Network dynamic of Basal Ganglia circuits in normal and parkinsonian conditions

Resum

Basal ganglia (BG) circuits are involved in different functions from movement control tocognitive/motivational processes. The loss of dopamine (DA) in these circuits triggers Parkinson¿sdisease (PD). In addition to DA depletion, PD patients present an early serotonergic (5-HT)alteration at the level of the BG nuclei. 5-HT modulates the activity of BG circuitry by acting on alarge variety of 5-HT receptor subtypes. Among them, the 5-HT2A receptor is expressed in bothmotor and associative/limbic territories of the BG nuclei being implicated in regulation of motor,executive and cognitive functions, as well as automatisms. In addition, 5-HT2A receptors may alsoplay a role in diseases linked to BG dysfunction, such as PD.Firstly, we investigated the specific contribution of 5-HT2A receptors on the dynamic regulation ofBG circuits. For that purpose, in vivo single-unit extracellular recordings of lateral and medialsubstantia nigra pars reticulata (SNr) neurons along with simultaneous electrical stimulation of themotor and mPF cortex were used. The results showed a topographical-dependent dissociation in theeffects triggered by the 5-HT2A agonist TCB-2, which specifically increased the medial SNr neuronactivity and had preferential action on mPF cortical information processing through the striato-nigraldirect pathway. These findings provide novel evidence about the specific signature of 5-HT2Areceptors on the dynamic regulation of BG circuits.Secondly, we focused on the study of BG dynamics in pathological conditions. In PD, dopaminergictherapy such as the administration of the precursor levodopa reduces the symptomatology andimproves movement execution in the early stage of the disease, but quickly triggers abnormal andinvoluntary movements known as levodopa-induced dyskinesia (LID). LID is very debilitating andrefractory to any further drug treatment. Hence, understanding the neuronal mechanism underlyingLID is fundamental to develop new therapeutic strategies. Recent studies have shown that LID iscaused by excessive neuronal activity in the striatum, however, how such striatal activity impacts BGdownstream circuits such as the external globus pallidus (GPe) to generate LID is still unknown. Inaddition, a subpopulation of GPe neurons called the arkypallidal (Arky-GPe) neurons, directly forma negative feedback loop with the striatum to powerfully control action inhibition in normalconditions. We used optical methods to monitor in vivo the calcium activity of Arky-GPe neuronsacross different motor and disease states. Having characterised the abnormal changes of activity, wethen used optogenetic manipulation to test their causal contribution to LID generation. We found thatoptogenetic reactivation of Arky-GPe neurons during LID reduces hyperkinetic behaviour andpromotes normal-like motor behaviour. These results pave the way to understand the complexmechanisms involved in the generation and maintenance of LID.