As the aging population grows, the need to understand age‐related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient. It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4‐phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice. Chaperone treatment increased p‐CREB, which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone‐treated aged mice. Hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p‐CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild‐type mouse model of aging. The implications of these results could have an impact on the development of therapies to improve health span across the aging population.

Many neurodegenerative diseases manifest in an overall aged population, the pathology of which is hallmarked by abnormal protein aggregation. It is known that across aging, sleep quality becomes less efficient and protein homeostatic regulatory mechanisms deteriorate. There is a known relationship between extended wakefulness and poorly consolidated sleep and an increase in cellular stress. In an aged population, when sleep is chronically poor, and proteostatic regulatory mechanisms are less efficient, the cell is inundated with misfolded proteins and suffers a collapse in homeostasis. In this review article, we explore the interplay between aging, sleep quality, and proteostasis and how these processes are implicated in the development and progression of neurodegenerative diseases like Alzheimer’s disease (AD). We also present data suggesting that reducing cellular stress and improving proteostasis and sleep quality could serve as potential therapeutic solutions for the prevention or delay in the progression of these diseases.

Homer proteins are a component of the post-synaptic density of neurons that are necessary for the maintenance and consolidation of behavioral state. The dominant negative protein homer1a is rapidly increased by neuronal activity and sleep loss. Homer1a knockout mice with globally absent homer1a have reduced ability to sustain wakefulness during the active period. It is not known whether homer1a is required globally or in very specific brain regions or neurons for its role in maintaining wake. In this study, we examined the expression of homer1a, an immediate early gene involved in intracellular signaling cascades, in mice subjected to extended wakefulness. We found that mice displayed increased expression of homer1a in the claustrum, a brain region thought to be involved in consciousness, as well as the cingulate and piriform cortices compared to non-sleep deprived mice. In situ hybridization (ISH) studies also indicate that homer1a is not induced in the known wake promoting regions with sleep deprivation, but is instead upregulated primarily in the claustrum and piriform cortex. Examination of homer1a expression levels with recovery sleep after sleep deprivation indicate that baseline homer1a expression levels were restored. Further, we have identified that homer1a is upregulated in excitatory neurons of the claustrum suggesting that homer1a promotes wakefulness through activating excitatory neurons. This work identifies regions previously unknown to be involved in sleep regulation that respond to acute sleep deprivation or enhanced waking.

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is equivalent. At our center, the primary general surgery group requires routine HIDA scans on all suspected cases of acute cholecystitis before deciding operative management. The purpose of this study was to perform a retrospective review of all HIDA scans performed in 2018 among emergency department cases of suspected cholecystitis. The specific aim was to evaluate the agreement between ultrasound (US) and HIDA scan findings and their association with operative decision-making. Secondary objectives were to evaluate discrepancies, insurance status, age, sex, ED length-of-stay, operative outcomes, and costs.Methods: HIDA scans were identified from our imaging record system from January 1, 2018 to December 31, 2018. An abnormal US (US+) was defined as the presence of gallstones plus either of the following: gallbladder wall thickening, pericholecystic fluid, sonographic Murphy's, or common bile duct dilatation. An abnormal HIDA (HIDA+) scan was defined as cystic duct obstruction and/or failure to visualize the gallbladder. Qualitative reviews of specific cases were summarized. STATA (College Station, TX) was used for statistical analysis.Results: N ¼ 550 patients who received both HIDA scan and gallbladder US. There were 348 cases of US+ and 234 cases of HIDA+. There was a 59.3% agreement between US and HIDA findings. n ¼ 169 of US+ and HIDA-and n ¼ 55 of US-and HIDA+. Pairwise correlation 0.236 (p<0.001). There was a net decrease in operative care of 114 cases by adding HIDA. 550 HIDA scans have an estimated aggregate charge of $773,300 whereas 114 fewer laparoscopic cholecystectomies would have an aggregate savings of $2,101,932.Conclusion: This is the largest single-center study of comparison between HIDA and US in emergency department patients. The use of HIDA scans suggested 49% of patients with US+ findings may not require urgent surgery whereas 27% of patients with non-diagnostic US demonstrated the need for surgical intervention. The routine use of HIDA scans may have a significant impact on costs and reimbursements for this common etiology. The clinical suspicion is the main driver of resource utilization and routine HIDA scans increase immediate costs, ED length-of-stay, and can result in a net decrease of costs for urgent operative care.

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