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.