Long-range and local connectivity of cholinergic interneurons in the nucleus accumbens

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PROJECT SUMMARY The nucleus accumbens (NAc) is a critical center for controlling reward-related and motivated behaviors, and becomes disrupted in neuropsychiatric disorders such as drug addiction and depression. The NAc consists of a core (NAcCore) and surrounding medial shell (NAcMS), each of which integrates distinct excitatory inputs from a wide range of brain areas. These NAc subregions contain a variety of cells, most of which are GABAergic, with the exception of cholinergic interneurons (CINs). Through the release of acetylcholine, CINs can powerfully modulate the local network to impact the output of the NAc. However, the ability of CINs to receive and process different long-range excitatory inputs is largely unexplored in the NAc. To understand the circuit mechanisms of normal and pathological behavior, it is necessary to study the synaptic organization of CINs in the NAc in a subregion- and input-specific manner. Here I use a combination of viral tracing methods, slice electrophysiology, and optogenetics in transgenic mice to establish the synaptic organization of CINs in the NAc. Aim 1 will identify which brain regions and local striatal cells synapse onto CINs in both the NAcMS and NAcCore. Aim 2 will assess how different types of long-range inputs contact and influence the firing of CINs in each NAc subregion. Aim 3 will test how different GABAergic interneurons mediate feed-forward inhibition of CINs to regulate their activity. Together, these experiments will provide critical insights into the synaptic organization of CINs within the NAc and how different inputs drive unique patterns of activity. This work is necessary for understanding how the NAc integrates converging inputs containing information about motivational drive, reward value, and attention, and ultimately how the circuitry of this key reward center is disrupted in neuropsychiatric disorders.