Environmental Circadian Disruption Elevates the IL-6 Response to Lipopolysaccharide in Blood

The immune system is regulated by circadian clocks within the brain and immune cells. Environmental circadian disruption (ECD), consisting of a 6-h phase advance of the light:dark cycle once a week for 4 weeks, elevates the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. This indicates that circadian disruption adversely affects immune function; however, it remains unclear how the circadian system regulates this response under ECD conditions. Here, we develop an assay using ex vivo whole-blood LPS challenge to investigate the circadian regulation of immune responses in mice and to determine the effects of ECD on these rhythms. LPS-induced IL-6 release in whole blood was regulated in a circadian manner, peaking during subjective day under both entrained and free-running conditions. This LPS-induced IL-6 release rhythm was associated with daily variation in both white blood cell counts and immune cell responsiveness. ECD increased the overall level of LPS-induced IL-6 release by increasing immune cell responsiveness and not by affecting immune cell number or the circadian regulation of this rhythm. This indicates that ECD produces pathological immune responses by increasing the proinflammatory responses of immune cells. Also, this newly developed whole blood assay can provide a noninvasive longitudinal method to quantify potential health consequences of circadian disruption in humans

The New England boarding school : an analysis of its historical development and contemporary uncertainty of purpose.

This file contains a tiff sequence for PER2::LUC imagign data from SCN slices collected from Mouse#337 (rostral SCN = Slice1, middle SCN = Slice2, caudal SCN = Slice3)

The economic case for investing in the prevention of mental health conditions in the UK

This report provides an overview of the economic case for the prevention of mental health conditions. To do this, we first estimated the societal costs of living with mental health conditions in the UK in 2019 and then reviewed what is known about the cost-effectiveness of wellevidenced actions to prevent these mental health conditions. To estimate costs, we used a prevalencebased costing approach. This measures the number of people living with mental health conditions over a specific short time period (usually one year) and estimates the average costs associated with these conditions over this time period. Our prevalencebased costing model makes use of data on prevalence from the 2019 Institute of Health Metrics and Evaluation Global Burden of Disease (GBD) study. The GBD study quantifies the impact of all health conditions, both infectious and non-communicable, including mental health conditions, as well as the impacts on injury, including intentional self-harm. As part of the study, the GBD systematically searches for and assesses mental health surveys around the globe. To allow for comparability in measurement, case definitions used by GBD predominantly adhered to international diagnostic criteria guidance, either the DSM-IV-TR, mainly used in the United States or the ICD-10 criteria used mainly elsewhere, as these are used by the majority of mental health surveys included in the GBD. The GBD study estimates are periodically updated, apply a common methodology, are subject to peer review, and are routinely used by the World Health Organization (WHO) when looking at the global impact of mental health conditions. Furthermore, GBD estimates are provided separately for all four nations of the UK, as well as at English Region level. These estimates are conservative, as the GBD does not include the impact of sub-diagnostic threshold mental health conditions, as well as risk factors such as undue stress which do not fit into diagnostic criteria, all of which will also have economic costs. We included 11 of 12 broad categories of mental disorder meeting diagnosable thresholds used in the GBD1. These were depressive disorders (major depressive disorder and dysthymia), anxiety disorders, bipolar affective disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder (ADHD), eating disorders (anorexia nervosa and bulimia nervosa), and a final category of other mental disorders (which mainly covers personality disorders). A detailed list of conditions is listed in Table A-2 in the appendix. We excluded the idiopathic intellectual disabilities category in the GBD. Neurological conditions such as dementia, as well as alcohol and substance use disorders, are not included. Although not all intentional self-harm is linked with a mental health condition, we also separately provide an estimate of the health and intangible costs associated with intentional self-harm, including suicide, reported in the GBD. All costs are calculated and reported in 2020 pounds sterling

Shell Neurons of the Master Circadian Clock Coordinate the Phase of Tissue Clocks Throughout the Brain and Body

Background: Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. Results: Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. Conclusions: Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior

Loneliness, coping, suicidal thoughts and self-harm during the COVID-19 pandemic: a repeat cross-sectional UK population survey

Objectives: There has been speculation on the impact of the COVID-19 pandemic and the associated lockdown on suicidal thoughts and self-harm and the factors associated with any change. We aimed to assess the effects and change in effects of risk factors including loneliness and coping, as well as pre-existing mental health conditions on suicidal thoughts and self-harm during the COVID-19 pandemic. Design: This study was a repeated cross-sectional online population-based survey. Participants and measures: Non-probability quota sampling was adopted on the UK adult population and four waves of data were analysed during the pandemic (17 March 2020 to 29 May 2020). Outcomes were suicidal thoughts and self-harm associated with the pandemic while loneliness, coping, pre-existing mental health conditions, employment status and demographics were covariates. We ran binomial regressions to evaluate the adjusted risks of the studied covariates as well as the changes in effects over time. Results: The proportion of individuals who felt lonely increased sharply from 9.8% to 23.9% after the UK lockdown began. Young people (aged 18–24 years), females, students, those who were unemployed and individuals with pre-existing mental health conditions were more likely to report feeling lonely and not coping well. 7.7%–10.0% and 1.9%–2.2% of respondents reported having suicidal thoughts and self-harm associated with the pandemic respectively throughout the period studied. Results from cross-tabulation and adjusted regression analyses showed young adults, coping poorly and with pre-existing mental health conditions were significantly associated with suicidal thoughts and self-harm. Loneliness was significantly associated with suicidal thoughts but not self-harm. Conclusions: The association between suicidality, loneliness and coping was evident in young people during the early stages of the pandemic. Developing effective interventions designed and coproduced to address loneliness and promote coping strategies during prolonged social isolation may promote mental health and help mitigate suicidal thoughts and self-harm associated with the pandemic

Network Dynamics Mediate Circadian Clock Plasticity

A circadian clock governs most aspects of mammalian behavior. Although its properties are in part genetically determined, altered light-dark environment can change circadian period length through a mechanism requiring de novo DNA methylation. We show here that this mechanism is mediated not via cell-autonomous clock properties, but rather through altered networking within the suprachiasmatic nuclei (SCN), the circadian “master clock,” which is DNA methylated in region-specific manner. DNA methylation is necessary to temporally reorganize circadian phasing among SCN neurons, which in turn changes the period length of the network as a whole. Interruption of neural communication by inhibiting neuronal firing or by physical cutting suppresses both SCN reorganization and period changes. Mathematical modeling suggests, and experiments confirm, that this SCN reorganization depends upon GABAergic signaling. Our results therefore show that basic circadian clock properties are governed by dynamic interactions among SCN neurons, with neuroadaptations in network function driven by the environment

The Economic Case for Investing in the Prevention of Mental Health Conditions in the UK

This report provides an overview of the economic case for the prevention of mental health conditions. To do this, we first estimated the societal costs of living with mental health conditions in the UK in 2019 and then reviewed what is known about the cost-effectiveness of wellevidenced actions to prevent these mental health conditions. To estimate costs, we used a prevalencebased costing approach. This measures the number of people living with mental health conditions over a specific short time period (usually one year) and estimates the average costs associated with these conditions over this time period. Our prevalencebased costing model makes use of data on prevalence from the 2019 Institute of Health Metrics and Evaluation Global Burden of Disease (GBD) study. The GBD study quantifies the impact of all health conditions, both infectious and non-communicable, including mental health conditions, as well as the impacts on injury, including intentional self-harm. As part of the study, the GBD systematically searches for and assesses mental health surveys around the globe. To allow for comparability in measurement, case definitions used by GBD predominantly adhered to international diagnostic criteria guidance, either the DSM-IV-TR, mainly used in the United States or the ICD-10 criteria used mainly elsewhere, as these are used by the majority of mental health surveys included in the GBD. The GBD study estimates are periodically updated, apply a common methodology, are subject to peer review, and are routinely used by the World Health Organization (WHO) when looking at the global impact of mental health conditions. Furthermore, GBD estimates are provided separately for all four nations of the UK, as well as at English Region level. These estimates are conservative, as the GBD does not include the impact of sub-diagnostic threshold mental health conditions, as well as risk factors such as undue stress which do not fit into diagnostic criteria, all of which will also have economic costs. We included 11 of 12 broad categories of mental disorder meeting diagnosable thresholds used in the GBD1. These were depressive disorders (major depressive disorder and dysthymia), anxiety disorders, bipolar affective disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder (ADHD), eating disorders (anorexia nervosa and bulimia nervosa), and a final category of other mental disorders (which mainly covers personality disorders). A detailed list of conditions is listed in Table A-2 in the appendix. We excluded the idiopathic intellectual disabilities category in the GBD. Neurological conditions such as dementia, as well as alcohol and substance use disorders, are not included. Although not all intentional self-harm is linked with a mental health condition, we also separately provide an estimate of the health and intangible costs associated with intentional self-harm, including suicide, reported in the GBD. All costs are calculated and reported in 2020 pounds sterling

mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction

Mammalian/mechanistic target of rapamycin (mTOR) signaling controls cell growth, proliferation, and metabolism in dividing cells. Less is known regarding its function in postmitotic neurons in the adult brain. Here we created a conditional mTOR knockout mouse model to address this question. Using the Cre-LoxP system, the mTOR gene was specifically knocked out in cells expressing Vip (vasoactive intestinal peptide), which represent a major population of interneurons widely distributed in the neocortex, suprachiasmatic nucleus (SCN), olfactory bulb (OB), and other brain regions. Using a combination of biochemical, behavioral, and imaging approaches, we found that mice lacking mTOR in VIP neurons displayed erratic circadian behavior and weakened synchronization among cells in the SCN, the master circadian pacemaker in mammals. Furthermore, we have discovered a critical role for mTOR signaling in mediating olfaction. Odor stimulated mTOR activation in the OB, anterior olfactory nucleus, as well as piriform cortex. Odor-evoked c-Fos responses along the olfactory pathway were abolished in mice lacking mTOR in VIP neurons, which is consistent with reduced olfactory sensitivity in these animals. Together, these results demonstrate that mTOR is a key regulator of SCN circadian clock synchrony and olfaction