Samet Kocaturk

Striatal cholinergic interneurons (CINs) exhibit a transient pause in tonic firing in response to salient stimuli, a hallmark of reinforcement learning that becomes synchronized with learning. Although thalamostriatal and dopaminergic inputs have been implicated in this pause, the underlying circuit mechanisms remain unclear. Here, we combine optogenetics, electrophysiology, and genetic approaches to examine inhibitory interactions within the CIN network. Synchronized activation of CINs in striatal slices elicited robust feedback inhibition in CINs, suppressing firing and generating pause-like responses. This inhibition was mediated by GABAA receptors and required β2-containing nicotinic acetylcholine receptors (β2-nAChR), and could be recruited by thalamostriatal activation. Dopamine is not required for this circuit but modulates it via D2 receptors. Surprisingly, cell-type–specific silencing and striatal β2-nAChR deletion excluded local GABAergic sources, whereas retrograde β2-nAChR deletion abolished inhibition, revealing an extrastriatal pathway. These findings identify a long-range inhibitory mechanism linking synchronized cholinergic activity to pause generation in striatal circuits.

Parkinson's disease (PD) is known to alter the intrinsic properties of striatal cholinergic interneurons (ChIs). However, how PD shapes ChI control of intrastriatal GABAergic circuits regulating principal spiny projection neurons (SPNs) is unknown. To fill this gap, striatal circuits in healthy and parkinsonian mice were interrogated. In ex vivo brain slices from healthy mice, optogenetic stimulation of ChIs evoked GABA _A receptor currents in both indirect and direct pathway SPNs that were attributable to nicotinic acetylcholine receptor (nAChR)-mediated activation of GABAergic interneurons (GIs). Simulations suggested that this circuit exerts a state-dependent control of SPN dendritic integration that was modulated by concomitant muscarinic receptor signaling. Surprisingly, in mouse models of prodromal and parkinsonian states, the ability of ChIs to engage this intrastriatal circuitry was disrupted because interneurons down-regulated nicotinic AChRs. Taken together, these studies suggest that impaired ChI control of GABAergic interneurons contributes to behavioral deficits in both prodromal and clinical PD states.