Date of Award

Spring 3-21-2025

Embargo Period

3-21-2030

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Lori McMahon

Abstract

The locus coeruleus (LC) produces noradrenaline (NA) for majority of the brain which influences functions like learning, memory, stress response, and sleep–wake cycles. The LC is the first brain region to accumulate hyperphosphorylated tau (pTau) in Alzheimer’s disease (AD) and this pTau accumulation occurs approximately the same time that women undergo the menopausal transition. Hormone deprivation contributes to the increased prevalence and severity of AD in females compared to males. This has been demonstrated in humans and animal models in many brain regions but remains unexplored in the LC.

The first hypothesis posited that LC-NA neurons are more active during the dark phase than the light phase. In vivo electrophysiology under anesthesia revealed that LC-NA neurons exhibit heightened baseline activity, stronger responses to foot shock during the dark phase, and more burst events. Heterogeneous modulation from stimulation supports the presence of diverse LC-NA neuron populations. Overall, recording during the animal's active phase provides a more informative snapshot of LC physiology than during its sleep phase.

The second hypothesis was that ovarian hormone deprivation would exacerbate LC dysfunction in the TgF344 AD rat. Following three months of hormone deprivation, in vivo electrophysiology recordings under anesthesia were done on six-month-old animals, coinciding with pTau accumulation and physiological dysfunction in the LC of this model. Surgical menopause increases baseline LC activity in both wild-type (WT) and TgF344AD rats. We see that neurons from TgF344AD rats show decreased interspike interval, but overall firing rate did not differ, presumably due to increased phasic firing uncovered in burst events. In response to stimulation, we report both potentiation and depression across neurons. We observed strong inhibition from ovarian hormones that is lacking in WT OVX but not TG OVX, suggesting loss of response to a stimulus.

In summary, our findings highlight the LC's heterogeneity, showing that diurnal rhythms and ovarian hormone deprivation significantly shape LC-NA baseline physiology and stimulus responsiveness. These insights not only deepen our understanding of LC function in AD but also point to potential windows for targeted therapeutic intervention in early stages of the disease.

Rights

Copyright is held by the author. All rights reserved.

Download

Available for download on Thursday, March 21, 2030

Share

COinS