Input-specific mechanisms of drug-evoked synaptic plasticity in the ventral tegmental area

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The mesolimbic dopamine (DA) system is composed of DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc). It plays a pivotal role in reinforcement learning and is often considered the center of the brain's reward system. Drugs of abuse such as cocaine, morphine, nicotine and amphetamine have different pharmacological effects, yet they all significantly impact reward and motivation at least in part by activating the mesolimbic DA system. An important research topic over the last decade has been to elucidate how drugs of abuse induce synaptic adaptations of glutamatergic inputs on VTA DA neurons. This body of work has led to the well-accepted theory that addiction is an aberrant form of learning and memory. In particular, a single injection of cocaine induces a strong and long-lasting (> 3 weeks) potentiation of excitatory inputs on DA neurons projecting to NAc medial shell. However, so far the origin of these inputs remains unknown due to major technical limitations. In recent years, state-of-the-art combinations of viral tracing methods and optogenetic tools made it possible to fully map the functional connectivity of the mesolimbic circuitry. As the result of these efforts, the next important step in addiction research is to identify specific inputs to mesolimbic DA neurons that are susceptible to drug-evoked synaptic plasticity. We hypothesize that different inputs to the VTA participate in related but independent circuits that are differentially modulated by drugs of abuse. To assess input-specific effects of cocaine-evoked synaptic potentiation, we will employ a multidisciplinary approach combining synaptic electrophysiology, viral tracing, immunohistochemistry and in vivo and ex vivo optogenetic experiments in mice. Because drug- evoked synaptic plasticity may contribute to addictive behaviors we will also investigate if optogenetic manipulations of specific VTA afferents promote or suppress drug-adaptive behaviors (e.g., cocaine-induced locomotor sensitization, cocaine-induced conditioned place preference). Given that the VTA is a major site of action of addictive drugs, and DA neurons projecting to NAc medial shell are particularly prone to undergo long-lasting drug-evoked synaptic adaptations, selective manipulations of inputs to these cells will provide a more comprehensive understanding of the precise nature of circuit remodeling caused by addictive drugs. Outcomes of this study may reveal important information for the development of more effective treatments of substance abuse and other mental disorders.