Transcriptomics-driven metabolic pathway analysis reveals similar alterations in lipid metabolism in mouse MASH model and human.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease worldwide, and can rapidly progress to metabolic dysfunction-associated steatohepatitis (MASH). Accurate preclinical models and methodologies are needed to understand underlying metabolic mechanisms and develop treatment strategies. Through meta-analysis of currently proposed mouse models, we hypothesized that a diet- and chemical-induced MASH model closely resembles the observed lipid metabolism alterations in humans. METHODS: We developed transcriptomics-driven metabolic pathway analysis (TDMPA), a method to aid in the evaluation of metabolic resemblance. TDMPA uses genome-scale metabolic models to calculate enzymatic reaction perturbations from gene expression data. We performed TDMPA to score and compare metabolic pathway alterations in MASH mouse models to human MASH signatures. We used an already-established WD+CCl4-induced MASH model and performed functional assays and lipidomics to confirm TDMPA findings. RESULTS: Both human MASH and mouse models exhibit numerous altered metabolic pathways, including triglyceride biosynthesis, fatty acid beta-oxidation, bile acid biosynthesis, cholesterol metabolism, and oxidative phosphorylation. We confirm a significant reduction in mitochondrial functions and bioenergetics, as well as in acylcarnitines for the mouse model. We identify a wide range of lipid species within the most perturbed pathways predicted by TDMPA. Triglycerides, phospholipids, and bile acids are increased significantly in mouse MASH liver, confirming our initial observations. CONCLUSIONS: We introduce TDMPA, a methodology for evaluating metabolic pathway alterations in metabolic disorders. By comparing metabolic signatures that typify human MASH, we show a good metabolic resemblance of the WD+CCl4 mouse model. Our presented approach provides a valuable tool for defining metabolic space to aid experimental design for assessing metabolism.

Steatotic liver disease, in which fat accumulates in the liver, is one of the most prevalent liver diseases worldwide and it is important to develop relevant animal models to help us understand its mechanisms. We aimed to assess the suitability of animal models for studying steatotic liver disease in humans. We developed an approach that evaluates how genes affect the metabolism or the chemical reactions and processes that occur in the body. We used it to compare a mouse model of the disease with human observations. Our results showed that there are significant changes in fat and energy metabolism in the mouse model. These observations match with changes observed in humans, suggesting it is a good model for studying human disease. Our findings could advance our understanding of the disease as well as help define strategies for its treatment.

Brief Interventions for Suicidal Youths in Medical Settings: A Meta-Analysis.

CONTEXT: Most youths who die by suicide have interfaced with a medical system in the year preceding their death, placing outpatient medical settings on the front lines for identification, assessment, and intervention. OBJECTIVE: Review and consolidate the available literature on suicide risk screening and brief intervention with youths in outpatient medical settings and examine common outcomes. DATA SOURCES: The literature search looked at PubMed, OVID, CINAHL, ERIC, and PsychInfo databases. STUDY SELECTION: Interventions delivered in outpatient medical settings assessing and mitigating suicide risk for youths (ages 10-24). Designs included randomized controlled trials, prospective and retrospective cohort studies, and case studies. DATA EXTRACTION: Authors extracted data on rates of referral to behavioral health services, initiation/adjustment of medication, follow-up in setting of assessment, suicidal ideation at follow-up, and suicide attempts and/or crisis services visited within 1 year of initial assessment. RESULTS: There was no significant difference in subsequent suicide attempts between intervention and control groups. Analysis on subsequent crisis service could not be performed due to lack of qualifying data. Key secondary findings were decreased immediate psychiatric hospitalizations and increased mental health service use, along with mild improvement in subsequent depressive symptoms. LIMITATIONS: The review was limited by the small number of studies meeting inclusion criteria, as well as a heterogeneity of study designs and risk of bias across studies. CONCLUSIONS: Brief suicide interventions for youth in outpatient medical settings can increase identification of risk, increase access to behavioral health services, and for crisis interventions, can limit psychiatric hospitalizations.

Microglia/macrophages are ultrastructurally altered by their proximity to spinal cord injury in adult female mice.

Traumatic spinal cord injury can cause immediate physical damage to the spinal cord and result in severe neurological deficits. The primary, mechanical tissue damage triggers a variety of secondary damage mechanisms at the injury site which significantly contribute to a larger lesion size and increased functional damage. Inflammatory mechanisms which directly involve both microglia (MG) and monocyte-derived macrophages (MDM) play important roles in the post-injury processes, including inflammation and debris clearing. In the current study, we investigated changes in the structure and function of MG/MDM in the injured spinal cord of adult female mice, 7 days after a thoracic contusion SCI. With the use of chip mapping scanning electron microscopy, which allows to image large samples at the nanoscale, we performed an ultrastructural comparison of MG/MDM located near the lesion vs adjacent regions to provide novel insights into the mechanisms at play post-injury. We found that MG/MDM located near the lesion had more mitochondria overall, including mitochondria with and without morphological alterations, and had a higher proportion of altered mitochondria. MG/MDM near the lesion also showed an increased number of phagosomes, including phagosomes containing myelin and partiallydigested materials. MG/MDM near the injury interacted differently with the spinal cord parenchyma, as shown by their reduced number of direct contacts with synaptic elements, axon terminals and dendritic spines. In this study, we characterized the ultrastructural changes of MG/MDM in response to spinal cord tissue damage in mice, uncovering changes in phagocytic activity, mitochondrial ultrastructure, and inter-cellular interactions within the spinal cord parenchyma.

When Eating Intuitively Is Not Always a Positive Response: Using Machine Learning to Better Unravel Eaters Profiles.

BACKGROUND: The aim of the present study was to identify eaters profiles using the latest advantages of Machine Learning approach to cluster analysis. METHODS: A total of 317 participants completed an online-based survey including self-reported measures of body image dissatisfaction, bulimia, restraint, and intuitive eating. Analyses were conducted in two steps: (a) identifying an optimal number of clusters, and (b) validating the clustering model of eaters profile using a procedure inspired by the Causal Reasoning approach. RESULTS: This study reveals a 7-cluster model of eaters profiles. The characteristics, needs, and strengths of each eater profile are discussed along with the presentation of a continuum of eaters profiles. CONCLUSIONS: This conceptualization of eaters profiles could guide the direction of health education and treatment interventions targeting perceptual and eating dimensions.

16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Inhibition of PANX1 Channels Reduces the Malignant Properties of Human High-Risk Neuroblastoma.

Pannexin 1 (PANX1) is expressed in many tissue types including tissues of neural origin. Neuroblastoma (NB) is a neural crest-derived malignancy mainly occurring in children. The majority of NB patients present with high-risk disease for which current therapies are ineffective. Here, we show that while PANX1 is expressed in NB of all stages, high PANX1 expression in high-risk NB is associated with a reduced survival probability. PANX1 channel inhibition using probenecid (PBN) or carbenoxolone (CBX) reduced the proliferation of our panel of high-risk NB cell lines. We show that expression of the Y10F PANX1 mutant, which cannot be phosphorylated on tyrosine 10 and acts in a dominant-negative manner, curtailed NB cell proliferation. Furthermore, PBN and CBX treatment halted the growth of NB spheroids and in some cases triggered the regression of established NB spheroids. Finally, both drugs reduced the progression of high-risk NB in vivo. Together our data indicate that PANX1 channels regulate human NB malignant properties and that the use of PBN or CBX may provide a new therapeutic approach for high-risk NB.

Astrocytes display ultrastructural alterations and heterogeneity in the hippocampus of aged APP-PS1 mice and human post-mortem brain samples.

The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer's disease (AD). To provide novel insights into the roles of astrocytes in the pathophysiology of AD, we performed a quantitative ultrastructural characterization of their intracellular contents and parenchymal interactions in an aged mouse model of AD pathology, as aging is considered the main risk factor for developing AD. We compared 20-month-old APP-PS1 and age-matched C57BL/6J male mice, among the ventral hippocampus CA1 strata lacunosum-moleculare and radiatum, two hippocampal layers severely affected by AD pathology. Astrocytes in both layers interacted more with synaptic elements and displayed more ultrastructural markers of increased phagolysosomal activity in APP-PS1 versus C57BL6/J mice. In addition, we investigated the ultrastructural heterogeneity of astrocytes, describing in the two examined layers a dark astrocytic state that we characterized in terms of distribution, interactions with AD hallmarks, and intracellular contents. This electron-dense astrocytic state, termed dark astrocytes, was observed throughout the hippocampal parenchyma, closely associated with the vasculature, and possessed several ultrastructural markers of cellular stress. A case study exploring the hippocampal head of an aged human post-mortem brain sample also revealed the presence of a similar electron-dense, dark astrocytic state. Overall, our study provides the first ultrastructural quantitative analysis of astrocytes among the hippocampus in aged AD pathology, as well as a thorough characterization of a dark astrocytic state conserved from mouse to human.

Examining the contribution of motivation in the job search of youth with developmental language disorder.

Background & aims: Youth with developmental language disorder (DLD) are at risk of experiencing challenges during their job search. It is thus crucial to promote efficient job search behaviors in terms of effort, intensity, and self-regulation. Based on self-determination theory (SDT), we verified the role of autonomous and controlled motivations in enhancing these behaviors. Methods: Study 1 included 37 young adults with DLD who have finished school, and Study 2 included 52 youth with DLD transitioning from school to work. They completed a questionnaire examining their job search behaviors and their motivation toward their job search. Results: Autonomous motivation positively predicted job search effort, intensity, and self-regulation. Small to moderate relations were observed in Study 1, and moderate to strong ones in Study 2. Controlled motivation was unrelated to the three behaviors. Conclusions: In line with SDT, autonomous motivation is an important foundation for positive job search behaviors among youth with DLD. Implications: Supporting the development of autonomous motivation is thus encouraged in transition services for this population.

Microglia in Human Postmortem Brain Samples: Quantitative Ultrastructural Analysis of Scanning Electron Microscopy Images.

In this protocol, we describe the specific steps required to prepare human postmortem brain samples for ultrastructural microglial analysis. A detailed procedure is provided to improve the ultrastructural quality of the samples, using aldehyde fixatives followed by immunoperoxidase staining of allograft inflammatory factor 1 (AIF1, also known as IBA1), a marker of myeloid cells, and cluster of differentiation 68 (CD68), a marker of phagolysosomal activity. Additionally, we describe an osmium-thiocarbohydrazide-osmium (OTO) post-fixation method that preserves and increases the contrast of cellular membranes in human postmortem brain samples, as well as the steps necessary to acquire scanning electron microscopy (SEM) images of microglial cell bodies. In the last section, we cover the quantitative analysis of various microglial cytoplasmic organelles and their interactions with other parenchymal elements.

Defining an Infant's Race and Ethnicity: A Systematic Review.

CONTEXT: Infant race and ethnicity are used ubiquitously in research and reporting, though inconsistent approaches to data collection and definitions yield variable results. The consistency of these data has an impact on reported findings and outcomes. OBJECTIVE: To systematically review and examine concordance among differing race and ethnicity data collection techniques presented in perinatal health care literature. DATA SOURCES: PubMed, CINAHL, and Ovid were searched on June 17, 2021. STUDY SELECTION: English language articles published between 1980 and 2021 were included if they reported on the United States' infant population and compared 2 or more methods of capturing race and/or ethnicity. DATA EXTRACTION: Two authors independently evaluated articles for inclusion and quality, with disagreements resolved by a third reviewer. RESULTS: Our initial search identified 4329 unique citations. Forty articles passed title/abstract review and were reviewed in full text. Nineteen were considered relevant and assessed for quality and bias, from which 12 studies were ultimately included. Discordance in infant race and ethnicity data were common among multiple data collection methods, including those frequently used in perinatal health outcomes research. Infants of color and those born to racially and/or ethnically discordant parents were the most likely to be misclassified across data sources. LIMITATIONS: Studies were heterogeneous in methodology and populations of study and data could not be compiled for analysis. CONCLUSIONS: Racial and ethnic misclassification of infants leads to inaccurate measurement and reporting of infant morbidity and mortality, often underestimating burden in minoritized populations while overestimating it in the non-Hispanic/Latinx white population.

Body perceptions, occupations, eating attitudes, and behaviors emerged during the pandemic: An exploratory cluster analysis of eaters profiles.

Introduction: COVID-19 pandemic negatively impacted people's mental and physical health. Three areas have been significantly impacted, among others: eating-related behaviors, occupational balance, and exposure to self-image due to videoconferencing. This study aims to explore and document eaters profiles that were reported during the pandemic in the general Canadian population using a holistic perspective, including body perceptions, attitudes, and eating behaviors (i.e., body image, behaviors, attitudes, and motivations regarding food), and occupations (i.e., physical activity and cooking). Methods: This cross-sectional study was conducted from May to September 2020. Two hundred and seventy-three Canada's residents, French speaking of 18 years of age and older, participated in an online survey on behaviors, attitudes, and motivations regarding food and eating as well as body image and occupations during the COVID-19 pandemic. A hierarchical cluster analysis was used to determine the eaters profiles. One-way ANOVA and Chi-square test were conducted to differentiate occupational characteristics between eaters profiles. Results: Three distinctive profiles were found during the COVID-19 pandemic and could be placed on a continuum: the Congruent-driven eater is at the functional pole of the continuum, whereas the Incongruent-driven eater is at the dysfunctional pole of the eaters continuum. In the middle of the continuum, the Incongruent-perceptual eater is at a critical crossing point. Significant differences were reported between eaters profiles. Discussion: The empirical results based on an eaters continuum conceptualization highlight the importance of understanding how people perceive their body to assess and promote food well-being.

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer's disease pathology and in human post-mortem brain samples.

A diverse heterogeneity of microglial cells was previously described in Alzheimer's disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1 stratum lacunosum-moleculare of 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aß) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aß plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.

All roads lead to heterogeneity: The complex involvement of astrocytes and microglia in the pathogenesis of Alzheimer's disease.

In recent years, glial cells have been acknowledged as key players in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative condition in which an accumulation of intracellular neurofibrillary tangles and extracellular fibrillar amyloid beta is notably observed in the central nervous system. Genome-wide association studies have shown, both in microglia and astrocytes, an increase in gene variants associated with a higher risk of developing late-onset AD. Microglia, the resident innate immune cells of the brain, and astrocytes, glial cells crucial for vascular integrity and neuronal support, both agglomerate near amyloid beta plaques and dystrophic neurites where they participate in the elimination of these harmful parenchymal elements. However, their role in AD pathogenesis has been challenging to resolve due to the highly heterogeneous nature of these cell populations, i.e., their molecular, morphological, and ultrastructural diversity, together with their ever-changing responsiveness and functions throughout the pathological course of AD. With the recent expansions in the field of glial heterogeneity through innovative advances in state-of-the-art microscopy and -omics techniques, novel concepts and questions arose, notably pertaining to how the diverse microglial and astrocytic states interact with each other and with the AD hallmarks, and how their concerted efforts/actions impact the progression of the disease. In this review, we discuss the recent advances and findings on the topic of glial heterogeneity, particularly focusing on the relationships of these cells with AD hallmarks (e.g., amyloid beta plaques, neurofibrillary tangles, synaptic loss, and dystrophic neurites) in murine models of AD pathology and post-mortem brain samples of patients with AD.

Investigating Microglial Ultrastructural Alterations and Intimate Relationships with Neuronal Stress, Dystrophy, and Degeneration in Mouse Models of Alzheimer's Disease.

In recent decades, microglia have taken the field of neuroscience by storm, with numerous studies identifying key roles for these cells in the pathophysiology of neurodegenerative conditions, such as Alzheimer's disease (AD). The heterogeneity of these cells (e.g., the presence of various subtypes like the disease-associated microglia, microglia associated with neurodegeneration, dark microglia, lipid droplet-accumulating microglia), and their ultrastructural alterations arising from environmental challenges have become a central focus of recent studies. Dark microglia are electron-dense cells defined by their ultrastructural markers of cellular stress using electron microscopy (EM). In this protocol, we first describe the steps required for proper brain tissue preparation for EM experiments. Ultrastructural analysis of microglia and neurons/synapses in AD mouse models is also detailed, using transmission or scanning EM. We next explain how to characterize several ultrastructural markers of cellular stress, dystrophy or degeneration, in microglia and neurons/synapses, with relation to amyloid beta plaques.

A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease.

Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.

N-3 PUFA Deficiency Affects the Ultrastructural Organization and Density of White Matter Microglia in the Developing Brain of Male Mice.

Over the last century, westernization of dietary habits has led to a dramatic reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). In particular, low maternal intake of n-3 PUFAs throughout gestation and lactation causes defects in brain myelination. Microglia are recognized for their critical contribution to neurodevelopmental processes, such as myelination. These cells invade the white matter in the first weeks of the post-natal period, where they participate in oligodendrocyte maturation and myelin production. Therefore, we investigated whether an alteration of white matter microglia accompanies the myelination deficits observed in the brain of n-3 PUFA-deficient animals. Macroscopic imaging analysis shows that maternal n-3 PUFA deficiency decreases the density of white matter microglia around post-natal day 10. Microscopic electron microscopy analyses also revealed alterations of microglial ultrastructure, a decrease in the number of contacts between microglia and myelin sheet, and a decreased amount of myelin debris in their cell body. White matter microglia further displayed increased mitochondrial abundance and network area under perinatal n-3 PUFA deficiency. Overall, our data suggest that maternal n-3 PUFA deficiency alters the structure and function of microglial cells located in the white matter of pups early in life, and this could be the key to understand myelination deficits during neurodevelopment.

N-3 PUFA deficiency disrupts oligodendrocyte maturation and myelin integrity during brain development.

Westernization of dietary habits has led to a progressive reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n-3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n-3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long-term deleterious consequences on white matter organization and hippocampus-prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first-generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n-3 PUFA deficient animals. Our findings identify a novel mechanism through which n-3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.

Microglia control glutamatergic synapses in the adult mouse hippocampus.

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1-/- mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.

Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk.

The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.

Neuroendocrine, neuroinflammatory and pathological outcomes of chronic stress: A story of microglial remodeling.

Microglia, the resident macrophage cells of the central nervous system (CNS), are involved in a myriad of processes required to maintain CNS homeostasis. These cells are dynamic and can adapt their phenotype and functions to the physiological needs of the organism. Microglia rapidly respond to changes occurring in their microenvironment, such as the ones taking place during stress. While stress can be beneficial for the organism to adapt to a situation, it can become highly detrimental when it turns chronic. Microglial response to prolonged stress may lead to an alteration of their beneficial physiological functions, becoming either maladaptive or pro-inflammatory. In this review, we aim to summarize the effects of chronic stress exerted on microglia through the neuroendocrine system and inflammation at adulthood. We also discuss how these effects of chronic stress could contribute to microglial involvement in neuropsychiatric and sleep disorders, as well as neurodegenerative diseases.