Psychostimulants target dopamine neurons, acting principally at the dopamine transporter. Ensuing actions in the postsynaptic striatal circuitry mediate both the acute behavioral response to the drug as well as longer-term neuroplastic changes associated with addiction. Extensive work has focused on dopamine release and on the actions of dopamine, but only recently with the advent of optogenetics have dopamine neuron synaptic actions become directly accessible to study. Optogenetics enables a functional connectome approach to determining dopamine neuron synaptic actions. In this approach, channelrhodopsin 2 is expressed comprehensively in an identified population of neurons and the sum total of the connections of the population of neurons onto identified target neurons measured to determine a functional connectivity index comprising the incidence of connections and their strength. Determining the functional connectome of striatal spiny projection neurons - the principal postsynaptic targets of dopamine neurons - has provided quantitative measures of functional connectivity, going beyond anatomical data to direct measures of synaptic strength. While spiny projection neurons appear to signal solely via GABA, dopamine neurons signal via dopamine as well as glutamate and GABA, and differentially target striatal neurons in different striatal regions. Dopamine neurons make robust glutamatergic synaptic connections with cholinergic interneurons in the ventral striatum, specifically in the medial shell of the nucleus accumbens that appear to be critically involved in mediating the acute behavioral response to amphetamine. A single low dose of amphetamine, which engenders motoric stimulation, significantly and selectively attenuates these glutamatergic connections. In contrast, a high amphetamine dose, which engenders stereotypic behavior, broadly attenuates dopaminergic connections throughout the striatum. This motivates the hypothesis that amphetamine-induced plasticity of specific populations of dopamine neuron synapses is critical for driving the striatal circuitry towards the addicted state. To address this hypothesis, the three specific aims are to: <1> Determine the dopamine neuron functional connectome in the striatum, mapping the synaptic actions of dopamine neurons across the striatum. <2> Determine how amphetamine modulates the dopamine neuron functional connectome following a single exposure, examining regional heterogeneity, and the timing and persistence of the modulation. <3> Determine the role of the most affected connections, as crucial mediators of amphetamine circuit and behavioral effects. Expressing amphetamine-induced actions in functional connectome terms enables a systematic synapses-to-circuits-to-behavior approach to elucidating the synaptic substrate of amphetamine action and the inception of addiction.
Dopamine neurons are the molecular target of amphetamine action. We will map their synapses to identify those most affected by amphetamine exposure. Then, in freely behaving mice we will modulate the most affected synapses to demonstrate their role in amphetamine-dependent behavior and as a treatment approach to addiction.
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