Learned associations between environmental contexts and experience are the basis of decision-making and allow organisms to guide behavior towards advantageous outcomes. Dysfunction in the neuronal processes that regulate these associations, especially in the nucleus accumbens (NAc), is a critical factor in the pathology of addiction. The NAc is a heterogeneous region primarily composed of two opposing cell types: D1 and D2 medium spiny projection neurons (MSNs). Optogenetic stimulation of these cells results in divergent behavioral outputs; thus, it is important to study these populations in isolation to understand the cell-type specific signals that underlie NAc-mediated learning processes. Under the primary mentorship of Dr. Eric Nestler and Dr. Paul Kenny at Icahn School of Medicine at Mount Sinai in New York, the Pathway to Independence Award will provide the opportunity to build on my expertise in cocaine self-administration and synaptic function while simultaneously developing my training and expertise in in vivo calcium imaging and optogenetics. In the mentored K-phase of this grant fiber photometry calcium imaging will be paired with cocaine self-administration in transgenic mouse lines that express Cre-recombinase in D1 or D2 MSN populations. These mice allow for cell-type specific expression of molecular targets, such as calcium indicators (GCaMP6f) and opsins (ChR2; NpHR). By expressing GCaMP6f in D1 or D2 MSNs, the temporally specific signals that mediate cue-induced cocaine seeking will be determined. Further, optogenetic stimulation and inhibition will allow for direct manipulation of these cells and the associated seeking behavior. The innovative combination of these tools will enable the mapping of how D1 and D2 MSNs encode cue information and concurrently establish causality. In the independent phase (R00), these cutting-edge techniques will be combined with the inducible ArcCreERT2 mice which express constructs (GCaMP6f/Opsins) selectively in cells that are activated by environmental stimuli during a temporally specific window. This will allow for the recording and manipulation of neuronal ensembles that are activated by cocaine or cocaine-paired cues to determine their role in drug seeking. Together, these data will elucidate the underlying neural processes that control associative learning and how cocaine exposure dysregulates MSN signaling to drive relapse following abstinence, which will expand our basic understanding of addiction and may lead to the development of novel therapeutic avenues. In summary, the research proposed in this Pathway to Independence Award will elucidate the neural mechanisms involved in addiction while simultaneously preparing me to develop a fully independent research program capable of integrating a wide range of circuit based and behavioral approaches to dissect the neurobiology of addiction. .
Drug abuse and addiction are syndromes that severely damage the lives of affected patients and their families, and constitute a major public health concern in the United States. Cocaine addiction is characterized by cycles of drug binges followed by abstinence and subsequent relapse; thus, pharmacological interventions that reduce cocaine craving and drug seeking during the abstinence period are ideal for preventing relapse. By studying cocaine self-administration, a paradigm that models chronic cocaine abuse in humans, we will be able to determine the neurochemical consequences of cocaine abuse and withdrawal in an attempt to develop novel pharmacotherapies to combat cocaine addiction and improve treatment outcomes in cocaine addicts.
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