Molecular Mechanisms of Sleep/Wake Regulation and Memory Formation in Young and Aged Mice

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Doctor of Philosophy (PhD)
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Molecular Biology
Neuroscience and Neurobiology
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Advancements in healthcare and medicine have greatly increased lifespan. Normal aging is accompanied by deterioration of key physiological processes, including sleep and cognition. Understanding the mechanisms by which these functions go awry with age is a critical step in identifying novel therapeutic strategies to improve quality of life for the elderly. One of the most prevalent complaints in the elderly is the deterioration of sleep/wake patterns, difficulties staying awake and reduced vigilance. Little is known about the molecular mechanisms controlling these states in the brain. Mouse models are ideally suited to address this question because they share many similarities with human biology and afford the ability to manipulate molecular pathways in vivo. In Chapter 2, we use polysomnography and conditional mutant animals to explore the molecular underpinnings involved in the maintenance of wakefulness. Our results indicate that the activity-dependent transcription factor cAMP response element binding protein (CREB) is critical in forebrain neurons for the maintenance of wakefulness. Interestingly, aging also reduces the ability to sustain wakefulness in the elderly. In Chapter 3, we use polysomnography in young and aged mice, combined with a novel statistical approach to closely examine how aging impacts the microstructure of sleep and wakefulness. We show that aging specifically impairs the ability to sustain long episodes of wake and non-rapid eye movement (NREM) sleep. Another major health concern for older individuals is the decline of cognitive function. In Chapter 4, we use object-based memory paradigms to investigate memory formation in aged mice. Object-based tasks are ideally suited for these studies because they circumvent the confounding alterations in motor function and stress response that accompany aging. We show that aging impairs the consolidation of memories related to the location of objects in space. Our findings indicate that the hippocampus, a brain region critical to spatial memory, is particularly vulnerable to aging. Taken together, our findings outline the molecular pathways involved in the regulation of sleep and wake and lay the groundwork for further understanding of how these systems are altered in the aged brain.

Ted Abel
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