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The recurrent hormonal fluctuations within reproductive cycles impact sleepwake behavior in women and in rats and mice used in preclinical models of sleep research. Strides have been made in sleep-related clinical trials to include equal numbers of women; however, the inclusion of female rodents in neuroscience and sleep research is lacking. Female animals are commonly omitted from studies over concerns of the effect of estrus cycle hormones on measured outcomes. This review highlights the estrous cycle's broad effects on sleep-wake behavior: from changes in sleep macroarchitecture to regionally specific alterations in neural oscillations. These changes are largely driven by cycle-dependent ovarian hormonal fluctuations occurring during proestrus and estrus that modulate neural circuits regulating sleep-wake behavior. Removal of estrous cycle influence by ovariectomy ablates characteristic sleep changes. Further, sex differences in sleep are present between gonadally intact females and males. Removal of reproductive hormones via gonadectomy in both sexes mitigates some, but not all sex differences. We examine the extent to which reproductive hormones and sex chromosomes contribute to sex differences in sleep-wake behavior. Finally, this review addresses the limitations in our understanding of the estrous cycle's impact on sleep-wake behavior, gaps in female sleep research that are well studied in males, and the implications that ignoring the estrous cycle has on studies of sleep-related processes. [ABSTRACT FROM AUTHOR]

Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable) deviation from healthy physiology. In contrast, a substantial diversity of bodily responses to SARS-CoV-2 infection have been reported in the clinical milieu. This raises the question of how to characterize the diversity of illness manifestations, and whether such characterization could reveal meaningful relationships across different illness manifestations. Here, we present a framework motivated by information theory to generate quantified maps of illness presentation, which we term "manifestations," as resolved by continuous physiological data from a wearable device (Oura Ring). We test this framework on five physiological data streams (heart rate, heart rate variability, respiratory rate, metabolic activity, and sleep temperature) assessed at the time of reported illness onset in a previously reported COVID-19-positive cohort (N = 73). We find that the number of distinct manifestations are few in this cohort, compared to the space of all possible manifestations. In addition, manifestation frequency correlates with the rough number of symptoms reported by a given individual, over a several-day period prior to their imputed onset of illness. These findings suggest that information-theoretic approaches can be used to sort COVID-19 illness manifestations into types with real-world value. This proof of concept supports the use of information-theoretic approaches to map illness manifestations from continuous physiological data. Such approaches could likely inform algorithm design and real-time treatment decisions if developed on large, diverse samples. [ABSTRACT FROM AUTHOR]

Introduction: Cross frequency coupling (CFC) between electrophysiological signals in the brain is a long-studied phenomenon and its abnormalities have been observed in conditions such as Parkinson's disease and epilepsy. More recently, CFC has been observed in stomach-brain electrophysiologic studies and thus becomes an enticing possible target for diseases involving aberrations of the gut-brain axis. However, current methods of detecting coupling, specifically phase-amplitude coupling (PAC), do not attempt to capture the phase and amplitude statistical relationships. Methods: In this paper, we first demonstrate a method of modeling these joint statistics with a flexible parametric approach, where we model the conditional distribution of amplitude given phase using a gamma distributed generalized linear model (GLM) with a Fourier basis of regressors. We perform model selection with minimum description length (MDL) principle, demonstrate a method for assessing goodness-of-fit (GOF), and showcase the efficacy of this approach in multiple electroencephalography (EEG) datasets. Secondly, we showcase how we can utilize the mutual information, which operates on the joint distribution, as a canonical measure of coupling, as it is non-zero and non-negative if and only if the phase and amplitude are not statistically independent. In addition, we build off of previous work by Martinez-Cancino et al., and Voytek et al., and show that the information density, evaluated using our method along the given sample path, is a promising measure of time-resolved PAC. Results: Using synthetically generated gut-brain coupled signals, we demonstrate that our method outperforms the existing gold-standard methods for detectable low-levels of phase-amplitude coupling through receiver operating characteristic (ROC) curve analysis. To validate our method, we test on invasive EEG recordings by generating comodulograms, and compare our method to the gold standard PAC measure, Modulation Index, demonstrating comparable performance in exploratory analysis. Furthermore, to showcase its use in joint gut-brain electrophysiology data, we generate topoplots of simultaneous high-density EEG and electrgastrography recordings and reproduce seminal work by Richter et al. that demonstrated the existence of gut-brain PAC. Using simulated data, we validate our method for different types of time-varying coupling and then demonstrate its performance to track time-varying PAC in sleep spindle EEG and mismatch negativity (MMN) datasets. Conclusions: Our new measure of PAC using Gamma GLMs and mutual information demonstrates a promising new way to compute PAC values using the full joint distribution on amplitude and phase. Our measure outperforms the most common existing measures of PAC, and show promising results in identifying time varying PAC in electrophysiological datasets. In addition, we provide for using our method with multiple comparisons and show that our measure potentially has more statistical power in electrophysiologic recordings using simultaneous gut-brain datasets. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a public health burden affecting millions of people. Sustained neuroinflammation after TBI is often associated with poor outcome. As a result, increased attention has been placed on the role of immune cells in post-injury recovery. Microglia are highly dynamic after TBI and play a key role in the post-injury neuroinflammatory response. Therefore, microglia represent a malleable post-injury target that could substantially influence long-term outcome after TBI. This review highlights the cell specific role of microglia in TBI pathophysiology. Microglia have been manipulated via genetic deletion, drug inhibition, and pharmacological depletion in various preclinical TBI models. Notably, colony stimulating factor 1 (CSF1) and its receptor (CSF1R) have gained much traction in recent years as a pharmacological target on microglia. CSF1R is a transmembrane tyrosine kinase receptor that is essential for microglia proliferation, differentiation, and survival. Small molecule inhibitors targeting CSF1R result in a swift and effective depletion of microglia in rodents. Moreover, discontinuation of the inhibitors is sufficient for microglia repopulation. Attention is placed on summarizing studies that incorporate CSF1R inhibition of microglia. Indeed, microglia depletion affects multiple aspects of TBI pathophysiology, including neuroinflammation, oxidative stress, and functional recovery with measurable influence on astrocytes, peripheral immune cells, and neurons. Taken together, the data highlight an important role for microglia in sustaining neuroinflammation and increasing risk of oxidative stress, which lends to neuronal damage and behavioral deficits chronically after TBI. Ultimately, the insights gained from CSF1R depletion of microglia are critical for understanding the temporospatial role that microglia develop in mediating TBI pathophysiology and recovery. [ABSTRACT FROM AUTHOR]

Molecular and physiological determinants of the timing of reproductive events, including the pre-ovulatory LH surge and seasonal fluctuations in fertility, are incompletely understood. We used the Cryptochrome 1-deficient duper mutant to examine the role of this core circadian clock gene in Syrian hamsters. We find that the phase of the LH surge and its stability upon shifts of the light: dark cycle are altered in duper mutants. The intensity of immunoreactive PER1 in GnRH cells of the preoptic area peaks earlier in the day in duper than wild type hamsters. We note that GnRH fibers coursing through the suprachiasmatic nucleus (SCN) contact vasopressin- and VIP-immunoreactive cells, suggesting a possible locus of circadian control of the LH surge. Unlike wild types, duper hamsters do not regress their gonads within 8 weeks of constant darkness, despite evidence of melatonin secretion during the subjective night. In light of the finding that the duper allele is a stop codon in Cryptochrome 1, our results suggest important neuroendocrine functions of this core circadian clock gene. [ABSTRACT FROM AUTHOR]

Introduction: Body temperature is essential for diagnosing, managing, and following multiple medical conditions. There are several methods and devices to measure body temperature, but most do not allow continuous and prolonged measurement of body temperature. Noninvasive skin temperature sensor combined with a heat flux sensor, also known as the "double sensor" technique, is becoming a valuable and simple method for frequently monitoring body temperature. Methods: Body temperature measurements using the "double sensor" method in a wearable monitoring device were compared with oral and core body temperature measurements using medical grade thermometers, analyzing data from two prospective clinical trials of different clinical scenarios. One study included 45 hospitalized COVID-19 patients in which oral measurements were taken using a hand-held device, and the second included 18 post-cardiac surgery patients in which rectal measurements were taken using a rectal probe. Results: In study 1, Bland-Altman analysis showed a bias of -0.04°C [0.34-(-0.43)°C, 95% LOA] with a correlation of 99.4% (p < 0.001). In study 2, Bland-Altman analysis showed a bias of 0.0°C [0.27-(-0.28)°C, 95% LOA], and the correlation was 99.3% (p < 0.001). In both studies, stratifying patients based on BMI and skin tone showed high accordance in all sub-groups. Discussion: The wearable monitor showed high correlation with oral and core body temperature measurements in different clinical scenarios. [ABSTRACT FROM AUTHOR]

Coordinated fluctuations in female reproductive physiology and thermoregulatory output have been reported for over a century. These changes occur rhythmically at the hourly (ultradian), daily (circadian), and multi-day (ovulatory) timescales, are critical for reproductive function, and have led to the use of temperature patterns as a proxy for female reproductive state. The mechanisms underlying coupling between reproductive and thermoregulatory systems are not fully established, hindering the expansion of inferences that body temperature can provide about female reproductive status. At present, numerous digital tools rely on temperature to infer the timing of ovulation and additional applications (e.g., monitoring ovulatory irregularities and progression of puberty, pregnancy, and menopause are developed based on the assumption that reproductive-thermoregulatory coupling occurs across timescales and life stages. However, without clear understanding of the mechanisms and degree of coupling among the neural substrates regulating temperature and the reproductive axis, whether such approaches will bear fruit in particular domains is uncertain. In this overview, we present evidence supporting broad coupling among the central circuits governing reproduction, thermoregulation, and broader systemic physiology, focusing on timing at ultradian frequencies. Future work characterizing the dynamics of reproductive-thermoregulatory coupling across the lifespan, and of conditions that may decouple these circuits (e.g., circadian disruption, metabolic disease) and compromise female reproductive health, will aid in the development of strategies for early detection of reproductive irregularities and monitoring the efficacy of fertility treatments. [ABSTRACT FROM AUTHOR]

Astrocytes are important regulators of blood flow and play a key role in the response to injury and disease in the central nervous system (CNS). Despite having an understanding that structural changes to these cells have consequences for local neurovascular physiology, individual astrocyte morphology remains largely unexplored in the retina. Here, we used MORF3 mice to capture full membranous morphology for over fifteen hundred individual astrocytes in the mouse retina, a highly metabolically active component of the CNS. We demonstrate that retinal astrocytes have been misrepresented as stellate in morphology due to marker use like GFAP and S100β which underestimates cell complexity. We also find that astrocytes contain recurring morphological motifs which are predictive of the underlying neurovascular architecture of the inner retina and suggestive of function. These motifs predict fine sampling and integration of retinal ganglion cell electrical activity with consequences for blood flow regulation. Additionally, our data shows that astrocytes participate in neurovascular interactions to a much greater degree than currently reported. 100% of cells contact the vasculature through one of three mutually exclusive classes of connections. Similarly, 100% of cells contact some neuronal element, be it an RGC axon or soma. Finally, we report that astrocyte morphology depends on retinal eccentricity, with cells appearing compressed near the nerve head and in the periphery. These results reveal a large degree of astrocyte morphological complexity that informs their contribution to neurovascular coupling in the retina. [ABSTRACT FROM AUTHOR]

Introduction: Sex bias has been an issue in many biomedical fields, especially in neuroscience. In rodent research, many scientists only focused on male animals due to the belief that female estrous cycle gives rise to unacceptable, high levels of variance in the experiments. However, even though female sexual behaviors are well known to be regulated by estrous cycle, which effects on other nonsexual behaviors were not always consistent in previous reports. Recent reviews analyzing published literature even suggested that there is no evidence for larger variation in female than male in several phenotypes. Methods: To further investigate the impact of estrous cycle on the variability of female behaviors, we conducted multiple behavioral assays, including the open field test, forced swimming test, and resident-intruder assay to assess anxiety-, depression-like behaviors, as well as social interaction respectively. We compared females in the estrus and diestrus stages across four different mouse strains: C57BL/6, BALB/c, C3H, and DBA/2. Results: Our results found no significant difference in most behavioral parameters between females in these two stages. On the other hand, the differences in behaviors among certain strains are relatively consistent in both stages, suggesting a very minimal effect of estrous cycle for detecting the behavioral difference. Last, we compared the behavioral variation between male and female and found very similar variations in most behaviors between the two sexes. Discussion: While our study successfully identified behavioral differences among strains and between the sexes, we did not find solid evidence to support the notion that female behaviors are influenced by the estrous cycle. Additionally, we observed similar levels of behavioral variability between males and females. Female mice, therefore, have no reason to be excluded in future behavioral research. [ABSTRACT FROM AUTHOR]

Astrocytes are an abundantly distributed population of glial cells in the central nervous system (CNS) that perform myriad functions in the normal and injured/ diseased brain. Astrocytes exhibit heterogeneous phenotypes in response to various insults, a process known as astrocyte reactivity. The accuracy and precision of brain signaling are primarily based on interactions involving neurons, astrocytes, oligodendrocytes, microglia, pericytes, and dendritic cells within the CNS. Astrocytes have emerged as a critical entity within the brain because of their unique role in recycling neurotransmitters, actively modulating the ionic environment, regulating cholesterol and sphingolipid metabolism, and influencing cellular crosstalk in diverse neural injury conditions and neurodegenerative disorders. However, little is known about how an astrocyte functions in synapse formation, axon specification, neuroplasticity, neural homeostasis, neural network activity following dynamic surveillance, and CNS structure in neurological diseases. Interestingly, the tripartite synapse hypothesis came to light to fill some knowledge gaps that constitute an interaction of a subpopulation of astrocytes, neurons, and synapses. This review highlights astrocytes' role in health and neurological/neurodegenerative diseases arising from the omnidirectional signaling between astrocytes and neurons at the tripartite synapse. The review also recapitulates the disruption of the tripartite synapse with a focus on perturbations of the homeostatic astrocytic function as a key driver to modulate the molecular and physiological processes toward neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Reactive astrogliosis is a reaction of astrocytes to disturbed homeostasis in the central nervous system (CNS), accompanied by changes in astrocyte numbers, morphology, and function. Reactive astrocytes are important in the onset and progression of many neuropathologies, such as neurotrauma, stroke, and neurodegenerative diseases. Single-cell transcriptomics has revealed remarkable heterogeneity of reactive astrocytes, indicating their multifaceted functions in a whole spectrum of neuropathologies, with important temporal and spatial resolution, both in the brain and in the spinal cord. Interestingly, transcriptomic signatures of reactive astrocytes partially overlap between neurological diseases, suggesting shared and unique gene expression patterns in response to individual neuropathologies. In the era of single-cell transcriptomics, the number of new datasets steeply increases, and they often benefit from comparisons and integration with previously published work. Here, we provide an overview of reactive astrocyte populations defined by single-cell or single-nucleus transcriptomics across multiple neuropathologies, attempting to facilitate the search for relevant reference points and to improve the interpretability of new datasets containing cells with signatures of reactive astrocytes. [ABSTRACT FROM AUTHOR]

Reactive astrogliosis is a reaction of astrocytes to disturbed homeostasis in the central nervous system (CNS), accompanied by changes in astrocyte numbers, morphology, and function. Reactive astrocytes are important in the onset and progression of many neuropathologies, such as neurotrauma, stroke, and neurodegenerative diseases. Single-cell transcriptomics has revealed remarkable heterogeneity of reactive astrocytes, indicating their multifaceted functions in a whole spectrum of neuropathologies, with important temporal and spatial resolution, both in the brain and in the spinal cord. Interestingly, transcriptomic signatures of reactive astrocytes partially overlap between neurological diseases, suggesting shared and unique gene expression patterns in response to individual neuropathologies. In the era of single-cell transcriptomics, the number of new datasets steeply increases, and they often benefit from comparisons and integration with previously published work. Here, we provide an overview of reactive astrocyte populations defined by single-cell or single-nucleus transcriptomics across multiple neuropathologies, attempting to facilitate the search for relevant reference points and to improve the interpretability of new datasets containing cells with signatures of reactive astrocytes. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) subtypes are a major cause of illness and mortality worldwide and pose a threat to human health. Although IAV infection is considered a self-limiting respiratory syndrome, an expanded spectrum of cerebral manifestations has been reported following IAV infection. Neurotropic IAVs, such as the H7N7 subtype, are capable of invading the central nervous system (CNS) and replicating in brain cells, resulting in microglia-induced neuroinflammation. Microglial cells, the brain's resident immune cells, are instrumental in the inflammatory response to viral infection. While activation of microglia is important to initially contain the virus, excessive activation of these cells leads to neuronal damage. Previous studies have shown that acute and even long-term IAV-induced neuroinflammation leads to CNS damage. Therefore, the search for possible preventive or therapeutic strategies is of great importance. In this study, we investigated the potential effect of vaccination against acute neuroinflammation induced by H7N7 infection and subsequent neuronal damage in the hippocampus, a particularly vulnerable brain region, comparing young and aged mice. Immunosenescence is one of the striking pathophysiological changes during mammalian aging that leads to "inflammaging" and critically limits the protection by vaccines in the elderly. The results suggest that formalin-inactivated H7N7 vaccine has a preventive effect against the inflammatory responses in the periphery and also in the CNS after H7N7 infection. Cytokine and chemokine levels, increased microglial density, and cell volume after H7N7 infection were all attenuated by vaccination. Further structural analysis of microglial cells also revealed a change in branching complexity after H7N7 infection, most likely reflecting the neuroprotective effect of the vaccination. In addition, synapse loss was prevented in vaccinated mice. Remarkably, engulfment of post-synaptic compartments by microglia can be proposed as the underlying mechanism for spine loss triggered by H7N7 infection, which was partially modulated by vaccination. Although young mice showed better protection against neuroinflammation and the resulting deleterious neuronal effects upon vaccination, a beneficial role of the vaccine was also observed in the brains of older mice. Therefore, vaccination can be proposed as an important strategy to prevent neurological sequelae of H7N7 infection. [ABSTRACT FROM AUTHOR]

Circadian rhythms influence virtually all aspects of physiology and behavior. This is problematic when circadian rhythms no longer reliably predict time. Circadian rhythm disruption can impair memory, yet we don't know how this fully works at the systems and molecular level. When trying to determine the root of a memory impairment, assessing neuronal activation with c-FOS is useful. This has yet to be assessed in the hippocampi of circadian rhythm disrupted rats in a hippocampal gold standard task. Rats were trained on the Morris water task (MWT), then received 6 days of a 21-h day (T21), 13 days of a normal light dark cycle, probe trial, and tissue extraction an hour later. Despite having impaired memory in the probe trial, compared to controls there were no differences in c-FOS expression in hippocampal sub regions: CA1; CA3; Dentate gyrus. These data confirm others in hamsters demonstrating that arrhythmicity which produces an impairment in spontaneous alternation does not affect c-FOS in the dentate gyrus. The current study indicates that the memory impairment induced by a lighting manipulation is likely not due to attenuated neuronal activation. Determining how the master clock in the brain communicates with the hippocampus is needed to untangle the relationship between circadian rhythms and memory. [ABSTRACT FROM AUTHOR]

Even though studies have shown that prenatal maternal stress is associated with increased reactivity of the HPA axis, the association between prenatal maternal stress and fetal glucocorticoid exposure is complex and most likely dependent on unidentified and poorly understood variables including nature and timing of prenatal insults. The precise mechanisms in which prenatal maternal stress influence neuroendocrine signaling between the maternal-placental-fetal interface are still unclear. The aim of this review article is to bring comprehensive basic concepts about prenatal maternal stress and mechanisms of transmission of maternal stress to the fetus. This review covers recent studies showing associations between maternal stress and alterations in offspring aggressive behavior, as well as the possible pathways for the “transmission” of maternal stress to the fetus: (1) maternal-fetal HPA axis dysregulation; (2) intrauterine environment disruption due to variations in uterine artery flow; (3) epigenetic modifications of genes implicated in aggressive behavior. Here, we present evidence for the phenomenon of intergenerational and transgenerational transmission, to better understands the mechanism(s) of transmission from parent to offspring. We discuss studies showing associations between maternal stress and alterations in offspring taking note of neuroendocrine, brain architecture and epigenetic changes that may suggest risk for aggressive behavior. We highlight animal and human studies that focus on intergenerational transmission following exposure to stress from a biological mechanistic point of view, and maternal stress induced epigenetic modifications that have potential to impact on aggressive behavior in later generations. [ABSTRACT FROM AUTHOR]

Fear memory in species varies according to the time of the day. Although the underlying molecular mechanisms have been extensively explored, they remain largely unknown. Here, we report that hippocampal Rac1 activity undergoes a time of day-dependent alteration both in nocturnal rats and diurnal tree shrews and that training at the lower hippocampal Rac1 activation period during the night leads to better contextual fear memory in rats. Furthermore, day and night reversion by 24 h darkness/24 h light housing inverses the external clock time of hippocampal Rac1 activation, but the better contextual fear memory still coincides with the lower Rac1 activation in rats during the night. Interestingly, exogenous melatonin treatment promotes hippocampal Rac1 activity and impairs better contextual fear memory acquired at the lower Rac1 activation period during the night, and Rac1-specific inhibitor NSC23766 compromises the effect of melatonin. These results suggest that the time of day-dependent alteration of hippocampal Rac1 activation regulates contextual fear memory in rats by forgetting. [ABSTRACT FROM AUTHOR]

Psychological stress, both leading up to and during pregnancy, is associated with increased risk for negative pregnancy outcomes. Although the neuroendocrine circuits that link the stress response to reduced sexual motivation and mating are well-described, the specific pathways by which stress negatively impacts gestational outcomes remain unclear. Using a mouse model of chronic psychological stress during pregnancy, we investigated 1) how chronic exposure to stress during gestation impacts maternal reproductive neuroendocrine circuitry, and 2) whether stress alters developmental outcomes for the fetus or placenta by mid-pregnancy. Focusing on the stress-responsive neuropeptide RFRP-3, we identified novel contacts between RFRP-3-immunoreactive (RFRP-3-ir) cells and tuberoinfundibular dopaminergic neurons in the arcuate nucleus, thus providing a potential pathway linking the neuroendocrine stress response directly to pituitary prolactin production and release. However, neither of these cell populations nor circulating levels of pituitary hormones were affected by chronic stress. Conversely, circulating levels of steroid hormones relevant to gestational outcomes (progesterone and corticosterone) were altered in chronically-stressed dams across gestation, and those dams were qualitatively more likely to experience delays in fetal development. Together, these findings suggest that, up until at least mid-pregnancy, mothers appear to be relatively resilient to the effects of elevated glucocorticoids on reproductive neuroendocrine system function. We conclude that understanding how chronic psychological stress impacts reproductive outcomes will require understanding individual susceptibility and identifying reliable neuroendocrine changes resulting from gestational stress. [ABSTRACT FROM AUTHOR]

Background: Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies. Questions Addressed: To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology. Evidence Surveyed: The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses. Conclusion: The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels. [ABSTRACT FROM AUTHOR]

The aims of the present study were to obtain sleep quality and sleep timing information in a group of university students and to evaluate the effects of a circadian hygiene education initiative. All students of the University of Padova (approximately 64,000) were contacted by e-mail (major campaigns in October 2019 and October 2020) and directed to an ad hoc website for collection of demographics and sleep quality/timing information. Participants (n = 5,740) received one of two sets of circadian hygiene advice ("A regular life" or "Bright days and dark nights"). Every month, they were then asked how easy it had been to comply and provided with the advice again. At any even month from joining, they completed the sleep quality/timing questionnaires again. Information on academic performance was obtained post hoc , together with representative samples of lecture (n = 5,972) and examination (n = 1,800) timings, plus lecture attendances (n = 25,302). Fifty-two percent of students had poor sleep quality, and 82% showed signs of social jetlag. Those who joined in October 2020, after several months of lockdown and distance learning, had better sleep quality, less social jetlag, and later sleep habits. Over approximately a year, the "Bright days and dark nights" advice resulted in significantly earlier get-up times compared with the "A regular life" advice. Similarly, it also resulted in a trend toward earlier midsleep (i.e., the midpoint, expressed as clock time, between sleep onset and sleep offset) and toward a decrease in the latency between wake-up and get-up time, with no impact on sleep duration. Significant changes in most sleep quality and sleep timing variables (i.e., fewer night awakenings, less social jetlag, and delayed sleep timing during lock-down) were observed in both advice groups over approximately a year, mostly in association with pandemic-related events characterizing 2020. Early chronotype students had better academic performances compared with their later chronotype counterparts. In a multivariate model, sleep quality, chronotype and study subject (science and technology, health and medical, or social and humanities) were independent predictors of academic performance. Taken together, these results underlie the importance of designing circadian-friendly university timetables. [ABSTRACT FROM AUTHOR]

Behavioral flexibility is critical to survival. Animals must adapt their behavioral responses based on changes in the environmental context, internal state, or experience. Studies in Drosophila melanogaster have provided insight into the neural circuit mechanisms underlying behavioral flexibility. Here we discuss how Drosophila behavior is modulated by internal and behavioral state, environmental context, and learning. We describe general principles of neural circuit organization and modulation that underlie behavioral flexibility, principles that are likely to extend to other species. [ABSTRACT FROM AUTHOR]

Tiling is a developmental process where cell populations become evenly distributed throughout a tissue. In this review, we discuss the developmental cellular tiling behaviors of the two major glial populations in the central nervous system (CNS)—oligodendrocyte progenitor cells (OPCs) and astrocytes. First, we discuss OPC tiling in the spinal cord, which is comprised of the three cellular behaviors of migration, proliferation, and contact-mediated repulsion (CMR). These cellular behaviors occur simultaneously during OPC development and converge to produce the emergent behavior of tiling which results in OPCs being evenly dispersed and occupying non-overlapping domains throughout the CNS. We next discuss astrocyte tiling in the cortex and hippocampus, where astrocytes migrate, proliferate, then ultimately determine their exclusive domains by gradual removal of overlap rather than sustained CMR. This results in domains that slightly overlap, allowing for both exclusive control of "synaptic islands" and astrocyte-astrocyte communication. We finally discuss the similarities and differences in the tiling behaviors of these glial populations and what remains unknown regarding glial tiling and how perturbations to this process may impact injury and disease. [ABSTRACT FROM AUTHOR]

Astrocytes are numerous glial cells of the central nervous system (CNS) and play important roles in brain homeostasis. These cells can directly communicate with neurons by releasing gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, into the multipartite synapse. Moreover, astrocytes respond to tissue injury in the CNS environment. Recently, astrocytic heterogeneity and plasticity have been discussed by several authors, with studies proposing a spectrum of astrocytic activation characterized by A1 /neurotoxic and A2 /neuroprotective polarization extremes. The fundamental roles of astrocytes in communicating with other cells and sustaining homeostasis are regulated by purinergic signaling. In the CNS environment, the gliotransmitter ATP acts cooperatively with other glial signaling molecules, such as cytokines, which may impact CNS functions by facilitating/inhibiting neurotransmitter release. Adenosine (ADO), the main product of extracellular ATP metabolism, is an important homeostatic modulator and acts as a neuromodulator in synaptic transmission via P1 receptor sensitization. Furthermore, purinergic signaling is a key factor in the tumor microenvironment (TME), as damaged cells release ATP, leading to ADO accumulation in the TME through the ectonucleotidase cascade. Indeed, the enzyme CD73, which converts AMP to ADO, is overexpressed in glioblastoma cells; this upregulation is associated with tumor aggressiveness. Because of the crucial activity of CD73 in these cells, extracellular ADO accumulation in the TME contributes to sustaining glioblastoma immune escape while promoting A2 -like activation. The present review describes the importance of ADO in modulating astrocyte polarization and simultaneously promoting tumor growth. We also discuss whether targeting of CD73 to block ADO production can be used as an alternative cancer therapy. [ABSTRACT FROM AUTHOR]

Adolescence is a period of continuous development, including the maturation of endogenous rhythms across systems and timescales. Although, these dynamic changes are well-recognized, their continuous structure and hormonal dependence have not been systematically characterized. Given the well-established link between core body temperature (CBT) and reproductive hormones in adults, we hypothesized that high-resolution CBT can be applied to passively monitor pubertal development and disruption with high fidelity. To examine this possibility, we used signal processing to investigate the trajectory of CBT rhythms at the within-day (ultradian), daily (circadian), and ovulatory timescales, their dependence on estradiol (E2), and the effects of hormonal contraceptives. Puberty onset was marked by a rise in fecal estradiol (fE2), followed by an elevation in CBT and circadian power. This time period marked the commencement of 4-day rhythmicity in fE2, CBT, and ultradian power marking the onset of the estrous cycle. The rise in circadian amplitude was accelerated by E2 treatment, indicating a role for this hormone in rhythmic development. Contraceptive administration in later adolescence reduced CBT and circadian power and resulted in disruption to 4-day cycles that persisted after discontinuation. Our data reveal with precise temporal resolution how biological rhythms change across adolescence and demonstrate a role for E2 in the emergence and preservation of multiscale rhythmicity. These findings also demonstrate how hormones delivered exogenously in a non-rhythmic pattern can disrupt rhythmic development. These data lay the groundwork for a future in which temperature metrics provide an inexpensive, convenient method for monitoring pubertal maturation and support the development of hormone therapies that better mimic and support human chronobiology. [ABSTRACT FROM AUTHOR]

The human brain contains a wide array of billions of neurons and interconnections, which are often simplified for analysis in vitro using compartmentalized microfluidic devices for neuronal cell culturing, to better understand neuronal development and disease. However, such devices are traditionally incompatible for high-pressure freezing and high-resolution nanoscale imaging and analysis of their sub-cellular processes by methods including electron microscopy. Here we develop a novel compartmentalized neuronal co-culture platform allowing reconstruction of neuronal networks with high variable spatial control, which is uniquely compatible for high-pressure freezing. This cryo-fixation method is well-established to enable high-fidelity preservation of the reconstructed neuronal networks and their sub-cellular processes in a near-native vitreous state without requiring chemical fixatives. To direct the outgrowth of neurites originating from two distinct groups of neurons growing in the two different compartments, polymer microstructures akin to microchannels are fabricated atop of sapphire disks. Two populations of neurons expressing either enhanced green fluorescent protein (EGFP) or mCherry were grown in either compartment, facilitating the analysis of the specific interactions between the two separate groups of cells. Neuronally differentiated PC12 cells, murine hippocampal and striatal neurons were successfully used in this context. The design of this device permits direct observation of entire neuritic processes within microchannels by optical microscopy with high spatial and temporal resolution, prior to processing for high-pressure freezing and electron microscopy. Following freeze substitution, we demonstrate that it is possible to process the neuronal networks for ultrastructural imaging by electron microscopy. Several key features of the embedded neuronal networks, including mitochondria, synaptic vesicles, axonal terminals, microtubules, with well-preserved ultrastructures were observed at high resolution using focused ion beam – scanning electron microscopy (FIB-SEM) and serial sectioning – transmission electron microscopy (TEM). These results demonstrate the compatibility of the platform with optical microscopy, high-pressure freezing and electron microscopy. The platform can be extended to neuronal models of brain disease or development in future studies, enabling the investigation of subcellular processes at the nanoscale within two distinct groups of neurons in a functional neuronal pathway, as well as pharmacological testing and drug screening. [ABSTRACT FROM AUTHOR]

Keywords: heart rate variability; COVID-19 pandemic; community prevalence; networked hardware/software systems; digital epidemiology; Internet of Healthy Things (IoHT) EN heart rate variability COVID-19 pandemic community prevalence networked hardware/software systems digital epidemiology Internet of Healthy Things (IoHT) 1 4 4 06/10/21 20210608 NES 210608 Introduction According to the Johns Hopkins Coronavirus Resources Center, the number of confirmed COVID-19 cases exceeds 170,558,922 worldwide today with more than 3,546,881 fatalities (2021). HRV has been described in this special HRV Horizons 2030 Frontiers series as follows: "HRV offers insights into humoral, neural, and neurovisceral processes in health and disorders of brain, body, and behavior but has yet to be fully potentiated in the digital age" (Owens, [25]). HRV research has produced extensive literature, with a recent PubMed search of the term "heart rate variability" producing more than 50,000 citations (Malik and Camm, [22]; Shaffer and Ginsberg, [33]), with rapidly evolving neuroscientific HRV studies (Holzman and Bridgett, [16]). [Extracted from the article]

In this article, I describe the development of the disruptive phase shift (DPS) protocol and its utility for studying how circadian dysfunction impacts memory processing in the hippocampus. The suprachiasmatic nucleus (SCN) of the Siberian hamster is a labile circadian pacemaker that is easily rendered arrhythmic (ARR) by a simple manipulation of ambient lighting. The DPS protocol uses room lighting to administer a phase-advancing signal followed by a phase-delaying signal within one circadian cycle to suppress clock gene rhythms in the SCN. The main advantage of this model for inducing arrhythmia is that the DPS protocol is non-invasive; circadian rhythms are eliminated while leaving the animals neurologically and genetically intact. In the area of learning and memory, DPS arrhythmia produces much different results than arrhythmia by surgical ablation of the SCN. As I show, SCN ablation has little to no effect on memory. By contrast, DPS hamsters have an intact, but arrhythmic, SCN which produces severe deficits in memory tasks that are accompanied by fragmentation of electroencephalographic theta oscillations, increased synaptic inhibition in hippocampal circuits, and diminished responsiveness to cholinergic signaling in the dentate gyrus of the hippocampus. The studies reviewed here show that DPS hamsters are a promising model for translational studies of adult onset circadian dysfunction in humans. [ABSTRACT FROM AUTHOR]

Understanding employee stress has become a key issue for top management for corporate growth and risk reduction. So far, annual employee satisfaction surveys (ESs) have been conducted to assess the soundness of an organization. However, since it is difficult to collect questionnaires quantitatively and continuously, there is a need for a practical method that can be used to frequently measure group stress levels with a small burden on employees. We propose such a method and evaluated four combinations of approaches, using activity/rest duration distributions from body motion data and generating estimation models on an individual/group basis. The optimal result was obtained when modeling was made on a group basis by using the activity duration distribution (r = 0.928, p < 0.001, estimation error: 1.36%), making it possible to assess the degree of the stress of employees quantitatively and easily, and this showed the possibility of this method being useful as a management guide for companies. [ABSTRACT FROM AUTHOR]

The circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in maternal body temperature, hormones and nutrients. Circadian disruption during pregnancy is associated with negative effects on developmental outcomes in the offspring, highlighting the importance of regular and robust 24-h rhythms over gestation. In the case of preterm birth (before 37 weeks of gestation), maternal cues no longer synchronize the neonate's circadian system, which may adversely affect the neonate. There is increasing evidence that introducing robust light-dark cycles in the Neonatal Intensive Care Unit has beneficial effects on clinical outcomes in preterm infants, such as weight gain and hospitalization time, compared to infants exposed to constant light or constant near-darkness. However, the biological basis for these effects and the relationship with the functional and anatomical development of the circadian system is not fully understood. In this review, we provide a concise overview of the effects of light-dark cycles on clinical outcomes of preterm neonates in the NICU and its alignment with the development of the circadian system. [ABSTRACT FROM AUTHOR]

Histopathological analysis of cellular changes in the stroked brain provides critical information pertaining to inflammation, cell death, glial scarring, and other dynamic injury and recovery responses. However, commonly used manual approaches are hindered by limitations in speed, accuracy, bias, and the breadth of morphological information that can be obtained. Here, a semi-automated high-content imaging (HCI) and CellProfiler histological analysis method was developed and used in a Yucatan miniature pig permanent middle cerebral artery occlusion (pMCAO) model of ischemic stroke to overcome these limitations. Evaluation of 19 morphological parameters in IBA1+ microglia/macrophages, GFAP+ astrocytes, NeuN+ neuronal, FactorVIII+ vascular endothelial, and DCX+ neuroblast cell areas was conducted on porcine brain tissue 4 weeks post pMCAO. Out of 19 morphological parameters assessed in the stroke perilesional and ipsilateral hemisphere regions (38 parameters), a significant change in 38 38 measured IBA1+ parameters, 34 38 GFAP+ parameters, 32 38 NeuN+ parameters, 31 38 FactorVIII+ parameters, and 28 38 DCX+ parameters were observed in stroked vs. non-stroked animals. Principal component analysis (PCA) and correlation analyses demonstrated that stroke-induced significant and predictable morphological changes that demonstrated strong relationships between IBA1+, GFAP+, and NeuN+ areas. Ultimately, this unbiased, semi-automated HCI and CellProfiler histopathological analysis approach revealed regional and cell specific morphological signatures of immune and neural cells after stroke in a highly translational porcine model. These identified features can provide information of disease pathogenesis and evolution with high resolution, as well as be used in therapeutic screening applications. [ABSTRACT FROM AUTHOR]

The circadian (24 h) clock system adapts physiology and behavior to daily recurring changes in the environment. Compared to the extensive knowledge assembled over the last decades on the circadian system in adults, its regulation and function during development is still largely obscure. It has been shown that environmental factors, such as stress or alterations in photoperiod, disrupt maternal neuroendocrine homeostasis and program the offspring's circadian function. However, the process of circadian differentiation cannot be fully dependent on maternal rhythms alone, since circadian rhythms in offspring from mothers lacking a functional clock (due to SCN lesioning or genetic clock deletion) develop normally. This mini-review focuses on recent findings suggesting that the embryo/fetal molecular clock machinery is present and functional in several tissues early during gestation. It is entrained by maternal rhythmic signals crossing the placenta while itself controlling responsiveness to such external factors to certain times of the day. The elucidation of the molecular mechanisms through which maternal, placental and embryo/fetal clocks interact with each other, sense, integrate and coordinate signals from the early life environment is improving our understanding of how the circadian system emerges during development and how it affects physiological resilience against external perturbations during this critical time period. [ABSTRACT FROM AUTHOR]

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges – a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy – and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (Per1 , Per2 , and Nr1d1), clock-controlled (Dbp) genes, as well as genes involved in sensing various signals, such as c-fos and Nr3c1. Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of c-fos and Nr3c1 in the fetal SCN. We identified c-fos as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the c-fos expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in Vip expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans. [ABSTRACT FROM AUTHOR]

Hantaviruses rewire the host cell and induce extensive membrane rearrangements for their replication and the morphogenesis of the virion. Transmission electron microscopy (TEM) is a powerful technique for imaging these pathological membrane changes especially when combined with large volume electron tomography. Excellent preservation of membrane structure can be obtained when chemical fixation is combined with cryofixation via high pressure freezing making the samples amenable to serial-section tomographic reconstruction. Taking advantage of this, we have optimized a hybrid method that employs aldehyde fixation, a step that is essential for virus inactivation, followed by high-pressure freezing for ultrastructural study of Hantaan (HTN) and Andes (AND) virus infected Vero E6 cells. HTNV and ANDV are two species of the Orthohantavirus , from the Old and New World, respectively, and the causative agents of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome in humans. We applied the method for the qualitative assessment of the perturbation of the endomembrane system induced by HTNV and ANDV in infected vs. mock-infected cells. Screening of serial-sections revealed consistency of membrane preservation across large volumes indicating potential of these samples for tomographic studies. Images revealed large-scale perturbations of the endomembrane system following HTNV-infection that included the dilation of the rough endoplasmic reticulum and fragmentation of the Golgi apparatus. Infected cells exhibited a tendency to accumulate large numbers of vacuoles that were especially apparent in ANDV. In summary, our hybrid method provides a path for the study of BSL-3 pathogens using cutting edge 3D-imaging technologies. [ABSTRACT FROM AUTHOR]

Understanding how building blocks of life contribute to physiology is greatly aided by protein identification and cellular localization. The two main labeling approaches developed over the past decades are labeling with antibodies such as immunoglobulin G (IgGs) or use of genetically encoded tags such as fluorescent proteins. However, IgGs are large proteins (150 kDa), which limits penetration depth and uncertainty of target position caused by up to ∼25 nm distance of the label created by the chosen targeting approach. Additionally, IgGs cannot be easily recombinantly modulated and engineered as part of fusion proteins because they consist of multiple independent translated chains. In the last decade single domain antigen binding proteins are being explored in bioscience as a tool in revealing molecular identity and localization to overcome limitations by IgGs. These nanobodies have several potential benefits over routine applications. Because of their small size (15 kDa), nanobodies better penetrate during labeling procedures and improve resolution. Moreover, nanobodies cDNA can easily be fused with other cDNA. Multidomain proteins can thus be easily engineered consisting of domains for targeting (nanobodies) and visualization by fluorescence microscopy (fluorescent proteins) or electron microscopy (based on certain enzymes). Additional modules for e.g., purification are also easily added. These nanobody-based probes can be applied in cells for live-cell endogenous protein detection or may be purified prior to use on molecules, cells or tissues. Here, we present the current state of nanobody-based probes and their implementation in microscopy, including pitfalls and potential future opportunities. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ1–42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ1–42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ1–42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ1–42-injected mice compared with controls. These molecular changes in Aβ1–42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ1–42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits. [ABSTRACT FROM AUTHOR]

Sodium (Na+) can accumulate in the skin tissue, sequestered by negatively charged glycosaminoglycans (GAGs). During dietary salt overload, the amount and charge density of dermal GAG molecules – e.g., hyaluronic acid (HA) and chondroitin sulfate (CS) – increases; however, the regulation of the process is unknown. Previously, it has been demonstrated that the level of cyclooxygenase-2 (COX-2) activity and the content of prostaglandin E2 (PGE2) are elevated in the skin due to high-salt consumption. A link between the COX-2/PGE2 system and GAG synthesis was also suggested. We hypothesized that in dermal fibroblasts (DFs) high-sodium concentration activates the COX-2/PGE2 pathway and also that PGE2 increases the production of HA. Our further aim was to demonstrate that the elevation of the GAG content is ceased by COX-2 inhibition in a salt overloaded animal model. For this, we investigated the messenger RNA (mRNA) expression of COX-2 and HA synthase 2 enzymes as well as the PGE2 and HA production of DFs by real-time reverse transcription PCR (qRT-PCR) and ELISA, respectively. The results showed that both high-sodium concentration and PGE2 treatment increases HA content of the media. Sodium excess activates the COX-2/PGE2 pathway in DFs, and COX-2 inhibition decreases the synthesis of HA. In the animal experiment, the HA- and CS disaccharide content in the skin of male Wistar rats was measured using high performance liquid chromatography-mass spectrometry (HPLC-MS). In the skin of rats receiving high-salt diet, the content of both HA‐ and monosulfated-CS disaccharides increased, whereas COX-2 inhibition blocked this overproduction. In conclusion, high-salt environment could induce GAG production of DFs in a COX-2/PGE2-dependent manner. Moreover, the COX-2 inhibition resulted in a decreased skin GAG content of the salt overloaded rats. These data revealed a new DF-mediated regulation of GAG synthesis in the skin during salt overload. [ABSTRACT FROM AUTHOR]

In humans, anxiety and cognitive processes are age, gender, and time of day dependent. The purpose of the present study was to assess whether the time of day and sex have an influence on anxiety and emotional memory in adult mice. Light-dark and passive avoidance (PA) tests were performed at the beginning and at the end of the light cycle, defined as Zeitgeber time (ZT) ZT0–2.5 and ZT9.5–12, respectively. A baseline difference in anxiety was not found, but on the 24 h retention trial of the PA test, females presented longer latencies to enter into the dark compartment at the ZT0–2.5 time point of the day. The data from the second test day (PA reversal trial) indicated that some animals associated the dark compartment with an aversive stimulus (shock), while others associated the aversive stimulus with crossing from one compartment to another. At the ZT9.5–12, female mice mainly related the aversive stimulus to transferring from one compartment to another, while male mice associated darkness with the aversive stimulus. There was a negative correlation between the frequency of light-dark transitions in the light-dark test and the PA latency on the 24 h retention trial in males tested at ZT0–2.5. The PA latency on the reversal and 24 h retention trials negatively correlated with a risk assessment behavior in male mice tested on ZT0–2.5 and ZT9.5–12, respectively. In conclusion, our data reveal that the impact of motor activity and risk assessment behavior on PA memory formation and applied behavioral strategies are time of day and sex dependent. [ABSTRACT FROM AUTHOR]

A hallmark feature of Alzheimer's disease (AD) and other Tauopathies, like Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is the accumulation of neurofibrillary tangles composed of the microtubule-associated protein Tau. As in AD, symptoms of FTDP-17 include cognitive decline, neuronal degeneration, and disruptions of sleep patterns. However, mechanisms by which Tau may lead to these disturbances in sleep and activity patterns are unknown. To identify such mechanisms, we have generated novel Drosophila Tauopathy models by replacing endogenous fly dTau with normal human Tau (hTau) or the FTDP-17 causing hTauV337M mutation. This mutation is localized in one of the microtubule-binding domains of hTau and has a dominant effect. Analyzing heterozygous flies, we found that aged hTauV337M flies show neuronal degeneration and locomotion deficits when compared to wild type or hTauWT flies. Furthermore, hTauV337M flies are hyperactive and they show a fragmented sleep pattern. These changes in the sleep/activity pattern are accompanied by morphological changes in the projection pattern of the central pacemaker neurons. These neurons show daily fluctuations in their connectivity, whereby synapses are increased during the day and reduced during sleep. Synapse formation requires cytoskeletal changes that can be detected by the accumulation of the end-binding protein 1 (EB1) at the site of synapse formation. Whereas, hTauWT flies show the normal day/night changes in EB1 accumulation, hTauV337M flies do not show this fluctuation. This suggests that hTauV337M disrupts sleep patterns by interfering with the cytoskeletal changes that are required for the synaptic homeostasis of central pacemaker neurons. [ABSTRACT FROM AUTHOR]

Chronic glial activation is characterized by an increased number of activated microglia and astroglia; these secrete free radicals and cytotoxic cytokines, subsequently causing neuronal damage. This study investigated the hypothesis that a soy-lecithin based phytosomal curcumin formulation can decrease glial activation in the brains of GFAP-IL6 mice, a model of chronic glial activation, which exhibits gliosis in various regions of the brain. Three doses of Meriva curcumin (MC) (874, 436, and 218 PPM) were fed to 3-month-old GFAP-IL6 and wild-type (WT) mice for 4 weeks. As markers of glial activation, the total numbers of Iba-1+ and TSPO+ microglia and macrophages, and GFAP+ astrocytes, were determined in the cerebellum and hippocampus by immunohistochemistry and unbiased stereology. Furthermore, the morphology of the glial cells was assessed by confocal microscopy and Sholl analysis. Administration of phytosomal curcumin led to a dose-dependent reduction in neuroinflammatory markers. Phytosomal curcumin (874 PPM) decreased the number of microglia by 26.2% in the hippocampus and by 48% in the cerebellum of the GFAP-IL6 mice compared with the GFAP-IL6 mice on normal food. Additionally, GFAP+ astrocyte numbers in the hippocampus of the GFAP-IL6 mice were decreased by 42%. The GFAP-IL6 mice exhibited a different microglial morphology to the WT mice, showing an increased soma size and perimeter. This difference was significantly reduced by the 874 PPM phytosomal curcumin dose. Our findings demonstrate that phytosomal curcumin is able to attenuate the inflammatory pathology, and potentially reverse the detrimental effects of chronic glial activation. [ABSTRACT FROM AUTHOR]

The levels of the astrocyte markers (GFAP, S100B) were increased unevenly in patients with schizophrenia. Reactive astrogliosis was found in approximately 70% of patients with schizophrenia. The astrocytes play a major role in etiology and pathogenesis of schizophrenia. Astrocytes produce the components that altered in schizophrenia extracellular matrix system which are involved in inflammation, functioning of interneurons, glio-, and neurotransmitter system, especially glutamate system. Astrocytes activate the interneurons through glutamate release and ATP. Decreased expression of astrocyte glutamate transporters was observed in patients with schizophrenia. Astrocytes influence on N-methyl-d-aspartate (NMDA) receptors via D-serine, an agonist of the glycine-binding site of NMDA receptors, and kynurenic acid, an endogenous antagonist. NMDA receptors, on its turn, control the impulses of dopamine neurons. Therefore following theories of schizophrenia are proposed. They are a) activation of astrocytes for neuroinflammation, b) glutamate and dopamine theory, as astrocyte products control the activity of NMDA receptors, which influence on the dopamine neurons. [ABSTRACT FROM AUTHOR]

Aging is associated with cognitive decline and dysregulation of the circadian system, which modulates hippocampal-dependent memory as well as biological processes underlying hippocampal function. While circadian dysfunction and memory impairment are common features of aging and several neurodegenerative brain disorders, how aging impacts the circadian expression patterns of proteins involved in processes that underlie hippocampal-dependent memory is not well understood. In this study, we profiled the hippocampal proteomes of young and middle-aged mice across two circadian cycles using quantitative mass spectrometry in order to explore aging-associated changes in the temporal orchestration of biological pathways. Of the ∼1,420 proteins that were accurately quantified, 15% (214 proteins) displayed circadian rhythms in abundance in the hippocampus of young mice, while only 1.6% (23 proteins) were rhythmic in middle-aged mice. Remarkably, aging disrupted the circadian regulation of proteins involved in cellular functions critical for hippocampal function and memory, including dozens of proteins participating in pathways of energy metabolism, neurotransmission, and synaptic plasticity. These included processes such as glycolysis, the tricarboxylic acid cycle, synaptic vesicle cycling, long-term potentiation, and cytoskeletal organization. Moreover, aging altered the daily expression rhythms of proteins implicated in hallmarks of aging and the pathogenesis of several age-related neurodegenerative brain disorders affecting the hippocampus. Notably, we identified age-related alterations in the rhythmicity of proteins involved in mitochondrial dysfunction and loss of proteostasis, as well as proteins involved in the pathogenesis of disorders such as Alzheimer's disease and Parkinson's disease. These insights into aging-induced changes in the hippocampal proteome provide a framework for understanding how the age-dependent circadian decline may contribute to cognitive impairment and the development of neurodegenerative diseases during aging. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is marked by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in large part, been dedicated to the understanding of Aβ and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain. Therefore, a better understanding of the neuroinflammatory environment in the brain in HD may lead to the development of targeted and innovative therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain. Therefore, a better understanding of the neuroinflammatory environment in the brain in HD may lead to the development of targeted and innovative therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Rationally designed behavioral tests are important tools to assess the function of specific brain regions. The hippocampus is a crucial neural substrate for spatial cognition, and many studies have linked hippocampal dysfunction with defects on spatial learning and memory in neurological conditions ranging from Alzheimer's disease to autoimmune syndromes, such as neuropsychiatric lupus. While our understanding of hippocampal function, from the molecular to the system levels, has increased dramatically over the last decades, this effort has not yet translated into efficacious therapies for cognitive impairment. We think that the availability of highly validated behavioral paradigms to measure cognition in mouse models is likely to enhance the potential success of preclinical therapeutic modalities. Here, we present an extensive study of the paddling pool task (PPT), first reported by Deacon and Rawlins, in which mice learn to escape from shallow water through a peripheral exit in a circular arena dubbed the clockmaze. We show that the PPT provides highly reliable results when assaying spatial cognition in C57/BL6 mice (120 males, 40 females) and BALB/c mice (40 males, 90 females). Additionally, we develop a robust algorithm for the assessment of escape strategies with clearly quantifiable readouts, enabling fine-granular phenotyping. Notably, the use of spatial strategy increases linearly across trials in the PPT. In a separate cohort of mice, we apply muscimol injections to silence the dorsal CA1 region of the hippocampus and show that the use of the spatial strategy in the PPT relies on the integrity of the dorsal hippocampus. Additionally, we compare directly the PPT and the Morris water maze (MWM) task in C57/BL6 mice (20 males, 20 females) and BALB/c mice (20 males, 20 females) and we find that the PPT induces significantly lower anxiety, exhaustion and hypothermia than the MWM. We conclude that the PPT provides a robust assessment of spatial cognition in mice, which can be applied in conjunction with other tests, to facilitate hypothesis testing and drug development to combat cognitive impairment. [ABSTRACT FROM AUTHOR]

Astrocytes, one of the largest glial cell population in the central nervous system (CNS), play a key function in several events of brain development and function, such as synapse formation and function, control of neurotransmitters release and uptake, production of trophic factors and control of neuronal survival. Initially described as a homogenous population, several evidences have pointed that astrocytes are highly heterogeneous, both morphologically and functionally, within the same region, and across different brain regions. Recent findings suggest that the heterogeneity in the expression profile of proteins involved in astrocyte function may predict the selective vulnerability of brain regions to specific diseases, as well as to the age-related cognitive decline. However, the molecular mechanisms underlying these changes, either in aging as well as in brain disease are scarce. Neuroinflammation, a hallmark of several neurodegenerative diseases and aging, is reported to have a dubious impact on glial activation, as these cells release pro- and anti-inflammatory cytokines and chemokines, anti-oxidants, free radicals, and neurotrophic factors. Despite the emerging evidences supporting that reactive astrocytes have a duality in their phenotype, neurotoxic or neuroprotective properties, depending on the age and stimuli, the underlying mechanisms of their activation, cellular interplays and the impact of regional astrocyte heterogeneity are still a matter of discussion. In this review article, we will summarize recent findings on astrocyte heterogeneity and phenotypes, as well as their likely impact for the brain function during aging and neural diseases. We will focus on the molecules and mechanisms triggered by astrocyte to control synapse formation in different brain regions. Finally, we will discuss new evidences on how the modulation of astrocyte phenotype and function could impact the synaptic deficits and glial dysfunction present in aging and pathological states. [ABSTRACT FROM AUTHOR]

A defining pathophysiological hallmark of Alzheimer's disease (AD) is the amyloid plaque; an extracellular deposit of aggregated fibrillar Aβ1-42 peptides. Amyloid plaques are hard, brittle structures scattered throughout the hippocampus and cerebral cortex and are thought to cause hyperphosphorylation of tau, neurofibrillary tangles, and progressive neurodegeneration. Reactive astrocytes and microglia envelop the exterior of amyloid plaques and infiltrate their inner core. Glia are highly mechanosensitive cells and can almost certainly sense the mismatch between the normally soft mechanical environment of the brain and very stiff amyloid plaques via mechanosensing ion channels. Piezo1, a non-selective cation channel, can translate extracellular mechanical forces to intracellular molecular signaling cascades through a process known as mechanotransduction. Here, we utilized an aging transgenic rat model of AD (TgF344-AD) to study expression of mechanosensing Piezo1 ion channels in amyloid plaque-reactive astrocytes. We found that Piezo1 is upregulated with age in the hippocampus and cortex of 18-month old wild-type rats. However, more striking increases in Piezo1 were measured in the hippocampus of TgF344-AD rats compared to age-matched wild-type controls. Interestingly, repeated urinary tract infections with Escherichia coli bacteria, a common comorbidity in elderly people with dementia, caused further elevations in Piezo1 channel expression in the hippocampus and cortex of TgF344-AD rats. Taken together, we report that aging and peripheral infection augment amyloid plaque-induced upregulation of mechanoresponsive ion channels, such as Piezo1, in astrocytes. Further research is required to investigate the role of astrocytic Piezo1 in the Alzheimer's brain, whether modulating channel opening will protect or exacerbate the disease state, and most importantly, if Piezo1 could prove to be a novel drug target for age-related dementia. [ABSTRACT FROM AUTHOR]

Astrocytes are the most prevalent glial cells in the brain. Historically considered as “merely supporting” neurons, recent research has shown that astrocytes actively participate in a large variety of central nervous system (CNS) functions including synaptogenesis, neuronal transmission and synaptic plasticity. During disease and injury, astrocytes efficiently protect neurons by various means, notably by sealing them off from neurotoxic factors and repairing the blood-brain barrier. Their ramified morphology allows them to perform diverse tasks by interacting with synapses, blood vessels and other glial cells. In this review article, we provide an overview of how astrocytes acquire their complex morphology during development. We then move from the developing to the mature brain, and review current research on perisynaptic astrocytic processes, with a particular focus on how astrocytes engage synapses and modulate their formation and activity. Comprehensive changes have been reported in astrocyte cell shape in many CNS pathologies. Factors influencing these morphological changes are summarized in the context of brain pathologies, such as traumatic injury and degenerative conditions. We provide insight into the molecular, cellular and cytoskeletal machinery behind these shape changes which drive the dynamic remodeling in astrocyte morphology during injury and the development of pathologies. [ABSTRACT FROM AUTHOR]

Depression is the second leading cause of disability worldwide. The effects of clinical depression may be mediated by neuroinflammation such as activation of microglia and high levels of proinflammatory cytokines in certain brain areas. Traditional Chinese medicine techniques such as electro-acupuncture (EA) are used extensively in Asia to treat mental health disorders. However, EA has not been rigorously studied in treatment of depression. This study was designed to assess the effectiveness of EA on depressive-like behavior and explore the role of hippocampal neuroinflammation in the potential antidepressant effect of EA. In this study, we used six chronic unpredictable stressors daily in a random sequence for 10 weeks. EA were performed on "Bai- Hui" (Du-20) (+) and "Yang-Ling-Quan" (GB-34, the right side; ) acupoints by an EA apparatus (HANS Electronic Apparatus, LH202H, 2/100 Hz, 0.3 mA) for 30 min once every other day for last 4 weeks. The behavior tests including open field test and forced swimming test, which are widely used to assess depressive and anxiety-like behavior were performed on the Monday and Tuesday of the eleventh week. The results showed that 10 week of chronic unpredictable stress (CUS) caused behavioral deficits in rats and neuroinflammation in hippocampus, such as increased expression of NLRP3 inflammasome components, upregulated mRNA level of IL-1b and the protein level of IL-1b mature form (p17) and activation of microglia. Moreover, 4 weeks of EA treatment significantly attenuated behavioral deficits caused by CUS. EA's antidepressant effect was accompanied by markedly decreased expression of certain NLRP3 inflammasome components and matured IL-1b. Meanwhile, EA treatment can significantly reverse CUS-induced increases in P2X7 receptor, Iba-1, IL-18, TNFa and IL-6 expression and decreases in GFAP expression. In conclusion, EA exhibited the antidepressant effect and alleviated the hippocampal neuroinflammation. These findings may provide insight into the role of hippocampal neuroinflammation in the antidepressant effect of EA. [ABSTRACT FROM AUTHOR]

In both vertebrate and invertebrate brains, neurons, glial cells and synapses are plastic, which means that the physiology and structure of these components are modified in response to internal and external stimuli during development and in mature brains. The term plasticity has been introduced in the last century to describe experience-dependent changes in synapse strength and number. These changes result from local functional and morphological synapse modifications; however, these modifications also occur more commonly in pre- and postsynaptic neurons. As a result, neuron morphology and neuronal networks are constantly modified during the life of animals and humans in response to different stimuli. Nevertheless, it has been discovered in flies and mammals that the number of synapses and size and shape of neurons also oscillate during the day. In most cases, these rhythms are circadian since they are generated by endogenous circadian clocks; however, some rhythmic changes in neuron morphology and synapse number and structure are controlled directly by environmental cues or by both external cues and circadian clocks. When the circadian clock is involved in generating cyclic changes in the nervous system, this type of plasticity is called circadian plasticity. It seems to be important in processing sensory information, in learning and in memory. Disruption of the clock may affect major brain functions. [ABSTRACT FROM AUTHOR]