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Principal Investigator: Mary Kay Lobo
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2024
Award: $525,941
Funding agency: National Institute on Drug Abuse
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.
Terms: <Adeno-Associated Viruses><Affect><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Basal Transcription Factor><Basal transcription factor genes><Behavior><Binding><Brain><Brain Nervous System><CNS plasticity><CRISPR><CRISPR/Cas system><CUT&RUN><Cell Body><Cell Nucleus><Cells><Chromatin><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clustered Regularly Interspaced Short Palindromic Repeats><Cocaine><Common Rat Strains><Cornu Ammonis><Dendrites><Dependoparvovirus><Dependovirus><Disease><Disorder><Dopamine><Dopamine Receptor><Drug abuse><Drugs><Dyn1><Dynamin D100><Dynamin DNM1 Gene Product><Dynamin I><Dynamin-1><Encephalon><Exposure to><Foundations><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic><Genetic Transcription><Globus Pallidus><Growth><Hippocampus><Hydroxytyramine><Intake><Intravenous><Label><Medial><Mediating><Mediator><Medication><Mice><Mice Mammals><Mitochondria><Modeling><Molecular><Molecular Interaction><Monitor><Motivation><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuronal Plasticity><Neurons><Nuclear><Nucleus><Nucleus Accumbens><Optics><Output><Pharmaceutical Preparations><Prefrontal Cortex><Process><Proteins><Proteomics><RNA Expression><Rat><Rats Mammals><Rattus><Recurrent disease><Regulation><Relapsed Disease><Rewards><RiboTag><Ribosomes><Role><Self Administered><Self Administration><Substance Use Disorder><Synapses><Synaptic><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription Process><Transcription factor genes><Ventral Tegmental Area><Viral><Work><abuse of drugs><abused drug><abused drugs><abuses drugs><adeno associated virus group><amygdaloid nuclear complex><behavior response><behavioral response><brain reward regions><cell type><central nervous system plasticity><cocaine exposure><cocaine seeking><cocaine self-administration><cocaine-exposed><drug abused><drug of abuse><drug seeking behavior><drug/agent><drugs abused><drugs of abuse><epigenome><exposed to cocaine><exposure to cocaine><exposure to psychostimulants><exposure to stimulants><genetic approach><genetic strategy><global gene expression><global transcription profile><high throughput analysis><hippocampal><lipidomics><metabolism measurement><metabolomics><metabonomics><mitochondrial><multiomics><multiple omics><nano-string><nanostring><neural plasticity><neuronal><neuronal circuit><neuronal circuitry><neuroplastic><neuroplasticity><ontogeny><optical><pallidum><panomics><prevent><preventing><psychostimulant exposure><response><reward circuitry><self-administer cocaine><sensor><social role><stimulant exposure><substance use and disorder><synapse><tool><transcription factor><transcriptome><transcriptomics><ventral tegmentum>