Background: Ample amount of data suggests role of rapid eye movement (REM) sleep deprivation as the cause and effect of mania. Studies have also suggested disrupted circadian rhythms contributing to the pathophysiology of mood disorders, including bipolar disorder. However, studies pertaining to circadian genes and effect of lithium treatment on clock genes are scant. Thus, we wanted to determine the effects of REM sleep deprivation on expression of core clock genes and determine whether epigenetics is involved. Next, we wanted to explore ultrastructural abnormalities in the hippocampus. Moreover, we were interested to determine oxidative stress, tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor levels in the central and peripheral systems.Methods: Rats were sleep deprived by the flower pot method and were then analyzed for various behaviors and biochemical tests. Lithium was supplemented in diet. Results:We found that REM sleep deprivation resulted in hyperactivity, reduction in anxiety-like behavior, and abnormal dyadic social interaction. Some of these behaviors were sensitive to lithium. REM sleep deprivation also altered circadian gene expression and caused significant imbalance between histone acetyl transferase/ histone deacetylase (HAT/HDAC) activity. Ultrastructural analysis revealed various cellular abnormalities. Lipid peroxidation and increased TNF-α levels suggested oxidative stress and ongoing inflammation. Circadian clock genes were differentially modulated with lithium treatment and HAT/HDAC imbalance was partially prevented.Moreover, lithium treatment prevented myelin fragmentation, disrupted vasculature, necrosis, inflammation, and lipid peroxidation, and partially prevented mitochondrial damage and apoptosis. Conclusions:Taken together, these results suggest plethora of abnormalities in the brain following REM sleep deprivation, many of these changes in the brain may be target of lithium's mechanism of action. K E Y W O R D SBDNF, circadian clock, HAT/HDAC, mania, oxidative stress, REM sleep deprivation | 267 ANDRABI et Al

Protein C, a member of the zymogen family of serine proteases in plasma, is one of the several vitamin K dependent glycoproteins known to induce anti-apoptotic activity. However, the target molecule involved in the mechanism needs to be investigated. We sought to investigate the pathways involved in the anti-apoptotic role of activated protein C (APC) on oxygen-glucose deprivation (OGD) induced ischemic conditions in in-vitro SH-SY5Y cells. SH-SY5Y cells were exposed to OGD in an airtight chamber containing 95% N2 and 5% CO2 and media deprived of glucose for 4 h following 24 h of reoxygenation. The cell toxicity, viability, expression of receptors such as endothelial cell protein C receptor (EPCR), protease-activated receptor (PAR)1, PAR3, and apoptosis-related proteins B-cell lymphoma 2 (BCL-2), BCL-2-like protein 4 (Bax), Poly [ADP-ribose] polymerase-1 (PARP-1) were assessed. Administration of APC decreased the cellular injury when compared to the OGD exposed group in a dose-dependent manner and displayed increased expression of PAR-1, PAR-3, and EPCR. The APC treatment leads to a reduction in PARP-1 expression and cleavage and apoptosis-inducing factor (AIF) expression. The reduction of caspase-3 activity and PARP-1 and AIF expression following APC administration results in restoring mitochondrial function with decreased cellular injury and apoptosis. Our results suggested that APC has potent protective effects against in-vitro ischemia in SH-SY5Y cells by modulating mitochondrial function.

We live on a planet that is bathed in daily and seasonal sunlight cycles. In this context, terrestrial life forms have evolved mechanisms that directly harness light energy (plants) or decode light information for adaptive advantage. In animals, the main light sensors are a family of G protein–coupled receptors called opsins. Opsin function is best described for the visual sense. However, most animals also use opsins for extraocular light sensing for seasonal behavior and camouflage. While it has long been believed that mammals do not have an extraocular light sensing capacity, recent evidence suggests otherwise. Notably, encephalopsin (OPN3) and neuropsin (OPN5) are both known to mediate extraocular light sensing in mice. Examples of this mediation include photoentrainment of circadian clocks in skin (by OPN5) and acute light-dependent regulation of metabolic pathways (by OPN3 and OPN5). This review summarizes current findings in the expanding field of extraocular photoreception and their relevance for human physiology. Expected final online publication date for the Annual Review of Vision Science, Volume 9 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Neurons in the hypothalamic preoptic area (POA) regulate multiple homeostatic processes, including thermoregulation and sleep, by sensing afferent input and modulating sympathetic nervous system output. The POA has an autonomous circadian clock and may also receive circadian signals indirectly from the suprachiasmatic nucleus. We have previously defined a subset of neurons in the POA termed QPLOT neurons that are identified by the expression of molecular markers (Qrfp, Ptger3, LepR, Opn5, Tacr3) that suggest receptivity to multiple stimuli. Because Ptger3, Opn5, and Tacr3 encode G-protein coupled receptors (GPCRs), we hypothesized that elucidating the G-protein signaling in these neurons is essential to understanding the interplay of inputs in the regulation of metabolism. Here, we describe how the stimulatory Gs-alpha subunit (Gnas) in QPLOT neurons regulates metabolism in mice. We analyzed Opn5cre; Gnasfl/fl mice using indirect calorimetry at ambient temperatures of 22°C (a historical standard), 10°C (a cold challenge), and 28°C (thermoneutrality) to assess the ability of QPLOT neurons to regulate metabolism. We observed a marked decrease in nocturnal locomotion of Opn5cre; Gnasfl/fl mice at both 28°C and 22°C, but no overall differences in energy expenditure, respiratory exchange, or food and water consumption. To analyze daily rhythmic patterns of metabolism, we assessed circadian parameters including amplitude, phase, and MESOR. Loss-of-function GNAS in QPLOT neurons resulted in several subtle rhythmic changes in multiple metabolic parameters. We observed that Opn5cre; Gnasfl/fl mice show a higher rhythm-adjusted mean energy expenditure at 22°C and 10°C, and an exaggerated respiratory exchange shift with temperature. At 28°C, Opn5cre; Gnasfl/fl mice have a significant delay in the phase of energy expenditure and respiratory exchange. Rhythmic analysis also showed limited increases in rhythm-adjusted means of food and water intake at 22°C and 28°C. Together, these data advance our understanding of Gαs-signaling in preoptic QPLOT neurons in regulating daily patterns of metabolism.