Elucidating Network Motifs and Improving Microcircuit Manipulations in the Primate Hippocampus

Abstract

The overall objective of this thesis is to elucidate previously unexplored nuances of hippocampal network communication while providing novel experimental and computational tools to motivate and enrich primate research. Much of the existing literature on the physiology and function of the hippocampus stems from work in rodents. However, while many anatomical features, physiological hallmarks, and reported functions of the rodent hippocampus translate well to studies in monkeys and humans, several primate-specific phenomena exist. Anatomical investigations reveal dramatic shifts in the organization of the hippocampus relative to other brain areas in the evolution from rodent to primate. Studies of continuous signals reveal that, in contrast to rodents, the primate hippocampus does not elicit continuous oscillations in recorded local field potentials (LFPs) as animals explore a given environment. Unfortunately, work in non-human primates (NHPs, monkeys) has historically lagged rodent hippocampal research in its conceptualizing of primate-specific theories of hippocampal function and applying novel tools, such as gene manipulation techniques. However, recent technological advances are bringing work in NHPs to new prominence. The work in this thesis presents several novel advancements in our theory of primate hippocampal function, our understanding of primate hippocampal physiology, methods for improving surgical methods related to genetic manipulations, and computational methods for analyzing noisy, non-stationary signals. In Chapter 2, I synthesize existing findings from the main cortical input to the monkey hippocampus, the entorhinal cortex (EC), to suggest that this region in primates is not just a simple relay to the hippocampus, but rather a diverse processor of multiple information streams that conveys highly specialized information to downstream regions. Chapter 3 contains a pipelinefor planning and validating in-vivo the types of intra-cranial viral injections needed for genetic manipulation procedures such as optogenetics. Chapter 4 presents novel methods for detecting sharp-wave ripples (SPW-Rs) co-occurring across the monkey hippocampus during quiescence and provides the first evidence of species-specific motifs of traveling ripples across the entire longitudinal axis in primates. Finally, Chapter 5 introduces a novel method for mitigating artifact in large, noisy datasets while preserving the underlying signal, as well as a visualization technique to characterize non-stationary time series data. The overarching objective of this thesis serves to elucidate nuances of hippocampal network communication not previously explored and provide new tools, both hands-on and computational, to empower primate researchers to continue to explore the unique unknowns of the primate hippocampus.