Hippocampal Representations of Time and Length During Fine Motor Behavior, and Alpha-Synuclein Drives Basal Ganglia Modulation in a Zebra Finch Parkinsonian Model

Abstract

The hippocampus is an integral structure for the construction and recollection of memory in both humans and non-human species. Since the mid-20th century, extensive work has elucidated its cellular responses to movement that form a robust foundation for spatial memory. The advent of in vitro recordings provided an in-depth understanding of how groups of neurons and single units in the hippocampus coordinate to form stable memories across the lifespan. Early discoveries using local field potential illustrated the importance of the hippocampal theta (4-9 Hz) oscillation in memory formation, and how its presence during movement orchestrates reliable activity of neurons representing spatial information. Hippocampal time cells were later discovered that responded to brief segments of time, which are believed to support the temporal properties of episodic memory. The first study of this thesis provides insight into how hippocampal theta oscillations differ among spatial navigation relative to fine-motor locomotion. The second follow-up study sought to elucidate whether hippocampal neurons can flexibly map onto segments of time and centimeters of string pulled (length) during a fine-motor behavior. In the first study, we found opposing responses in theta frequency and power between spatial navigation and fine-motor locomotion. While theta frequency and power were positively related to spatial navigation speed, theta oscillations were reduced to a lower frequency while power increased with fine-motor speed. The ‘pull’ and ‘push’ paw motions (associated with advancing an animal through space) were positively related to theta frequency and power and were phase locked to theta. The second follow-up investigation found hippocampal activity during discrete segments of time and a novel dimension of the ‘length’ during fine-motor behavior. These results illustrate how the hippocampus may differentially support the perception of movement through space and fine-motor behavior, and how it flexibly responds to abstract dimensions beyond traditional 2D navigation.The final study presented in this thesis explored the neuronal correlates of vocal deficits by classifying the activity of cell types in Area X, a song nucleus of the avian basal ganglia (BG), in an anesthetized zebra finch adeno-associated virus (AAV) model of Parkinson’s disease (PD). In the early 20th century, it was established that the motor deficits in PD stem from degeneration in the BG. While vocal dysfunctions are the first symptoms of PD and present prior to the onset of tremors, little is known of the neural substrates underlying early vocal symptoms. An analysis of the two neuron classes, putative medium spiny neurons and pallidal neurons, revealed reduced firing rates and alterations in waveform shape, which could indicate changes in membrane-bound channels, in both cell types among AAV animals relative to controls. These results suggest that reduced firing rate and alterations to intrinsic membrane excitability may contribute to the early vocal deficits observed in PD. Collectively, these findings reveal novel hippocampal responses to limb movement and segments of length during fine-motor behavior, and suggest that neuronal modulation in the BG may underlie vocal motor impairments observed in early PD.