Date of Award

January 2018

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Alex Kwan

Abstract

Depression and other stress-related mood disorders are associated with cognitive dysfunctions, including deficits in reward processing and behavioral flexibility. The prefrontal cortex (PFC) is particularly vulnerable to stress-induced impairments in both structure and function. However, it is not well understood specifically how chronic stress affects PFC neuronal activity, or how changes in PFC activity might correlate with behavioral deficits. We performed a longitudinal behavioral and imaging study in mice subjected to chronic social defeat stress (CSDS), a well-established model of depressive behaviors in rodents. Mice were trained on an operant sucrose preference task involving varying concentrations of sucrose and water rewards to assess adaptability to changing reward values; task performance was measured repeatedly before, during, and after 10 consecutive days of social defeat. In a subset of mice, two-photon calcium imaging of pyramidal neuron activity in the M2 secondary motor region of medial PFC (mPFC) was recorded while animals were concurrently engaged in the sucrose preference task. CSDS caused a significant decrease in sucrose preference, abolishing preference for sucrose over water. Stressed mice also exhibited a significant increase in total acquisition of both sucrose and water rewards. Notably, stress had a major effect on reward acquisition strategy; mice subjected to chronic stress shifted from exhibiting reward-directed behavior (in which actions are continually modified in response to changes in outcome value) towards a much more repetitive and reward-insensitive pattern of activity. Collection of imaging data in conjunction with behavioral data is ongoing, with preliminary analysis of neuronal activity patterns showing evidence of distinct neuronal subpopulations, as well as a trend towards hyperactivity in acute stress and hypoactivity in chronic stress. Continuation of imaging experiments will provide further insight into the effect of chronic stress on mPFC neural dynamics.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/25/2100

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