Targeted Activation of Cholinergic Interneurons Accounts for the Modulation of Dopamine by Striatal Nicotinic Receptors.

Abstract Striatal dopamine (DA) is a major player in action selection and reinforcement. DA release is under strong local control by striatal ACh acting at axonal nicotinic ACh receptors (nAChRs) on DA axons. Striatal nAChRs have been shown to control how DA is released in response to ascending activity from DA neurons, and they also directly drive DA release following synchronized activity in a small local cholinergic network. The source of striatal ACh has been thought to arise solely from intrinsic cholinergic interneurons (ChIs), but recent findings have identified a source of cholinergic inputs to striatum from brainstem nuclei, the pedunculopontine nucleus (PPN) and laterodorsal tegmentum (LDT). Here, we used targeted optogenetic activation alongside DA detection with fast-scan cyclic voltammetry to test whether ChIs alone and/or brainstem afferents to the striatum can account for how ACh drives and modulates DA release in rat striatum. We demonstrate that targeted transient light activation of rat striatal ChIs drives striatal DA release, corroborating and extending previous observations in mouse to rat. However, the same light stimulation targeted to cholinergic brainstem afferents did not drive DA release, and nor did it modulate DA release activated subsequently by electrical stimulation, whereas targeted activation of ChIs did so. We were unable to obtain any evidence for DA modulation by PPN/LDT stimulation. By contrast, we could readily identify that striatal ChIs alone are sufficient to provide a source of ACh that powerfully regulates DA via nAChRs. Significance statement Striatal acetylcholine (ACh) can powerfully regulate striatal dopamine (DA). Until recently, cholinergic interneurons were thought to be the only source of striatal ACh, but brainstem cholinergic neurons have now been revealed to innervate striatum. Here, we use targeted optogenetic activation in rats to explore which input accounts for the rapid regulation of striatal DA release. We find that targeted activation of striatal cholinergic interneurons in rat striatal slices can reproduce how striatal ACh drives and modulates dopamine release in mouse, but we could not find comparable evidence for a role for brainstem cholinergic inputs. Activation of cholinergic interneurons alone can reproduce the previously documented effects of activating all striatal ACh systems on DA release.