Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Neuroscience
Supervisor
Bussey, Timothy J.
2nd Supervisor
Saksida, Lisa M.
Co-Supervisor
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.
Summary for Lay Audience
Cognitive impairments in stimulus-response (S-R) learning and habitual behaviours are common in many neurological diseases, affecting patients’ cost of care, quality of life, caregiver burden. In conditions like synucleinopathies, including Parkinson’s disease, these impairments often occur early in the disease process, but we do not fully understand why. In this thesis, we used a rodent model to study how these cognitive functions work in the brain and how they go awry in disease.
Specifically, we tested normal and genetically modified mice on a touchscreen-based cognitive task that closely resembles tasks commonly used in clinical settings, aiming to make our results as relevant as possible to human patients. Initially, we improved this testing method by integrating it with advanced techniques to record and manipulate neural activity. This groundwork was essential, as it allowed us to investigate how chemicals in the brain signal and influence cognitive function.
Then we explored the role of dopamine in the brain in mediating S-R learning and habitual behaviours. Using techniques which allowed us to record and manipulate dopamine signals as mice performed our cognitive task, we revealed that dopamine signalling is highly variable across brain regions, each with distinct roles in cognition. This finding is particularly important as treatments for brain diseases often effect the brain broadly, but more targeted therapies are possible.
Next, we applied our findings to synucleinopathies. The build-up and spread of the protein α-synuclein is a common feature of these diseases, but its effect on cognition is often overlooked. We created a mouse model of synucleinopathy and found that α-synuclein pathology causes severe cognitive problems before motor issues, resembling the progression of symptoms commonly observed in Parkinson’s disease patients. Finally, we connected these findings back to dopamine, revealing that α-synuclein pathology also disrupts dopamine signalling in one of the brain regions we had previously identified as critical for performing our cognitive task.
Taken together, these findings identify a new target in the brain which may help reduce cognitive impairments in patients with synucleinopathies and advance our understanding of how the brain processes S-R learning and habitual behaviours in healthy and diseased states.
Recommended Citation
Princz-Lebel, Oren, "Striatal Dopamine Neuromodulation in Cognitive Function During Health and Disease" (2024). Electronic Thesis and Dissertation Repository. 10222.
https://ir.lib.uwo.ca/etd/10222