Self-paced VS cued movement initiation : characterising behaviour and underlying neural circuits

• Autor(a) principal: Coelho, Pedro Daniel da Cruz Chita Matos
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/162616
• topic: Parkinson’s disease; movement initiation; self-paced; cued; Ciências Médicas

Abstract The ability to initiate movement at the right timing and with the accurate vigour is pivotal for survival. Despite its great importance, Parkinson’s disease (PD) patients struggle with movement initiation, and even when successful, generated movements tend to be less vigorous. It comes as a surprise then, that PD patients seem to be less impaired when movement initiation is triggered by an external cue, leading to the aphorism that these patients "react better than they act". This cueing phenomenon observed in PD patients and the mechanisms by which it occurs remain, to this day, rather obscured and under a great debate. Viability of cueing strategies for the treatment of PD requires a degree of reproducibility and understanding which is not met currently. Altogether, it is the poor understanding of the neuronal circuits underlying self-paced and cued initiation and how they are differentially impaired in PD that has enticed our research. To this end, we have developed a behavioural task that allowed us to train mice to initiate the same action either in a self-paced or a cued manner. During learning, mice progressively increased the probability of initiating movement following the cue, while applying a different strategy during the self-paced paradigm, as intended. Multiple parameters were taken into consideration to show that animals were completing the task efficiently, at the same time reproducing the two types of movement initiation. To reproduce the problems of movement initiation produced by the loss of dopamine in PD, we tested the effect of dopamine receptors antagonists in mice freely exploring an open field and selected the option that provided a reduction of ~20% in selfpaced initiations. The optimised dosage was then applied on proficient animals that had undergone all phases of the behavioural task. In accordance with the observation in PD patients, we found no impairment in cued initiation probability which contrasted with a significant reduction of self-paced initiations. Altogether, we have developed a robust behavioural task that successfully reproduces both types of initiations, and that when it is combined with a manipulation that impairs dopaminergic activity, leads to the replication of the cueing phenomenon seen in PD patients. Although some degree of optimisation is at hand, this task can now be used in combination with mice models of PD with greater face validity, and combined with neural recording techniques that will allow us to better understand the cueing phenomenon at the neural circuits level.