scholarly journals REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Percy Griffin ◽  
Patrick W Sheehan ◽  
Julie M Dimitry ◽  
Chun Guo ◽  
Michael F Kanan ◽  
...  
Keyword(s):  
Daily Variation ◽  
Brain Health ◽  
Astrocyte Activation ◽  
Synaptic Regulation ◽  
Microglial Phagocytosis ◽  
Synapse Loss ◽  
The Brain ◽  
Master Clock ◽  
Clock Protein ◽  
Diurnal Regulation

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

scholarly journals REV-ERBα mediates complement expression and circadian regulation of microglial synaptic phagocytosis

2020 ◽  
Author(s):  
Percy Griffin ◽  
Patrick W. Sheehan ◽  
Julie M. Dimitry ◽  
Chun Guo ◽  
Michael F. Kanan ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Transcriptional Repression ◽  
Wild Type ◽  
Brain Health ◽  
Astrocyte Activation ◽  
Synaptic Regulation ◽  
Microglial Phagocytosis ◽  
The Brain ◽  
Master Clock ◽  
Clock Protein

ABSTRACTThe circadian clock has been shown to regulate various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 induces robust increases in the expression of complement genes such as C3, C4b and C1q in the hippocampus. Loss of downstream REV-ERBα-mediated transcriptional repression led to increases in C4b in neurons and astrocytes as well as C3 protein in microglia and astrocytes. REV-ERBα deletion induced complement C3/C4b gene expression and increased microglial phagocytosis of synapses in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis in wild type mice which was abrogated by REV-ERBα deletion. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, thereby illuminating a novel mechanism of synaptic regulation by the circadian clock.

scholarly journals Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

2018 ◽  
Author(s):  
Brian V. Lananna ◽  
Collin J. Nadarajah ◽  
Mariko Izumo ◽  
Michelle R. Cedeño ◽  
David D. Xiong ◽  
...  
Keyword(s):  
Circadian Clock ◽  
List Type ◽  
Brain Health ◽  
Glutathione S Transferase ◽  
Astrocyte Activation ◽  
The Core ◽  
A Cell ◽  
Clock Protein

SummaryCircadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism, and via a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a novel mechanism by which the circadian clock could influence many aspects of brain function and neurologic disease.HighlightsCircadian disruption promotes astrocyte activation.Astrocyte-specific deletion of the circadian clock gene BMAL1 induces astrocyte activation.BMAL1 regulates astrocyte activation by altering glutathione-s-transferase signaling.Loss of astrocyte BMAL1 enhances neuronal cell death in a co-culture system.eTOC blurbLananna et al. show that the circadian clock protein BMAL1 regulates astrocyte activation via a cell autonomous-mechanism involving diminished glutathione-s-transferase signaling. This finding elucidates a novel function of the core circadian clock in astrocytes, and reveals a BMAL1 as a modulator of astrogliosis.

scholarly journals Social Volunteering in Aging Adults Increases Regions of the Amygdala and Correlates With Enhanced Generativity

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 795-795
Author(s):  
Michelle Carlson
Keyword(s):  
Social Engagement ◽  
Controlled Trial ◽  
Well Being ◽  
Health Study ◽  
Brain Health ◽  
Volunteer Program ◽  
Intention To Treat ◽  
Intervention Impact ◽  
Aging Adults ◽  
The Brain

Abstract The Brain Health Study (BHS) of the Baltimore Experience Corps Trial (BECT) examined whether a randomized, controlled trial of an intergenerational social volunteer program, entitled Experience Corps, increased subregions of the amygdala related to socioemotional memory and risk for Alzheimer’s disease in aging adults. We further assessed functional correlates of these intervention-related changes and changes in aging adults’ developmental need to be generative, or, to give back to the well-being of others. The BHS simultaneously randomized 112 men and women (59 intervention; 53 control) within BECT to evaluate intervention impact on biomarkers of brain health at baseline and annual follow-ups during the two-year trial. Intention-to-treat analyses revealed program-specific increases in the shape of the centromedial and basomedial regions of the left amygdala (p’s≤0.05 adjusted), which were correlated with increases in generativity (p’s =0.06). Meaningful social engagement buffered amygdalar declines important to preservation of emotionally salient memory and risk for dementia. Part of a symposium sponsored by Brain Interest Group.

Abstract MP16: Excessive White Matter Hyperintensity Burden and Functional Outcomes After Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sungmin Hong ◽  
Anne-katrin Giese ◽  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
Anna Bonkhoff ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Life Time ◽  
Stroke Recovery ◽  
White Matter Hyperintensity ◽  
Brain Health ◽  
Stroke Outcomes ◽  
The Brain

Objective: Ability of the brain to recover after an acute ischemic stroke (AIS) is linked to the pre-stroke burden of white matter hyperintensity (WMH), a radiographic marker of brain health. We sought to determine the excessive WMH burden in an AIS population and investigate its association with 3-month stroke outcomes. Data: We used 2,435 subjects from the MRI-GENIE study. Three-month functional outcomes of 872 subjects among those subjects were measured by 90-day modified Ranking Scale (mRS). Methods: We automatically quantified WMH volume (WMHv) on FLAIR images and adjusted for a brain volume. We modeled a trend using the factor analysis (FA) log-linear regression using age, sex, atrial fibrillation, diabetes, hypertension, coronary artery disease and smoking as input variables. We categorized three WMH burden groups based on the conditional probability given by the model (LOW: lower 33%, MED: middle 34%, and HIGH: upper 33%). The subgroups were compared with respect to mRS (median and dichotomized odds ratio (OR) (good/poor: mRS 0-2/3-6)). Results: Five FA components out of seven with significant relationship to WMHv (p<0.001) were used for the regression modeling (R 2 =0.359). The HIGH group showed higher median (median=2, IQR=2) mRS score than LOW (median=1, IQR=1) and MED (median=1, IQR=1). The odds (OR) of good AIS outcome for LOW and MED were 1.8 (p=0.0001) and 1.6 (p=0.006) times higher than HIGH, respectively. Conclusion: Once accounted for clinical covariates, the excessive WMHv was associated with worse 3-month stroke outcomes. These data suggest that a life-time of injury to the white matter reflected in WMH is an important factor for stroke recovery and an indicator of the brain health.

scholarly journals Big data to smart data in Alzheimer's disease: The brain health modeling initiative to foster actionable knowledge

2016 ◽  
Vol 12 (9) ◽  
pp. 1014-1021 ◽  
Author(s):  
Hugo Geerts ◽  
Penny A. Dacks ◽  
Viswanath Devanarayan ◽  
Magali Haas ◽  
Zaven S. Khachaturian ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Big Data ◽  
Brain Health ◽  
Actionable Knowledge ◽  
Smart Data ◽  
The Brain

scholarly journals Long-term cyclic aerobic training preserves the brain's health in elderly persons (brief review)

2016 ◽  
Vol 24 (4) ◽  
pp. 152-163
Author(s):  
A S Radchenko ◽  
B B Davydov ◽  
A N Kalinichenko
Keyword(s):  
Aerobic Training ◽  
Brain Perfusion ◽  
Favorable Effect ◽  
Elderly Persons ◽  
Periodical Literature ◽  
Brain Health ◽  
Memory State ◽  
Age Related ◽  
The Brain

It was identified on the base of special periodical literature analyze that cyclic muscular work systematically performed during large part of the person's life (former athlete) provides mainly the favorable effect on the brain. Ventricular-arterial coupling improvement ameliorates brain perfusion, and creates function advantages to brain health in old age. At that, the gray and white matter fading hampered, especially in structures that associated with visual control and human body spatial orientation, motor control and memory state, and age-related attenuation of cognitive functions in comparison with sedentary persons of the same age.

scholarly journals The Brain Health Assessment for Detecting and Diagnosing Neurocognitive Disorders

2018 ◽  
Vol 66 (1) ◽  
pp. 150-156 ◽  
Author(s):  
Katherine L. Possin ◽  
Tacie Moskowitz ◽  
Sabrina J. Erlhoff ◽  
Kirsten M. Rogers ◽  
Erica T. Johnson ◽  
...  
Keyword(s):  
Health Assessment ◽  
Neurocognitive Disorders ◽  
Brain Health ◽  
The Brain

scholarly journals Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning

2018 ◽  
Vol 115 (24) ◽  
pp. 6303-6308 ◽  
Author(s):  
Balázs A. Györffy ◽  
Judit Kun ◽  
György Török ◽  
Éva Bulyáki ◽  
Zsolt Borhegyi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Sensory Deprivation ◽  
Complement Cascade ◽  
Synapse Elimination ◽  
Microglial Phagocytosis ◽  
Synapse Loss ◽  
Preferential Localization ◽  
Proteomic Investigation ◽  
Apoptosis Markers ◽  
Synaptic Pruning

C1q, a member of the immune complement cascade, is implicated in the selective pruning of synapses by microglial phagocytosis. C1q-mediated synapse elimination has been shown to occur during brain development, while increased activation and complement-dependent synapse loss is observed in neurodegenerative diseases. However, the molecular mechanisms underlying C1q-controlled synaptic pruning are mostly unknown. This study addresses distortions in the synaptic proteome leading to C1q-tagged synapses. Our data demonstrated the preferential localization of C1q to the presynapse. Proteomic investigation and pathway analysis of C1q-tagged synaptosomes revealed the presence of apoptotic-like processes in C1q-tagged synapses, which was confirmed experimentally with apoptosis markers. Moreover, the induction of synaptic apoptotic-like mechanisms in a model of sensory deprivation-induced synaptic depression led to elevated C1q levels. Our results unveiled that C1q label-based synaptic pruning is triggered by and directly linked to apoptotic-like processes in the synaptic compartment.

scholarly journals Measurement of CMRO2 and its relationship with CBF in hypoxia with an extended calibrated BOLD method

2019 ◽  
Vol 40 (10) ◽  
pp. 2066-2080
Author(s):  
Yaoyu Zhang ◽  
Yayan Yin ◽  
Huanjie Li ◽  
Jia-Hong Gao
Keyword(s):  
Cerebral Blood Volume ◽  
Pulse Sequence ◽  
Blood Oxygen Level Dependent ◽  
Extended Model ◽  
Brain Health ◽  
Blood Oxygen Level ◽  
Oxygen Conditions ◽  
Health And Disease ◽  
The Brain ◽  
Mild Hypoxia

Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) are physiological parameters that not only reflect brain health and disease but also jointly contribute to blood oxygen level-dependent (BOLD) signals. Nevertheless, unsolved issues remain concerning the CBF–CMRO2 relationship in the working brain under various oxygen conditions. In particular, the CMRO2 responses to functional tasks in hypoxia are less studied. We extended the calibrated BOLD model to incorporate CMRO2 measurements in hypoxia. The extended model, which was cross-validated with a multicompartment BOLD model, considers the influences of the reduced arterial saturation level and increased baseline cerebral blood volume (CBV) and deoxyhemoglobin concentration on the changes of BOLD signals in hypoxia. By implementing a pulse sequence to simultaneously acquire the CBV-, CBF- and BOLD-weighted signals, we investigated the effects of mild hypoxia on the CBF and CMRO2 responses to graded visual stimuli. Compared with normoxia, mild hypoxia caused significant alterations in both the amplitude and the trend of the CMRO2 responses but did not impact the corresponding CBF responses. Our observations suggested that the flow-metabolism coupling strategies in the brain during mild hypoxia were different from those during normoxia.

scholarly journals The Expanding Cell Diversity of the Brain Vasculature

2020 ◽  
Vol 11 ◽  
Author(s):  
Jayden M. Ross ◽  
Chang Kim ◽  
Denise Allen ◽  
Elizabeth E. Crouch ◽  
Kazim Narsinh ◽  
...  
Keyword(s):  
Regional Blood Flow ◽  
Cell Types ◽  
Brain Health ◽  
Vascular Cell ◽  
Brain Vasculature ◽  
Genomic Technologies ◽  
Cell Diversity ◽  
Cell Type Specific ◽  
Neurologic Function ◽  
The Brain

The cerebrovasculature is essential to brain health and is tasked with ensuring adequate delivery of oxygen and metabolic precursors to ensure normal neurologic function. This is coordinated through a dynamic, multi-directional cellular interplay between vascular, neuronal, and glial cells. Molecular exchanges across the blood–brain barrier or the close matching of regional blood flow with brain activation are not uniformly assigned to arteries, capillaries, and veins. Evidence has supported functional segmentation of the brain vasculature. This is achieved in part through morphologic or transcriptional heterogeneity of brain vascular cells—including endothelium, pericytes, and vascular smooth muscle. Advances with single cell genomic technologies have shown increasing cell complexity of the brain vasculature identifying previously unknown cell types and further subclassifying transcriptional diversity in cardinal vascular cell types. Cell-type specific molecular transitions or zonations have been identified. In this review, we summarize emerging evidence for the expanding vascular cell diversity in the brain and how this may provide a cellular basis for functional segmentation along the arterial-venous axis.

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