Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Steven F. Maier

Second Advisor

Michael P. Saddoris

Third Advisor

Linda R. Watkins

Fourth Advisor

John K. Hewitt

Fifth Advisor

Christopher A. Lowry

Abstract

Stress is an etiological factor in the onset of depression, anxiety, and post-traumatic stress disorder (PTSD). Therefore, significant efforts have been made to identify factors that produce stress resilience in hopes of mitigating stress outcomes. In a laboratory setting, rats given behavioral control over a stressor (escapable tailshock, ES) are protected from depression and anxiety-like behavioral changes that are present in rats exposed to an equivalent but uncontrollable stressor (inescapable tailshock, IS). Similar to behavioral control, the NMDA receptor antagonist ketamine has gained attention for its ability to prevent outcomes of IS when administered far in advance of the stressor. Despite promising results of preclinical studies performed in male rats, the effects of behavioral control and ketamine in female rats remains unknown.

Here, the effects of behavioral control and ketamine on stress-induced behavioral changes and the neural circuit-level processes that mediate these effects in female rats are explored. We assessed whether behavioral control and ketamine prevent stress-induced dorsal raphe nucleus (DRN) activation and behavioral changes associated with DRN activation. We also assessed whether behavioral control and ketamine engage an inhibitory prelimbic cortex (PL) to DRN (PL-DRN) circuit.

Behavioral control failed to mitigate DRN activation and behavioral outcomes induced by stress, as it does in males. Moreover, behavioral control failed to selectively engage PL neurons that project to the DRN. Pharmacological activation of the PL restored the stress-buffering effects of control. Conversely, ketamine given prior to IS reduced typical stress-induced DRN activation and accompanying behavioral changes. Proactive ketamine altered PL neural ensembles so that a later experience with IS now activated these cells, which it ordinarily would not. Chemogenetic inhibition of the PL-DRN circuit at the time of stress prevented ketamine-induced stress resilience.

The present experiments provide the first evidence demonstrating a bidirectional influence of ketamine and behavioral control on neural circuits of resilience in females. Ketamine, but not behavioral control, engages an inhibitory PL-DRN circuit and prevents stress-induced behavioral changes. Taken together, this underscores the importance of examining sex differences when studying neural circuits underlying stress resilience and translating these findings to the development of preventative strategies for stress-related disorders.

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