Psychology ETDs

Publication Date

Summer 7-15-2021

Abstract

Spatial navigation and memory are impaired in the early stages of Alzheimer's disease (AD) and are prominent behavioral markers of preclinical AD. The TgF344-AD rat model of AD exhibits similar behavioral and pathological features to humans and thus serves as an excellent model to investigate the mechanisms underlying spatial impairment in AD. Brain regions in the parahippocampal cortex contain spatially responsive pyramidal cells that support spatial navigation and memory including place cells, grid cells, and head direction cells. Furthermore, GABAergic interneurons in these regions support precise temporal organization of spike dynamics and may play a critical role in maintaining reliable spatial representations. Both pathological and electrophysiological markers have identified evidence of hyperexciatablility and GABAergic dysfunction across various rodent models of AD-like pathology; consistent with the theoretical framework of excitatory---inhibitory imbalance underlying cognitive decline in AD. Critically, TgF344-AD rats exhibit GABAergic cell loss and epileptiform activity in local field potential traces as early as 9 months of age in areas within the parahippocampal cortex. The presence of GABAergic pathology and epileptiform activity suggests that local microcircuitry may be disrupted. The postsubiculum, a region within the parahippocampal cortex, contains a large population of cells that propagate vestibular driven head direction information to cortical targets. Importantly, the integrity of this circuit relies on several types of GABAergic interneurons to maintain spiking dynamics of head direction cells during fast head turns or sustained head position. Therefore, interneuron dysfunction resulting from AD-like pathology would predict diminished integrity, instability, and poor discrimination of the head direction signal within postsubicular cell populations. The broad goal of the current research was to establish whether postsubicular head direction cells and GABAergic interneurons show dysfunctional firing dynamics in TgF344-AD rats. The first aim of this research addressed this goal by characterizing the firing characteristics of postsubicular head direction cells and GABAergic interneurons during active exploration. The second aim evaluated the response of postsubicular head direction cells following environmental manipulations, such as cue rotation or environment change. The results indicated that putative interneurons exhibited a higher degree of directional encoding in TgF344-AD rats, with little difference observed in pyramidal head direction cells. Furthermore, a local visual cue controlled the preferred direction of head direction cells in TgF344-AD rats, indicating landmark anchoring is intact in aged TgF344-AD rats. This work indicated alterations of the postsubicular head direction cell circuit in TgF344-Ad rats. More broadly, these findings helped establish whether the altered firing of putative excitatory and inhibitory neurons contributed to the disruption of cellular networks that support spatial navigation and memory; thus, informing targeted treatment development for AD.

Degree Name

Psychology

Level of Degree

Doctoral

Department Name

Psychology

First Committee Member (Chair)

Benjamin J. Clark

Second Committee Member

Claudia D. Tesche

Third Committee Member

Derek A. Hamilton

Fourth Committee Member

Jeremy Hogeveen

Fifth Committee Member

Samuel A. McKenzie

Language

English

Keywords

Alzheimer's disease, head direction cells, spatial navigation

Document Type

Dissertation

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