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

Katherine R Brimblecombe,Sarah Threlfell,Stephanie J Cragg,Polina Kosillo,Daniel Dautan,Juan Mena-Segovia

doi:10.1523/eneuro.0397-17.2018

Katherine R Brimblecombe, Sarah Threlfell + Show 4 more

Open Access

https://doi.org/10.1523/eneuro.0397-17.2018

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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.

Highlights

The striatum is the primary input-receiving nucleus of the basal ganglia, and the modulation of information flow through the striatum is crucial to basal ganglia function including motor control and reward-driven behaviors
Striatal injections resulted in detectable ChR2-enhanced yellow fluorescent protein (eYFP) expression in striatum and an absence of retrograde transduction of ChR2-eYFP expression in pedunculopontine nucleus (PPN)/laterodorsal tegmentum (LDT) cholinergic neurons in brainstem, whereas PPN/LDT injections resulted in ChR2-eYFP expression in PPN/LDT and in neuropil in striatum (Fig. 1A), as shown previously following striatal versus PPN/LDT injections of AAV2-EF1a-DIO-YFP in ChAT-Cre rats (Dautan et al, 2014)
ChR2-eYFP expression was confirmed as originating from neurons immunopositive for ChAT in striatum (Fig. 1B), as has been confirmed previously for expression in PPN/LDT neurons following brainstem injections (Dautan et al, 2016)

Summary

Introduction

The striatum is the primary input-receiving nucleus of the basal ganglia, and the modulation of information flow through the striatum is crucial to basal ganglia function including motor control and reward-driven behaviors. Striatal ACh plays powerful roles in regulating excitability of striatal neurons, and in directly regulating DA transmission (Zhou et al, 2001; Rice and Cragg, 2004; Zhang and Sulzer, 2004; Cragg, 2006; Threlfell et al, 2010, 2012; Cachope et al, 2012). It has been proposed that in vivo, when striatal cholinergic interneurons (ChIs) pause their firing in response to salient and conditioned stimuli (Aosaki et al, 1994; Apicella et al, 1997), or when nicotine causes receptor desensitization, nAChRs will turn off and allow DA release to better reflect the frequency of activity in DA neurons (Rice and Cragg, 2004; Cragg, 2006).

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