Dissertation

Dissection of Detailed Motor Behaviors and Circuit Functions of the Basal Ganglia in Health and Disease

Nguyen, Katrina P

2022

Overview

When you first learn a new skill, the cognitive demand is quite high: each action sequence is meticulously planned and carefully executed, requiring your full attention. However, with enough practice, these coordinated movements become smooth, efficient, and instinctive. How do movements across our limbs and bodies evolve with time as we progress from an amateur to a skilled state? What happens in cases of neurological diseases? While there are frameworks for detailed psychophysical characterization of motor behavior in humans and non-human primates to tackle these questions, rodent behavior remains relatively unquantified, despite being one of the primary model organisms to study neuronal circuits and function. By exploring the structure of behavior and locomotor kinematics in mice, we move closer to unifying how complex behaviors are expressed and adapt across species. This has the potential to better inform us about where and when to apply therapeutic interventions in cases of injury or disease. With the long-term goal of better linking actions to circuit function, in this thesis we revisit classic motor paradigms in mice and carefully characterize behavior with a high degree of temporal and spatial precision. In the first part of this thesis, we identify distinct locomotor kinematics during skill acquisition in mice and find that they evolve over unique time courses as the task is mastered. This suggests that mice exhibit distinct phases of skill learning and draws parallels to observations in human and non-human primate studies of motor acquisition. In the second part of this thesis, we ask how locomotion and behavior are altered in a unilateral mouse model of Parkinson’s Disease. We identified postures and patterns of motor behaviors that are more resilient to dopamine depletion, implying that compensatory mechanisms in the brain affect motor output non-uniformly. In the final part of this thesis, we examine the indirect pathway of the basal ganglia’s role in motor suppression and avoidance. While pathway-specific activation of the striatum has been shown to reliably produce opposing effects on motor and reinforcement, how downstream pallidal targets of indirect pathway spiny neurons (iSPNs) mediate behavior is largely unknown. Here, we examine how iSPN modulation of the external globus pallidus controls motor and affective behaviors and show evidence suggesting that the motor suppressing effects of iSPNs are driven through inhibitory collaterals within the striatum. Overall, this thesis carefully dissects mouse behavior and circuits across a variety of traditional motor tasks in health and disease.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biomedical engineering / Neurosciences
• ISBN: 9798351471662