Microglial Transcriptional Signatures in the Central Nervous System: Toward A Future of Unraveling Their Function in Health and Disease.

Microglia, the resident immune cells of the central nervous system (CNS), are primarily derived from the embryonic yolk sac and make their way to the CNS during early development. They play key physiological and immunological roles across the life span, throughout health, injury, and disease. Recent transcriptomic studies have identified gene transcript signatures expressed by microglia that may provide the foundation for unprecedented insights into their functions. Microglial gene expression signatures can help distinguish them from macrophage cell types to a reasonable degree of certainty, depending on the context. Microglial expression patterns further suggest a heterogeneous population comprised of many states that vary according to the spatiotemporal context. Microglial diversity is most pronounced during development, when extensive CNS remodeling takes place, and following disease or injury. A next step of importance for the field will be to identify the functional roles performed by these various microglial states, with the perspective of targeting them therapeutically.

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses.

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.

Suppression of Presynaptic Glutamate Release by Postsynaptic Metabotropic NMDA Receptor Signalling to Pannexin-1.

The impact of pannexin-1 (Panx1) channels on synaptic transmission is poorly understood. Here, we show that selective block of Panx1 in single postsynaptic hippocampal CA1 neurons from male rat or mouse brain slices causes intermittent, seconds long increases in the frequency of sEPSC following Schaffer collateral stimulation. The increase in sEPSC frequency occurred without an effect on evoked neurotransmission. Consistent with a presynaptic origin of the augmented glutamate release, the increased sEPSC frequency was prevented by bath-applied EGTA-AM or TTX. Manipulation of a previously described metabotropic NMDAR pathway (i.e., by preventing ligand binding to NMDARs with competitive antagonists or blocking downstream Src kinase) also increased sEPSC frequency similar to that seen when Panx1 was blocked. This facilitated glutamate release was absent in transient receptor potential vanilloid 1 (TRPV1) KO mice and prevented by the TRPV1 antagonist, capsazepine, suggesting it required presynaptic TRPV1. We show presynaptic expression of TRPV1 by immunoelectron microscopy and link TRPV1 to Panx1 because Panx1 block increases tissue levels of the endovanilloid, anandamide. Together, these findings demonstrate an unexpected role for metabotropic NMDARs and postsynaptic Panx1 in suppression of facilitated glutamate neurotransmission.SIGNIFICANCE STATEMENT The postsynaptic ion and metabolite channel, pannexin-1, is regulated by metabotropic NMDAR signaling through Src kinase. This pathway suppresses facilitated release of presynaptic glutamate during synaptic activity by regulating tissue levels of the transient receptor potential vanilloid 1 agonist anandamide.

Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice.

Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

Interactive effects of compounding multidimensional stressors on maternal and male and female rat offspring outcomes.

Exposure to adverse childhood experiences (ACEs) is a risk factor for the development of psychiatric disorders in addition to cardiovascular associated diseases. This risk is elevated when the cumulative burden of ACEs is increased. Laboratory animals can be used to model the changes (as well as the underlying mechanisms) that result in response to adverse events. In this study, using male and female Sprague Dawley rats, we examined the impact of increasing stress burden, utilizing both two adverse early life experiences (parental/offspring high fat diet + limited bedding exposure) and three adverse early life experiences (parental/offspring high fat diet + limited bedding exposure + neonatal inflammation), on maternal care quality and offspring behavior. Additionally, we measured hormones and hippocampal gene expression related to stress. We found that the adverse perinatal environment led to a compensatory increase in maternal care. Moreover, these dams had reduced maternal expression of oxytocin receptor, compared to standard housed dams, in response to acute stress on postnatal day (P)22. In offspring, the two-hit and three-hit models resulted in a hyperlocomotor phenotype and increased body weights. Plasma leptin and hippocampal gene expression of corticotropin releasing hormone (Chrh)1 and Crhr2 were elevated (males) while expression of oxytocin was reduced (females) following acute stress. On some measures (e.g., hyperlocomotion, leptin), the magnitude of change was lower in the three-hit compared to the two-hit model. This suggests that multiple early adverse events can have interactive, and often unpredictable, impacts, highlighting the importance of modeling complex interactions amongst stressors during development.

Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety.

Increased anandamide (AEA) signaling through inhibition of its catabolic enzyme fatty acid amide hydrolase (FAAH) in the basolateral complex of amygdala (BLA) is thought to buffer against the effects of stress and reduces behavioral signs of anxiety and fear. However, examining the role of AEA signaling in stress, anxiety, and fear through pharmacological depletion has been challenging due to the redundant complexity of its biosynthesis and the lack of a pharmacological synthesis inhibitor. We developed a herpes simplex viral vector to rapidly yet transiently overexpress FAAH specifically within the BLA to assess the impact of suppressing AEA signaling on stress, fear, and anxiety in male rats. Surprisingly, FAAH overexpression in BLA dampened stress-induced corticosterone release, reduced anxiety-like behaviors, and decreased conditioned fear expression. Interestingly, depleting AEA signaling in the BLA did not prevent fear conditioning itself or fear reinstatement. These effects were specific to the overexpression of FAAH because they were reversed by intra-BLA administration of an FAAH inhibitor. Moreover, the fear-suppressive effects of FAAH overexpression were also mitigated by intra-BLA administration of a low dose of a GABAA receptor antagonist, but not an NMDA/AMPA/kainate receptor antagonist, suggesting that they were mediated by an increase in GABAergic neurotransmission. Our data suggest that a permissive AEA tone within the BLA might gate GABA release and that loss of this tone through elevated AEA hydrolysis increases inhibition in the BLA, which in turn reduces stress, anxiety, and fear. These data provide new insights on the mechanisms by which amygdalar endocannabinoid signaling regulates emotional behavior.SIGNIFICANCE STATEMENT Amygdala endocannabinoid signaling is involved in the regulation of stress, anxiety, and fear. Our data indicate that viral-mediated augmentation of anandamide hydrolysis within the basolateral amygdala reduces behavioral indices of stress, anxiety, and conditioned fear expression. These same effects have been previously documented with inhibition of anandamide hydrolysis in the same brain region. Our results indicate that the ability of anandamide signaling to regulate emotional behavior is nonlinear and may involve actions at distinct neuronal populations, which could be influenced by the basal level of anandamide. Modulation of anandamide signaling is a current clinical therapeutic target for stress-related psychiatric illnesses, so these data underscore the importance of fully understanding the mechanisms by which anandamide signaling regulates amygdala-dependent changes in emotionality.

Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.

Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid-CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety.

Divergent responses of inflammatory mediators within the amygdala and medial prefrontal cortex to acute psychological stress.

There is now a growing body of literature that indicates that stress can initiate inflammatory processes, both in the periphery and brain; however, the spatiotemporal nature of this response is not well characterized. The aim of this study was to examine the effects of an acute psychological stress on changes in mRNA and protein levels of a wide range of inflammatory mediators across a broad temporal range, in key corticolimbic brain regions involved in the regulation of the stress response (amygdala, hippocampus, hypothalamus, medial prefrontal cortex). mRNA levels of inflammatory mediators were analyzed immediately following 30min or 120min of acute restraint stress and protein levels were examined 0h through 24h post-termination of 120min of acute restraint stress using both multiplex and ELISA methods. Our data demonstrate, for the first time, that exposure to acute psychological stress results in an increase in the protein level of several inflammatory mediators in the amygdala while concomitantly producing a decrease in the protein level of multiple inflammatory mediators within the medial prefrontal cortex. This pattern of changes seemed largely restricted to the amygdala and medial prefrontal cortex, with stress producing few changes in the mRNA or protein levels of inflammatory mediators within the hippocampus or hypothalamus. Consistent with previous research, stress resulted in a general elevation in multiple inflammatory mediators within the circulation. These data indicate that neuroinflammatory responses to stress do not appear to be generalized across brain structures and exhibit a high degree of spatiotemporal specificity. Given the impact of inflammatory signaling on neural excitability and emotional behavior, these data may provide a platform with which to explore the importance of inflammatory signaling within the prefrontocortical-amygdala circuit in the regulation of the neurobehavioral responses to stress.

Acute Psychological Stress Modulates the Expression of Enzymes Involved in the Kynurenine Pathway throughout Corticolimbic Circuits in Adult Male Rats.

Tryptophan is an essential dietary amino acid that is necessary for protein synthesis, but also serves as the precursor for serotonin. However, in addition to these biological functions, tryptophan also serves as a precursor for the kynurenine pathway, which has neurotoxic (quinolinic acid) and neuroprotective (kynurenic acid) metabolites. Glucocorticoid hormones and inflammatory mediators, both of which are increased by stress, have been shown to bias tryptophan along the kynurenine pathway and away from serotonin synthesis; however, to date, there is no published data regarding the effects of stress on enzymes regulating the kynurenine pathway in a regional manner throughout the brain. Herein, we examined the effects of an acute psychological stress (120 min restraint) on gene expression patterns of enzymes along the kynurenine pathway over a protracted time-course (1-24 h post-stress termination) within the amygdala, hippocampus, hypothalamus, and medial prefrontal cortex. Time-dependent changes in differential enzymes along the kynurenine metabolism pathway, particularly those involved in the production of quinolinic acid, were found within the amygdala, hypothalamus, and medial prefrontal cortex, with no changes seen in the hippocampus. These regional differences acutely may provide mechanistic insight into processes that become dysregulated chronically in stress-associated disorders.

A robust capillary liquid chromatography/tandem mass spectrometry method for quantitation of neuromodulatory endocannabinoids.

RATIONALE: Methods for quantifying anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are needed to support programs investigating molecular mechanisms of the central nervous system. Existing methods, while useful, are not well adapted to efficiently process large numbers of very small tissue samples. A unique challenge involves the disparity in endogenous levels of AEA (pmol/g tissue) and 2-AG (nmol/g tissue). METHODS: A simplified one-step solvent extraction procedure was developed for recovering endocannabinoids from rat brain tissues, and combined with capillary liquid chromatography/tandem mass spectrometry (LC/MS/MS). Various multiple reaction monitoring (MRM)-based methods were evaluated for limit of detection (LOD) and robustness. RESULTS: The optimized simultaneous quantitation method achieves an LOQ of 50 amol for AEA and 25 fmol for 2-AG, both with a linearity over 3 orders of magnitude, and elution times under 3 min. Accuracy, expressed as relative error (RE), is less than 12% for AEA and less than 6% for 2-AG. Precision, expressed as relative standard deviation (RSD), is less than 6% for AEA and less than 3% for 2-AG. Sample handling routines are sufficiently robust to support the automated analysis of thousands of samples from a range of tissue types. CONCLUSIONS: The microscale method is a sensitive, economical and robust alternative to the larger scale LC/MS methods currently implemented for quantitation of AEA and 2-AG.

Viral-induced encephalitis initiates distinct and functional CD103+ CD11b+ brain dendritic cell populations within the olfactory bulb.

Dendritic cells (DC) are antigen-presenting cells found in both lymphoid and nonlymphoid organs, including the brain (bDC) of Cd11c/eyfp transgenic C57BL/6 mice. Using an intranasal vesicular stomatitis virus infection, we demonstrated that EYFP(+) cells amass in areas associated with viral antigens, take on an activated morphology, and project their processes into infected neuronal tissue within the olfactory bulb. These bDC separated into three EYFP(+) CD45(+) CD11b(+) populations, all but one being able to functionally promote both T lymphocyte proliferation and T(H)1 cytokine production. One population was shown to emanate from the brain and a second population was peripherally derived. The third population was of indeterminate origin, being both radiosensitive and not replenished by donor bone marrow. Finally, each EYFP(+) population contained CD11b(+) CD103(+) subpopulations and could be distinguished in terms of CD115, Gr-1, and Ly-6C expression, highlighting mucosal and monocyte-derived DC lineages.

Enhancing axonal myelination in seniors: A review exploring the potential impact cannabis has on myelination in the aged brain.

Consumption of cannabis is on the rise as public opinion trends toward acceptance and its consequent legalization. Specifically, the senior population is one of the demographics increasing their use of cannabis the fastest, but research aimed at understanding cannabis' impact on the aged brain is still scarce. Aging is characterized by many brain changes that slowly alter cognitive ability. One process that is greatly impacted during aging is axonal myelination. The slow degradation and loss of myelin (i.e., demyelination) in the brain with age has been shown to associate with cognitive decline and, furthermore, is a common characteristic of numerous neurological diseases experienced in aging. It is currently not known what causes this age-dependent degradation, but it is likely due to numerous confounding factors (i.e., heightened inflammation, reduced blood flow, cellular senescence) that impact the many cells responsible for maintaining overall homeostasis and myelin integrity. Importantly, animal studies using non-human primates and rodents have also revealed demyelination with age, providing a reliable model for researchers to try and understand the cellular mechanisms at play. In rodents, cannabis was recently shown to modulate the myelination process. Furthermore, studies looking at the direct modulatory impact cannabis has on microglia, astrocytes and oligodendrocyte lineage cells hint at potential mechanisms to prevent some of the more damaging activities performed by these cells that contribute to demyelination in aging. However, research focusing on how cannabis impacts myelination in the aged brain is lacking. Therefore, this review will explore the evidence thus far accumulated to show how cannabis impacts myelination and will extrapolate what this knowledge may mean for the aged brain.

Microglia: A pharmacological target for the treatment of age-related cognitive decline and Alzheimer's disease.

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS. Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress. Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.

Environmental Enrichment Engages Vesicular Zinc Signaling to Enhance Hippocampal Neurogenesis.

Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus.

A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice.

Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMP-activated protein kinase (AMPK). AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in agouti-related protein (AgRP) neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings.

Present and future of microglial pharmacology.

Microglia, brain resident immune cells, modulate development, activity, and plasticity of the central nervous system. Mechanistically implicated in numerous neurological pathologies, microglia emerge as strong contenders for novel neurotherapies. Shifting away from merely an attenuation of excessive microglial inflammatory and phagocytic activities, current therapies aim toward targeting the complex context-dependent microglial heterogeneity, unveiled by large-scale genetic studies and emerging single-cell analyses. Although lacking the necessary selectivity, initial therapies attempting to target specific state-associated microglial properties and functions (e.g., inflammatory activity, phagocytosis, proliferation, metabolism, or surveillance) are currently under pre- or even clinical (Phase I-IV) investigation. Here, we provide an update on current microglial therapeutic research and discuss what the future in the field might look like.

Sex and stressor modality influence acute stress-induced dynamic changes in corticolimbic endocannabinoid levels in adult Sprague Dawley rats.

Research over the past few decades has established a role for the endocannabinoid system in contributing to the neural and endocrine responses to stress exposure. The two endocannabinoid ligands, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), both play roles in regulating the stress response and both exhibit dynamic changes in response to stress exposure. Most of this previous research, however, was conducted in male rodents. Given that, especially in rodents, the stress response is influenced by sex, an understanding of how these dynamic responses of endocannabinoids in response to stress is influenced by sex could provide insight into sex differences of the acute stress response. We exposed adult, Sprague Dawley rats to different commonly utilized acute stress modalities, specifically restraint, swim and foot shock stress. Thirty minutes following stress onset, we excised the amygdala, hippocampus and medial prefrontal cortex, corticolimbic brain regions involved in the stress response, to measure endocannabinoid levels. When AEA levels were altered in response to restraint and swim stress, they were reduced, whereas exposure to foot shock stress led to an increase in the amygdala. 2-AG levels, when they were altered by stress exposure were only increased, specifically in males in the amygdala following swim stress, and in the hippocampus and medial prefrontal cortex overall following foot shock stress. This increase in 2-AG levels following stress only in males was the only sex difference found in stress-induced changes in endocannabinoid levels. There were no consistent sex differences observed. Collectively, these data contribute to our further understanding of the interactions between stress and endocannabinoid function.

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.

Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is marked by cardio-respiratory alterations, with increasing reports also indicating neurological and psychiatric symptoms in infected individuals. During COVID-19 pathology, the central nervous system (CNS) is possibly affected by direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion, exaggerated systemic inflammatory responses, or hypoxia. Psychosocial stress imposed by the pandemic further affects the CNS of COVID-19 patients, but also the non-infected population, potentially contributing to the emergence or exacerbation of various neurological or mental health disorders. Microglia are central players of the CNS homeostasis maintenance and inflammatory response that exert their crucial functions in coordination with other CNS cells. During homeostatic challenges to the brain parenchyma, microglia modify their density, morphology, and molecular signature, resulting in the adjustment of their functions. In this review, we discuss how microglia may be involved in the neuroprotective and neurotoxic responses against CNS insults deriving from COVID-19. We examine how these responses may explain, at least partially, the neurological and psychiatric manifestations reported in COVID-19 patients and the general population. Furthermore, we consider how microglia might contribute to increased CNS vulnerability in certain groups, such as aged individuals and people with pre-existing conditions.