Striatal cholinergic interneurons contribution to the cognitive deficits of Parkinson's disease : optogenetic and behavioural approaches in mice

La maladie de Parkinson (MP) se caractérise essentiellement par des symptômes moteurs, mais comprend également des troubles psychiatriques et cognitifs. La MP est causée par la perte progressive des neurones dopaminergiques (DA) qui projettent vers le striatum. Au niveau de cette structure, les neurones DA interagissent avec les interneurones cholinergiques (CINs) pour moduler certaines fonctions motrices et cognitives. Par des approches comportementale, lésionnelle et optogénétique chez la souris, mes travaux de thèse montrent qu’une lésion des neurones DA ou une inactivation des CINs induit de l’impulsivité ainsi que des troubles de flexibilité ; ces dysfonctionnements cognitifs pourraient précéder l’apparition des troubles moteurs et ainsi constituer des marqueurs précoces de la maladie. L’interaction entre ces deux populations de neurones ne semble cependant pas être impliquée dans le développement de ces troubles cognitifs spécifiques dans notre modèle murin de la MP.Parkinson’s disease (PD) is mainly characterized by motor symptoms but also includes psychiatric and cognitive impairments. PD is caused by the progressive loss of dopaminergic (DA) neurons that project towards the striatum. In this structure, DA neurons interact with cholinergic interneurons (CINs) to modulate several motor and cognitive functions. With behavioural, lesional and optogenetic approaches, in mice, my thesis work shows that a lesion of DA neurons or an inactivation of CINs induces impulsivity and flexibility disorders; these cognitive dysfunctions could precede the onset of motor symptoms and thus constitute early markers of the disease. The interaction between these two neuronal populations does not seem, however, to be involved in the development of these specifics cognitive deficits in our mice model of PD

Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine-depleted mice

International audienceEarly non-motor symptoms such as mood disorders and cognitive deficits are increasingly recognised in Parkinson's disease (PD). They may precede the characteristic motor symptomatology caused by dopamine (DA) neuronal loss in the substantia nigra pars compacta (SNc). It is well known that striatal cholinergic interneurons (ChIs) are emerging as key regulators of PD motor symptom, however, their involvement in the cognitive and affective alterations occurring in the premotor phase of PD is poorly understood. We used optogenetic photoinhibition of striatal ChIs in mice with mild nigrostriatal 6-hydroxydopamine (6-OHDA) lesions and assessed their role in anxiety-like behaviour in the elevated plus maze, social memory recognition of a congener and visuospatial object recognition. In transgenic mice specifically expressing halorhodopsin (eNpHR) in cholinergic neurons, striatal ChIs photoinhibi-tion reduced the anxiety-like behaviour and reversed social and spatial short-term memory impairment induced by moderate DA depletion (e.g., 50% loss of tyrosine hydroxylase TH-positive neurons in the SNc). Systemic injection of telenzepine (0.3 mg/kg), a preferential M1 muscarinic cholinergic receptors antagonist, improved anxiety-like behaviour, social memory recognition but not spatial memory deficits. Our results suggest that dysfunction of the striatal cholinergic system may play a role in the short-term cognitive and emotional deficits of partially DA-depleted mice. Blocking cholinergic activity with M1 muscarinic receptor antagonists may represent a possible therapeutic target, although not exclusive, to modulate these early non-motor deficits

Interactions entre contrôle inhibiteur et flexibilité comportementale: impact de la dénervation dopaminergique au niveau du striatum dorsomédian chez la souris

International audienceIn 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 (nosepoke 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