Striatal Dopamine Neuromodulation in Cognitive Function During Health and Disease
Abstract
Cognitive impairments in stimulus-response (S-R) learning and habitual behaviours are key features of numerous neurological diseases, profoundly impacting patients’ cost of care, quality of life, and caregiver burden. In conditions such as synucleinopathies, including Parkinson’s disease, these impairments are common complications in early prodromal disease stages, but their underlying mechanisms remain poorly understood. In this thesis, we took a preclinical approach to begin unraveling how these cognitive functions are processed and controlled in the brain and how they malfunction in states of disease.
We evaluated wildtype and transgenic mice using a touchscreen-based cognitive paradigm designed to mirror human assessments of S-R learning, aiming to facilitate high cross-species translation. Initially, we optimized the integration of this cognitive testing platform with advanced optical techniques for recording and manipulating neural activity, which laid the groundwork for subsequent investigations. Once complete, we then explored the role of striatal dopamine (DA) in the acquisition and expression of S-R learning, a key neuromodulator proposed to facilitate the strengthening of S-R associations underlying habitual behaviour. Using techniques such as in vivo fiber photometry and inhibitory chemogenetics, we uncovered heterogeneous, transient, and population-level DA dynamics across the striatum that played distinct, causal roles in cognition.
Subsequently, we extended these findings into the context of synucleinopathies. While the aggregation and spreading of the protein α-Synuclein are common hallmarks of synucleinopathies, their impact on high-level cognition is often understudied and underappreciated. In a mouse model of synucleinopathy, we induced α-Synuclein pathology by inoculating α-Synuclein pre-formed fibrils into M83 hemizygous mice and assessed their impact on the acquisition of S-R learning. We observed severe cognitive deficits that appeared prior to the onset of major motor impairment, recapitulating the progression of symptoms commonly observed in patients with Parkinson’s disease. Finally, combining our methodologies, we investigated the impact of α-Synuclein pathology on striatal DA dynamics during the acquisition of S-R learning, revealing disruptions in DA dynamics at the population-level following α-Synuclein pathology inoculation. Collectively, our findings represent a critical first step toward understanding the neurobiology of S-R learning and habitual behaviours in health and disease.