Dissecting circuit- and stage-specific neural adaptations in an animal model of drug addiction

University Of California, San Diego, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): Progressive stages of drug addiction are well defined by clinical observations and animal behavior experiments. Recognizing these stages of progression comes largely from observing outward signs of addicted behaviors. What is missing from understanding stages of drug addiction is the knowledge of neural circuits responsible for stage-specific symptoms. Many studies suggested that distinct cell types in nucleus accumbens (NAc) plays different roles in the drug addiction. However, the detailed circuit organization of different cell types in NAc and associated brain areas has not been fully elucidated. Moreover, how other brain areas engaged to modulate different subpopulations of neurons in NAc during the progression into drug addiction has not been systemically analyzed. This is partly because we lack the efficient methods to monitor the neural adaptation in circuit-specific manners in different brain areas at the same time as stages progress towards addiction. Using cocaine addiction in mice as a model system, I propose a new paradigm for studying drug addiction by monitoring the neural adaptation in brain circuitries related to different cell types in NAc during each stage of addiction progression. To achieve this, we use a monosynaptic rabies virus system expressing fluorescent marker or synaptic markers to generate brain-wide maps of neurons that form synapses with different cell types in NAc. First, we will elucidate afferent connections to different cell types in NAc in whole brain. Second, we will examine the dynamics of structural plasticity and synapses in different brain areas projecting to each cell type of NAc t the different stages of cocaine addiction at the same time in the same brain. By this means we will fill in some of the most important information missing in cocaine addiction research: which neural circuits engage, and what modifications do they undergo from stage to stage as addiction progresses? Understanding drug-induced circuit level modifications at different stages of addiction will provide a valuable framework for guiding future studies on drug addiction as well as the roles of reward circuitry, which eventually lead to develop better therapeutic strategy for this mental disorder. Furthermore, the approach used here for the anatomical and functional characterization of neural circuitry can be used to investigate models of any neuropsychiatric or neurodegenerative disease that progresses in stages.