Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Robert L. Spencer

Second Advisor

Serge Campeau

Third Advisor

Jerry W. Rudy

Fourth Advisor

Joanna J. Arch

Fifth Advisor

Kenneth P. Wright Jr.

Abstract

Circadian rhythms are 24-hour fluctuations in physiology and behavior that are driven by the oscillatory expression of positive arm (Clock, Bmal1) and negative arm (Period, Per; Cryptochrome, Cry) core clock genes. Glucocorticoid hormone (CORT) circulation exhibits robust circadian rhythmicity, which stabilizes physiological and behavioral clocks during times of unanticipated environmental change. In Chapter 2 of this dissertation, I extend CORT’s stabilizing nature to the effect of constant light-induced disruption of circadian locomotor activity. In Chapter 3, I show that the presence and appropriate circadian phasing of CORT circulation is necessary for normal prefrontal cortex (PFC) Per1, Per2, and Bmal1 mRNA expression in rats. In Chapter 4, I describe circadian variation in PFC-dependent cued conditioned fear extinction learning (a behavior that is often disrupted in human psychopathology), as evidenced by enhanced extinction recall and attenuated fear renewal in rats when they are trained/tested during their active phase. In Chapter 5, I provide evidence that optimal extinction learning requires the presence of a functional PFC molecular clock, as evidenced by exaggerated fear behavior in rats after PFC Per1 knockdown through RNA interference. Furthermore, removal of CORT via adrenalectomy (ADX) impairs extinction learning in rats trained/tested during their active phase but has no effect on rats trained/tested during their inactive phase (described in Chapters 4 and 5). Complete normalization of this ADX effect requires an undisrupted history of circadian CORT circulation and acute CORT circulation at the time of extinction testing/training—neither is sufficient by itself. I submit that circadian CORT entrainment of PFC clock gene expression, which is necessary for optimal extinction learning, primes PFC neurons to respond to acute CORT during active phase extinction training/testing, thereby enabling learning-associated neuroplasticity. The research presented in this report provides evidence of heretofore uncharacterized CORT-dependent circadian entrainment of the PFC molecular clock and establishes the functional ramifications of its disruption. Many psychiatric disorders are associated with impaired circadian rhythmicity, abnormal basal and stress-induced CORT release, and impaired PFC function. Therefore, the clinical implications of the research presented in this dissertation are apparent.

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