Preoptic/Hypothalamic Mechanisms of Sleep-Wake Regulation

Va Greater Los Angeles Healthcare System, Los Angeles CA

Investigators

Linked publications & trials

Abstract

An estimated 54.1 million Americans, including 18.2 million Veterans (49% of the Veteran population), are elderly and at higher risk for developing chronic sleep disturbance. Chronic insufficient or disrupted sleep is associated with a spectrum of adverse health conditions, including anxiety, depressive disorders, obesity, cardiovascular disease, cognitive decline, and Alzheimer's disease. Chronic neuroinflammation shares similar health risks and a bidirectional relationship with sleep disruption. Recently, we found that chronic local inflammation in the preoptic-basal forebrain (POA-BF) of young mice induces sleep disturbance resembling those in aging. Our preliminary data further suggests: a) that lipopolysaccharide (LPS) given peripherally also triggers similar but late-onset sleep disruption after 8 weeks; and b) that preoptic-hypothalamic (POA) tissues from LPS-treated and aged mice had higher levels of microglia activation, a marker of neuroinflammation, lower levels of ATP-binding cassette transporter A1 (ABCA1) and higher intracellular cholesterol accumulation; lower levels of arginyltransferase1 (ATE1) and F- actin; and an increased levels of caspase-3. We propose a series of innovative preclinical studies to investigate: a) can significant peripheral inflammation induce lasting neuroinflammation in pivotal sleep-regulating systems, resulting in sleep impairments similar to aging? b) does the decreased expression of ABCA1 and ATE1 during aging or chronic neuroinflammation disrupt cholesterol balance, causing intracellular cholesterol accumulation and cytoskeletal defects? do these changes cause dysfunction of critical sleep-regulatory systems leading to sleep disturbances? and c) how effective are anti-inflammatory and cholesterol efflux-enhancing drugs in mitigating sleep disturbances in aging or conditions characterized by chronic neuroinflammation? Specific Aim 1: will determine if peripheral inflammation triggers lasting sleep-wake disruptions resembling aging. We will evaluate if LPS (IP) treatment triggers long-term sleep-wake impairments similar to aging, depending upon age and post-treatment duration (experiment-1). Specific aim 2: will determine if glia and neurons in the POA exhibit signs of increased inflammation, intracellular cholesterol buildup, and cytoskeletal defects in aging and after LPS treatment. We will assess markers of inflammation, levels of ABCA1 and ATE1, intracellular cholesterol accumulation, and cytoskeletal defects in glia and neurons using western blot (experiment-2) and immunohistochemistry (experiment-3) of the POA tissue from aged and LPS-treated mice. Specific aim-3: will determine if key sleep-regulatory neurons in the POA exhibit functional decline due to inflammation exposure. Using fiber photometry, we will determine if the activity of sleep-promoting VLPO neurons projecting to the hypocretin field (VLPOPRJ) in relation to spontaneous sleep and homeostatic sleep challenge decline paralleling the sleep disruption in LPS mice (experiment-4). Using designer receptors exclusively activated by designer drugs approach, we will further assess the declining ability of VLPOPRJ neurons to promote sleep in LPS-treated mice (Experiment 5). Specific aim 4: will determine whether anti- inflammatory and cholesterol efflux-enhancing drugs improve sleep disruption in both aging and chronic inflammation. We will assess if TO901317, a synthetic liver X receptor agonist that ameliorates neuroinflammation and enhances ABCA1 expression, improves sleep continuity in aged mice (Experiment 6) and mice with LPS-induced chronic inflammation (Experiment 7). These preclinical studies will provide critical insights into the mechanisms driving sleep disturbances in aging and diseases with chronic neuroinflammatory conditions, including those originating peripherally. The findings may help develop new therapeutic options for optimizing sleep in those with chronic inflammatory conditions and elderly, including elderly Veterans.