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.

Grant Number: 1R21DA064023-01
NIH Institute/Center: NIH
Principal Investigator: Adam Carter