Synaptic organization of cholinergic interneurons in the nucleus accumbens - PROJECT SUMMARY The nucleus accumbens (NAc) is part of the ventral striatum, plays a key role in motivated behaviors, and is disrupted in substance use disorder. Almost all striatal cells are GABAergic, with the exception of cholinergic interneurons (CINs), which represent only 1% of the total population. CINs are the only source of acetylcholine in the striatum, which regulates other cell types, synaptic connections, and neuromodulators. Recent studies have highlighted the importance of CINs and acetylcholine modulation in both the function and dysfunction of the NAc. However, most of what we know about the local and long-range connections onto these cells comes from work in the dorsal striatum. For example, cortical and thalamic inputs show markedly different short-term dynamics and have distinct influences on the firing of CINs. Recent work from our lab in the NAc medial shell (NAcMS) shows CINs receive very different long-range excitatory and local inhibitory inputs. For example, hippocampal and thalamic inputs are excitatory, but can also activate local interneurons that mediate feed- forward inhibition. However, little is known about the equivalent connectivity onto CINs in the NAc core (NAcCore), which has different behavioral roles and distinct inputs and outputs. Here, we characterize how diverse excitatory and inhibitory inputs contact CINs in the NAcCore and influence their firing. We use a combination of anatomy, slice electrophysiology, and optogenetics to examine synaptic connectivity and function in the mouse brain. In Aim 1, we use cell-type specific retrograde anatomy to identify which cells in the local circuit and other brain regions synapse onto CINs. Our preliminary data indicate a variety of input structures, including long-range inputs from prefrontal cortex, midline thalamus, and ventral pallidum. In Aim 2, we use slice electrophysiology and optogenetics to focus on how long-range inputs contact and influence CINs. Our preliminary data suggest long-range inputs can have markedly different properties, including cortical and thalamic excitation, as well as ventral pallidal inhibition. In Aim 3, we explore how long-range excitatory inputs engage GABAergic interneurons that in turn contact CINs and mediate feed-forward inhibition. Our recent results suggest that local inhibitory circuits can be very different between the dorsal and ventral striatum. Together, our experiments will provide important information about how CINs integrate and process a variety of excitatory and inhibitory inputs. Our results will help explain how this important class of interneurons participates in their local and long-range circuits to guide motivated behaviors and become disrupted in mental health disorders.
