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In Parkinson's disease, nigrostriatal dopamine (DA) degeneration is commonly associated with motor symptomatology. However, non-motor symptoms affecting cognitive function, such as behavioural flexibility and inhibitory control may also appear early in the disease. Here we addressed the role of DA innervation of the dorsomedial striatum (DMS) in mediating these functions in 6-hydroxydopamine (6-OHDA)-lesioned mice using instrumental conditioning in various tasks. Behavioural flexibility was studied in a simple reversal task (nose-poke discrimination) or in reversal of a two-step sequence of actions (central followed by lateral nose-poke). Our results show that mild DA lesions of the DMS induces behavioural flexibility deficits in the sequential reversal learning only. In the first sessions following reversal of contingency, lesioned mice enhanced perseverative sequence of actions to the initial rewarded side then produced premature responses directly to the correct side omitting the central response, thus disrupting the two-step sequence of actions. These deficits may be linked to increased impulsivity as 6-OHDA-lesioned mice were unable to inhibit a previously learned motor response in a cued response inhibition task assessing proactive inhibitory control. Our findings show that partial DA denervation restricted to DMS impairs behavioural flexibility and proactive response inhibition in mice. Such striatal DA lesion may thus represent a valuable animal model for exploring deficits in executive control documented in early stage of Parkinson's disease., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Unlabelled: Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease., Significance Statement: The striatum, where dopaminergic and cholinergic systems interact, is the pivotal structure of basal ganglia involved in pathophysiological changes underlying Parkinson's disease. Here, using optogenetic and pharmacological approaches, we investigated the involvement of striatal cholinergic interneurons (ChIs) and muscarinic receptor subtypes (mAChRs) in the occurrence of a wide range of motor deficits such as akinesia, bradykinesia, motor coordination, and sensorimotor neglect after unilateral nigrostriatal 6-hydroxydopamine lesion in mice. Our results show that photoinhibition of ChIs in the dorsal striatum and pharmacological blockade of muscarinic receptors, specifically postsynaptic M1 and M4 mAChRs, alleviate lesion-induced motor deficits. The present study points to these receptor subtypes as potential targets for the symptomatic treatment of parkinsonian-like motor symptoms., (Copyright © 2016 the authors 0270-6474/16/369162-12$15.00/0.)

Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson's disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)