Aging is associated with reduced circadian (daily) rhythm amplitude in physiology and behavior, and decreased function of the prefrontal cortex (PFC). Similar effects are seen in younger mice experiencing circadian desynchrony (CD) caused by exposure to 20h light-dark cycles (T20). Given changes in PFC structure/function, underlying metabolic functioning of the PFC may also occur. We aimed to determine whether there are similarities in neurometabolism between Aged and CD mice. Using enzymatic amperometric biosensors, we recorded lactate concentration changes in the medial PFC in freely-behaving mice. Young mice displayed a circadian rhythm of lactate, which was severely blunted by CD, while Aging only changed the rhythm in constant conditions. We simultaneously probed the relationship between arousal state and PFC lactate rhythms, showing relationships between arousal state and lactate concentration, and documenting changes that occurred in CD and aging. Finally, using RT-qPCR, we found changes in genes related to metabolism and plasticity in both Aged and CD mice.Together, these data suggest both Aging and light cycle manipulation can disrupt mPFC neurometabolism. Highlights• Lactate recordings were taken in Aged and circadian desynchronized (CD) mice.• Lactate displayed a circadian rhythm in Control mice which was blunted in CD mice.• The sleep state/lactate relationship was influenced by Aging, CD, and light.• Both Aging and CD changed the expression of genes related to neurometabolism.

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Aims: The hypothalamic pituitary adrenal (HPA) axis is the key neuroendocrine mediator of the stress response and controls many aspects of physiology and behavior. We previously showed that experimentally disrupting normal HPA function in mice led to altered neural and behavioral responses to acute stress. When exposed to prolonged or repeated stress, organisms undergo adaptation in many processes of metabolism, endocrine function, and behavior. Further, many of these processes are thought to be driven by HPA secreted hormones. In this study, we aimed to test this hypothesis by disrupting normal HPA axis function and measuring metabolic, endocrine, and neural outcomes following repeated stress exposure. Methods : HPA axis function in male C57BL/6 mice was disrupted via noninvasive, oral corticosterone administration, which we have shown blunts hormonal and behavioral stress responses. Mice were then exposed to repeated immobilization stress (2h/d for 14d), during which time body weight was measured to assess metabolic adaptation to stress. Mice were euthanized and adipose tissue, adrenal glands, blood, and brain were collected for analysis. We evaluated the effects of HPA disruption on mass of white adipose tissue and adrenal glands, and determined plasma corticosterone concentrations as a measure of endocrine adaptation to stress. Using RTqPCR we investigated the effects of HPA disruption on the expression of genes related to synaptic excitability in the medial prefrontal cortex (mPFC), a brain region known to regulate behavioral and emotional responses to stress. Results: Repeated stress led to body weight loss in all mice, however body weight loss was exaggerated by HPA disruption, suggesting increased sensitivity to stress. Additionally, this decrease in body weight could not be accounted for by decreased white adipose mass alone, suggesting effects on other tissues caused by HPA disruption. Repeated stress increased adrenal weight similarly in all mice, but only elevated levels of plasma corticosterone in Control mice, demonstrating altered endocrine adaptation to stress after HPA disruption. Finally, we observed increased gene expression of the astrocytic glutamate exchanger xCT in the mPFC following repeated stress only in HPA disrupted mice, suggesting that HPA disruption affects processes of neural adaptation. Conclusions: HPA axis disruption increased sensitivity to metabolic outcomes of repeated stress exposure and altered endocrine stress adaptation. Additionally, effects on mPFC gene expression suggest altered neural adaptation to stress. These results support the hypothesis that an intact HPA axis is crucial in mediating adaptive responses to stress, and that dysfunction of this system may be linked to negative health outcomes of stress exposure. Sources of Research Support: NSF 1553067 and NIA R21AG050054 to INK.

IntroductionUnderstanding how environmental interact challenges with genetic predispositions modulate health and wellbeing is an important area of biomedical research. Circadian rhythms play an important role in coordinating the multitude of cellular and tissue processes that organisms use to predict and adapt to regular changes in the environment, and robust circadian rhythms contribute to optimal physiological and behavioral responses to challenge. However, artificial lighting and modern round-the-clock lifestyles can disrupt the circadian system, leading to desynchronization of clocks throughout the brain and body. When coupled with genetic predispositions, circadian desynchronization may compound negative outcomes. Polymorphisms in the brain-derived neurotrophic (BDNF) gene contribute to variations in neurobehavioral responses in humans, including impacts on sleep, with the common Val66Met polymorphism linked to several negative outcomes.MethodsWe explored how the Val66Met polymorphism modulates the response to environmental circadian desynchronization (ECD) in a mouse model. ECD was induced by housing adult male mice in a 20 h light-dark cycle (LD10:10; 10 h light, 10 h dark). Sleep and circadian activity were recorded in homozygous (Met) mice and their wild-type (Val) littermates in a standard 24 h LD cycle (LD12:12), then again after 20, 40, and 60 days of ECD.ResultsWe found ECD significantly affected the sleep/wake timing in Val mice, however, Met mice maintained appropriate sleep timing after 20 days ECD, but not after 40 and 60 days of ECD. In addition, the rise in delta power at lights on was absent in Val mice but was maintained in Met mice. To elucidate the circadian and homeostatic contribution to disrupted sleep, mice were sleep deprived by gentle handling in LD12:12 and after 20 days in ECD. Following 6 h of sleep deprivation delta power was increased for both Val and Met mice in LD12:12 and ECD conditions. However, the time constant was significantly longer in the Val mice during ECD compared to LD12:12, suggesting a functioning but altered sleep homeostat.DiscussionThese data suggest the Val66Met mutation is associated with an ability to resist the effects of LD10:10, which may result in carriers suffering fewer negative impacts of ECD.