Date of Award

1-1-2020

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Psychology

Program

Behavioral Neuroscience

Content Description

1 online resource (vi, 135 pages) : illustrations (some color)

Dissertation/Thesis Chair

Christine K. Wagner

Committee Members

Damian Zuloaga, Andrew Poulos

Keywords

Cajal-Retzius, Dentate Gyrus, Episodic memory, Perforant path, Progesterone Receptor, Progesterone, Dentate gyrus, Gene expression, Rats as laboratory animals

Subject Categories

Neuroscience and Neurobiology

Abstract

The hippocampus is a critical structure for the encoding and retrieval of declarative memories in humans, including episodic-memories. In rodents the steroid hormone receptor progesterone receptor (PR) is expressed in the dentate gyrus (DG) of the hippocampus during the postnatal period, a key stage in development of DG cytoarchitecture and connectivity. During the first postnatal week, the main cortical input to the hippocampal circuit, the perforant path, innervates the molecular layer (MOL) of the DG and forms temporary initial synaptic connections with pioneer neurons. By the third postnatal week, long-term synapses have been established with granule cells, the principle neurons of the DG. During this critical period of development, the establishment of the perforant path connections with the DG are particularly vulnerable to disturbance. As a transcription factor, PR activity is able to alter gene transcription, and consequently cellular processes of the cells in which it is expressed, potentially disrupting typical development of DG connectivity and impairing adult behavior mediated by this circuit such as episodic-like memory. In this thesis I describe the expression of PR in males and female rats in the MOL of the DG at postnatal day 7, as well as identify the phenotype of PR expressing cells. I go on to illustrate the effect of postnatal PR inhibition on the developmentally critical glycoprotein reelin, as well as innervation of the MOL by perforant path. Finally, I demonstrate the effects of postnatal PR inhibition on episodic-like memory in adult rats. In Chapter 2 the postnatal expression of PR across the rostrocaudal extent of the DG MOL is compared in males and females. Additionally, the phenotype of PR expressing cells was determined through immunohistochemistry. Results indicate that no sex difference in PR expression was detected at postnatal day 7 (P7), and PR cells are Cajal-Retzius (CR) cells, a type of pioneer neuron critical to dentate morphogenesis and connectivity. The determination that PR is expressed in CR cells suggests PR may interact or regulate any or all of the developmental mechanisms CR cells perform, through PRs role as a transcription factor. In Chapter 3, the effect of postnatal PR inhibition on the CR-secreted protein reelin was examined. Postnatal treatment of rat pups with the PR antagonist RU486 revealed an increase in the number of reelin-ir cells in the P7 MOL, but no concomitant change in a second marker of CR cells, calretinin, suggesting the increase in reelin-ir may be due to intracellular accumulation of the protein. Reelin modulates both gross innervation of the MOL by the perforant path, and synaptogenesis in the MOL during the postnatal period. Therefore, in Chapter 4 the effect of PR inhibition on the innervation of the DG MOL was assessed by immunohistochemistry for the vesicular associated protein synaptophysin, a marker of synaptic boutons. At P7 perforant path axons are elaborating and making connections with CR cells of the MOL, conversely by P21 functional connections between the perforant path and DG granule cells have formed. Treatment of rat pups with RU486 from P1-7 increased the area of synaptophysin-ir in males at P7, and increased the density of syanptophysin-ir in females at P21, suggesting atypical innervation of the DG MOL by the perforant path. The DG is theorized to integrate sensory components processed in the entorhinal cortex into a conjoined episodic-like memory, and these components are transmitted to the DG by the perforant path. In Chapter 5, the impact of postnatal PR inhibition on episodic-like memory was assessed. Adult male rats treated with RU486 from P1-7 demonstrated impairment on the episodic-like memory task when compared to controls. This task requires the rat to form an integrated memory for what occurred, where, and when it occurred. Interestingly, PR inhibition spared the ability to form associative memories, the components of an integrated episodic-like memory, in a task of relative recency, suggesting PR specifically impaired the ability to integrate episodic components. Altogether, the results of the present thesis demonstrate that PR is expressed in CR cells of the developing DG, and illustrate the key role of PR activity in the normal development of perforant path/DG connectivity and subsequent display of episodic-like memory.

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