Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Recent advances have revealed the medial preoptic area (MPA) as a key site for the regulation of torpor in mice. The MPA is estrogen-sensitive and estrogens also have potent effects on both temperature and metabolism. Here, we demonstrate that estrogen-sensitive neurons in the MPA can coordinate hypothermia and hypometabolism in mice. Selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, whereas selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor in both female and male mice, their effects on thermoregulation and torpor bout initiation exhibit differences across sex. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency.
Poor sleep is a hazard of daily life that oftentimes cannot be avoided. Gender differences in daily sleep and wake patterns are widely reported; however, it remains unclear how biological sex, which is comprised of genetic and endocrine components, directly influences sleep regulatory processes. In the majority of model systems studied thus far, sex differences in daily sleep amount are predominant during the active (wake) phase of the sleep-wake cycle. The pervasiveness of sex differences in sleep amount throughout phylogeny suggests a strong underlying genetic component. The goal of the current study is to determine if sex differences in active-phase sleep amount are dependent on sex chromosomes in mice.Sleep was examined in the four-core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of sex phenotype (male or female). In this line, sex phenotype is determined by the presence or absence of the Sry gene, which is dissociated from the Y chromosome. Polysomnographic sleep recordings were obtained from gonadectomized (GDX) FCG mice to examine spontaneous sleep states and the ability to recover from sleep loss. We report that during the active-phase, the presence of the Sry gene accounts for most sex differences during spontaneous sleep; however, during recovery from sleep loss, sex differences in sleep amount are partially driven by sex chromosome complement. These results suggest that genetic factors on the sex chromosomes encode the homeostatic response to sleep loss.
Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time. Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. Methods: We performed a prospective study using Mini-Mental State Examination, amyloid- (A) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients. Results: MCI, FTD, and DLB patients patients volunteered for the addition of a -3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, A phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitro -3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. Conclusion: Add-on -3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.
Nitrergic neurons of the dorsal raphe nucleus (DRN) may play a role in physiological stress responses. The caudal lateral wings (CLW) are unique compared to other rostral-caudal DRN sub-regions because they contain distinct nitric oxide (NO) synthase (NOS) populations that are independent of tryptophan hydroxylase (TPH). NOS neurons in the CLW are also highly activated during acute restraint stress. However, the effects of acute stress duration on NOS activation in the CLW are unclear. Here NADPH-d, an index of NOS activity, is used to show that sub-regions of the DRN have differential NOS activation in response to 6 hours of restraint stress in rats. We report increased NOS activity through 6 hours of restraint in the caudal lateral wings and ventromedial sub-regions. These data suggest that, NOS neurons may play a dynamic role in the response to stress duration.
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