Mapping somatodendritic circuits of midbrain dopamine neurons

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Project Summary The mesocorticolimbic dopamine (DA) system plays a central role in the acquisition of behaviors reinforced by drugs of abuse. Dopamine neurons in the midbrain substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) innervate a vast number of terminal regions to mediate diverse functions such as locomotion, reward encoding, and motivation. Because DA neurons largely project to a single terminal site, they form distinct non- overlapping populations involved in different functions in predominantly separate circuits. Previous work has shown that DA cells can locally modulate the excitability of neighboring DA neurons via somatodendritic dopamine release, which acts on inhibitory D2 autoreceptors located on the soma and dendrites of DA neurons. This inhibition regulates midbrain dopamine neuron firing and thus regulates the amount and timing of dopamine released at downstream projection sites. Furthermore, recent work has found that somatodendritically released dopamine acts in a localized point-to-point manner, as in synaptic transmission. This evidence and the fact that DA populations form discrete circuits, raises the likelihood that there exists a specific pattern of somatodendritic connectivity between projection-specific DA populations. Because the local circuitry between pre- and post- synaptic DA neurons within the VTA and SNc is unknown, the role of somatodendritic signaling in integrating diverse afferents and shaping output signals to target sites is unclear. Additionally, since glutamatergic inputs drive dopamine neuron burst firing, they regulate both terminal and somatodendritic DA release. The use of drugs of abuse is known to alter glutamatergic inputs on DA neurons, thus studying the pattern of somatodendritic inhibition driven by glutamate inputs could provide insights into circuit mechanisms that can dampen DA signaling and curb the reinforcing properties of drugs of abuse. The goal of this proposal is to determine the local somatodendritic circuitry that modulates the activity of dopamine populations within the midbrain. Aim 1 will examine whether there is specific somatodendritic connectivity between projection-specific DA populations in the SNc and VTA. Aim 2 will examine the pattern of somatodendritic connectivity driven by different glutamatergic inputs to midbrain DA populations. Together, these aims will provide critical information about the circuit organization between midbrain DA neurons and the role of somatodendritic signaling in shaping output signals. In view of the critical role of the DA system in mediating important functions and its role in addiction, it is essential that we have a more complete understanding of the somatodendritic circuitry between dopamine neurons and how these circuits are activated by glutamate inputs.