Decoding brain circuit underlying metabolic regulation of sleep-wake behavior

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Project Summary / Abstract Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder and the most common form of dementia in elderly population, yet no disease modifying therapies are currently available for AD. In addition to aging, obesity and poor sleep quality have also been known to greatly increase the risk of developing AD and AD- related dementia (ADRD). Obesity is commonly associated with leptin resistance and leptin deficient obese ob/ob and db/db mice have been reported to exhibit not only severe sleep fragmentation and poor sleep quality but also worsened AD-like pathology and cognitive impairment, which raise an important question whether increased AD risk in leptin deficiency is due to defect in leptin signaling per se or poor sleep quality caused by obesity and leptin deficiency. The main objective of this AD supplement application is therefore to test the novel idea that improving sleep quality is sufficient to ameliorate AD-like pathology and cognitive impairment in obese leptin deficient mice. This idea stems from the development of novel genetic mouse models with conditional leptin deficiencies made through research funded by the parent grant R01 HL 153274 and several important observations in these mouse models. In research proposed in parent grant, we found that leptin signaling in the lateral hypothalamic area (LHA), a brain region historically known as “feeding center”, plays a key role in sleep-wake regulation without drastically affecting body weight homeostasis. Specifically, we found that selectively restoring leptin receptor (LepR) signaling in the LHA of obese LepR-null mice is sufficient to normalize severe sleep fragmentations and improve overall sleep quality, while selective deletion of LepRs in the LHA disrupts normal sleep-wake cycle without significant change in body weight. Given the literature support that brain LepR signaling play protective role in AD/ADRD pathogenesis, and that poor sleep quality exacerbate these pathological conditions, in this research supplement we propose to test the hypothesis that protective effect of brain leptin signaling against AD/ADRD is mediated by LHA LepR signaling which improve sleep quality in the context of obesity. This hypothesis will be tested by pursuing following two specific aims: determine if selective restoration of LHA leptin signaling ameliorate AD-like pathology and memory impairments associated with aging in obese LepR-null mice and 2) determine if selective loss of LHA leptin signaling in 3xTg-AD mutant mice exacerbate AD-like pathology and memory impairments. The proposed research is significant as it is not only expected to clarify the role of poor sleep quality in mediating obesity- associated risk of developing AD-like pathology but also identify a key brain region whereby leptin signaling ameliorate AD-like pathology, which may help to develop an effective strategy to manage or prevent obesity- associated AD risk.