Differential cortical and thalamic engagement of cholinergic interneurons in the nucleus accumbens core

Cholinergic interneurons (CINs) in the nucleus accumbens (NAc) play a key role in regulating motivated behaviors. Here we examine the connectivity and functional impact of cortical and thalamic inputs onto CINs in the NAc core of mice of either sex. We first use cell-type specific retrograde anatomy to identify the prefrontal cortex and thalamus as putative afferents. We then combine ex vivo slice physiology and optogenetics to characterize the properties of synapses onto CINs. We demonstrate that thalamic inputs strongly facilitate, whereas cortical inputs exhibit marked depression. We also show that a combination of AMPA and NMDA receptors contribute to both cortical and thalamic responses. Lastly, we establish how these inputs and receptors evoke action potentials and influence spontaneous firing. Our findings show how CINs in the NAc core process long-range inputs, highlighting differences from equivalent circuits in other parts of striatum.Significance statement Cholinergic interneurons provide the primary source of acetylcholine in the striatum and are important for behavior and disease. The types of afferents that drive these interneurons have been examined in dorsal striatum but remain understudied in the nucleus accumbens. We found that inputs from prefrontal cortex and thalamus are the main drivers in the mouse nucleus accumbens core. We compare the sign, dynamics, and impact of these two excitatory inputs, showing how they engage multiple glutamate receptors to influence cholinergic interneuron firing.