Drug abuse is a major global problem with often devastating societal consequences. While therapeutics designed to treat drug addiction have focused on medicinal intervention with concurrent behavioral therapy, much progress remains to be made in reducing this major social and economic burden. Many drugs of abuse work on the dopamine (DA) pathway in the brain, which is normally activated by neurons in the ventral tegmental area (VTA) that function, in part, to signal reward. However, DA neurons are not a homogenous population, but rather are composed of multiple subtypes with distinct functions. Two of the major projection sites of these VTA neurons, the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), are also brain regions strongly implicated in addiction. While existing data suggest that the NAc-projecting population is unique from the mPFC-projecting population, little is known about how these populations are distinct; what brain areas differentially activate these distinct populations remains a mystery. To date, it has been difficul to study the detailed connectivity within the VTA, as multiple neuron types are intermingled within the VTA, and existing technologies do not permit genetic access to specific subtypes of neurons. Using a new rabies virus- based transsynaptic tracing approach, I will construct a detailed input-output map of VTA DA neuron subpopulations. Once the detailed connectivity has been established, I will examine the synaptic properties of a subset of these connections, and will compare these against all excitatory inputs onto the same neurons. Lastly, I will examine the ways in which these synapses are altered in response to a rewarding or aversive stimulus. These data will allow for the identification of the exact loci and mechanisms of plasticity occurring on specific VTA DA neuron subpopulations. This knowledge would permit highly targeted disruptions of these synaptic changes, ultimately allowing us to assess the contribution of input-specific synaptic plasticity to drug- related behaviors. In the future, these analyses can be combined with behavioral studies to analyze the role of these specific synapses in drug addiction and relapse.
Most major drugs of abuse increase dopamine (DA) release into multiple structures in the brain, including forebrain structures such as the nucleus accumbens and the medial prefrontal cortex. Understanding the neuronal circuitry that controls DA release into the nucleus accumbens and the medial prefrontal cortex, and identifying the specific synapses that undergo changes with experience will lead to a better understanding of how to treat and prevent drug abuse and relapse.
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