1-MSNs on ventral pallidum (VP) and ventral tegmental area (VTA) output regions in IVSA at the level of drug seeking behavior, dopamine dynamics, and molecular adaptations. Finally, we perform a large scale profiling across reward circuit neurons after IVSA of mitochondrial dynamics, mitochondrial molecular mediators and transcriptional regulators, and mito-omics. We further, use CRISPR epigenome tools to characterize cocaine- mediated transcription factor regulation of mitochondrial dynamics and mitochondrial molecular mediators across reward circuit neuron subtypes. Collectively our studies will provide a foundation for the impact of cocaine on mitochondrial processes and molecular mediators in reward circuitry.