Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Kisler Kassandra,Nelson Amy R,Rege Sanket V,Ramanathan Anita,Wang Yaoming,Ahuja Ashim,Lazic Divna,Tsai Philbert S,Zhao Zhen,Zhou Yi,Boas David A,Sakadžić Sava,Zlokovic Berislav V Nature neuroscience Pericytes are perivascular mural cells of brain capillaries. They are positioned centrally in the neurovascular unit between endothelial cells, astrocytes and neurons. This position allows them to regulate key neurovascular functions of the brain. The role of pericytes in the regulation of cerebral blood flow (CBF) and neurovascular coupling remains, however, under debate. Using loss-of-function pericyte-deficient mice, here we show that pericyte degeneration diminishes global and individual capillary CBF responses to neuronal stimuli, resulting in neurovascular uncoupling, reduced oxygen supply to the brain and metabolic stress. Neurovascular deficits lead over time to impaired neuronal excitability and neurodegenerative changes. Thus, pericyte degeneration as seen in neurological disorders such as Alzheimer's disease may contribute to neurovascular dysfunction and neurodegeneration associated with human disease. 10.1038/nn.4489
    Brain Exercise and Brain Outcomes: Does Cognitive Activity Really Work to Maintain Your Brain? Blacker Deborah,Weuve Jennifer JAMA psychiatry 10.1001/jamapsychiatry.2018.0656
    Neurotransmitter Switching in the Developing and Adult Brain. Spitzer Nicholas C Annual review of neuroscience Neurotransmitter switching is the gain of one neurotransmitter and the loss of another in the same neuron in response to chronic stimulation. Neurotransmitter receptors on postsynaptic cells change to match the identity of the newly expressed neurotransmitter. Neurotransmitter switching often appears to change the sign of the synapse from excitatory to inhibitory or from inhibitory to excitatory. In these cases, neurotransmitter switching and receptor matching thus change the polarity of the circuit in which they take place. Neurotransmitter switching produces up or down reversals of behavior. It is also observed in response to disease. These findings raise the possibility that neurotransmitter switching contributes to depression, schizophrenia, and other illnesses. Many early discoveries of the single gain or loss of a neurotransmitter may have been harbingers of neurotransmitter switching. 10.1146/annurev-neuro-072116-031204
    Lactate in the brain: from metabolic end-product to signalling molecule. Magistretti Pierre J,Allaman Igor Nature reviews. Neuroscience Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system. 10.1038/nrn.2018.19
    Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Cree Bruce A C,Niu Jianqin,Hoi Kimberly K,Zhao Chao,Caganap Scott D,Henry Roland G,Dao Dang Q,Zollinger Daniel R,Mei Feng,Shen Yun-An A,Franklin Robin J M,Ullian Erik M,Xiao Lan,Chan Jonah R,Fancy Stephen P J Brain : a journal of neurology Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest. 10.1093/brain/awx312
    Melatonin induces mechanisms of brain resilience against neurodegeneration. Corpas Rubén,Griñán-Ferré Christian,Palomera-Ávalos Verónica,Porquet David,García de Frutos Pablo,Franciscato Cozzolino Silvia M,Rodríguez-Farré Eduard,Pallàs Mercè,Sanfeliu Coral,Cardoso Bárbara R Journal of pineal research Melatonin is an endogenous pleiotropic molecule which orchestrates regulatory functions and protective capacity against age-related ailments. The increase in circulating levels of melatonin through dietary supplements intensifies its health benefits. Investigations in animal models have shown that melatonin protects against Alzheimer's disease (AD)-like pathology, although clinical studies have not been conclusive. We hypothesized that melatonin induces changes in the brain that prevent or attenuate AD by increasing resilience. Therefore, we treated healthy nontransgenic (NoTg) and AD transgenic (3xTg-AD) 6-month-old mice with a daily dose of 10 mg/kg of melatonin until 12 months of age. As expected, melatonin reversed cognitive impairment and dementia-associated behaviors of anxiety and apathy and reduced amyloid and tau burden in 3xTg-AD mice. Remarkably, melatonin induced cognitive enhancement and higher wellness level-related behavior in NoTg mice. At the mechanism level, NF-κB and proinflammatory cytokine expressions were decreased in both NoTg and 3xTg-AD mice. The SIRT1 pathway of longevity and neuroprotection was also activated in both mouse strains after melatonin dosing. Furthermore, we explored new mechanisms and pathways not previously associated with melatonin treatment such as the ubiquitin-proteasome proteolytic system and the recently proposed neuroprotective Gas6/TAM pathway. The upregulation of proteasome activity and the modulation of Gas6 and its receptors by melatonin were similarly displayed by both NoTg and 3xTg-AD mice. Therefore, these results confirm the potential of melatonin treatment against AD pathology, by way of opening new pathways in its mechanisms of action, and demonstrating that melatonin induces cognitive enhancement and brain resilience against neurodegenerative processes. 10.1111/jpi.12515
    Lipocalin-2 protects the brain during inflammatory conditions. Kang S S,Ren Y,Liu C-C,Kurti A,Baker K E,Bu G,Asmann Y,Fryer J D Molecular psychiatry Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2 mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in wild-type (WT) mice injected with LPS, Lcn2 mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared with WT mice injected with LPS, Lcn2 mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, nucleotide-binding oligomerization domain-like receptor signaling and Janus kinase-signal transducer and activator of transcription signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae. 10.1038/mp.2016.243
    Brain immunology and immunotherapy in brain tumours. Sampson John H,Gunn Michael D,Fecci Peter E,Ashley David M Nature reviews. Cancer Gliomas, the most common malignant primary brain tumours, remain universally lethal. Yet, seminal discoveries in the past 5 years have clarified the anatomy, genetics and function of the immune system within the central nervous system (CNS) and altered the paradigm for successful immunotherapy. The impact of standard therapies on the response to immunotherapy is now better understood, as well. This new knowledge has implications for a broad range of tumours that develop within the CNS. Nevertheless, the requirements for successful therapy remain effective delivery and target specificity, while the dramatic heterogeneity of malignant gliomas at the genetic and immunological levels remains a profound challenge. 10.1038/s41568-019-0224-7
    The mucosal immune system: master regulator of bidirectional gut-brain communications. Powell Nick,Walker Marjorie M,Talley Nicholas J Nature reviews. Gastroenterology & hepatology Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota-gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut-brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis. 10.1038/nrgastro.2016.191
    B-1a lymphocytes promote oligodendrogenesis during brain development. Tanabe Shogo,Yamashita Toshihide Nature neuroscience During brain development, the immune system mediates neurogenesis, gliogenesis and synapse formation. However, it remains unclear whether peripheral lymphocytes contribute to brain development. Here we identified the subtypes of lymphocytes that are present in neonatal mouse brains and investigated their functions. We found that B-1a cells, a subtype of B cells, were abundant in the neonatal mouse brain and infiltrated into the brain in a CXCL13-CXCR5-dependent manner. B-1a cells promoted the proliferation of oligodendrocyte-precursor cells (OPCs) in vitro, and depletion of B-1a cells from developing brains resulted in a reduction of numbers of OPCs and mature oligodendrocytes. Furthermore, neutralizing Fcα/μR, the receptor for the Fc region of IgM secreted by B-1a cells, inhibited OPC proliferation and reduced the proportion of myelinated axons in neonatal mouse brains. Our results demonstrate that B-1a cells infiltrate into the brain and contribute to oligodendrogenesis and myelination by promoting OPC proliferation via IgM-Fcα/μR signaling. 10.1038/s41593-018-0106-4
    Inflammasome signalling in brain function and neurodegenerative disease. Heneka Michael T,McManus Róisín M,Latz Eicke Nature reviews. Neuroscience The mammalian CNS is an intricate and fragile structure, which on one hand is open to change in order to store information, but on the other hand is vulnerable to damage from injury, pathogen invasion or neurodegeneration. During senescence and neurodegeneration, activation of the innate immune system can occur. Inflammasomes are signalling complexes that regulate cells of the immune system, which in the brain mainly includes microglial cells. In microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway. Several other inflammasomes have been described in microglia and the other cells of the brain, including astrocytes and neurons, where their activation and subsequent caspase 1 cleavage contribute to disease development and progression. 10.1038/s41583-018-0055-7
    How and why do T cells and their derived cytokines affect the injured and healthy brain? Filiano Anthony J,Gadani Sachin P,Kipnis Jonathan Nature reviews. Neuroscience The evolution of adaptive immunity provides enhanced defence against specific pathogens, as well as homeostatic immune surveillance of all tissues. Despite being 'immune privileged', the CNS uses the assistance of the immune system in physiological and pathological states. In this Opinion article, we discuss the influence of adaptive immunity on recovery after CNS injury and on cognitive and social brain function. We further extend a hypothesis that the pro-social effects of interferon-regulated genes were initially exploited by pathogens to increase host-host transmission, and that these genes were later recycled by the host to form part of an immune defence programme. In this way, the evolution of adaptive immunity may reflect a host-pathogen 'arms race'. 10.1038/nrn.2017.39
    Loss of Brain Aerobic Glycolysis in Normal Human Aging. Goyal Manu S,Vlassenko Andrei G,Blazey Tyler M,Su Yi,Couture Lars E,Durbin Tony J,Bateman Randall J,Benzinger Tammie L-S,Morris John C,Raichle Marcus E Cell metabolism The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG. 10.1016/j.cmet.2017.07.010
    Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Xu Bing,Zhang Yu,Du Xu-Fei,Li Jia,Zi Hua-Xing,Bu Ji-Wen,Yan Yong,Han Hua,Du Jiu-Lin Cell research Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication. 10.1038/cr.2017.62
    Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Obri Arnaud,Khrimian Lori,Karsenty Gerard,Oury Franck Nature reviews. Endocrinology A remarkable, unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse, as its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behaviour. The regulation of cognitive function by osteocalcin, together with the fact that its circulating levels decrease in midlife compared with adolescence in all species tested, raised the prospect that osteocalcin might be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this Review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young wild-type mice. The diversity and amplitude of the functions of osteocalcin in the brain, during development and postnatally, had long called for the identification of its receptor in the brain, which was also recently achieved. This Review presents our current understanding of the biology of osteocalcin in the brain, highlighting the bony vertebrate specificity of the regulation of cognitive function and pointing toward where therapeutic opportunities might exist. 10.1038/nrendo.2017.181
    Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain. Van Steenwinckel Juliette,Schang Anne-Laure,Krishnan Michelle L,Degos Vincent,Delahaye-Duriez Andrée,Bokobza Cindy,Csaba Zsolt,Verdonk Franck,Montané Amélie,Sigaut Stéphanie,Hennebert Olivier,Lebon Sophie,Schwendimann Leslie,Le Charpentier Tifenn,Hassan-Abdi Rahma,Ball Gareth,Aljabar Paul,Saxena Alka,Holloway Rebecca K,Birchmeier Walter,Baud Olivier,Rowitch David,Miron Veronique,Chretien Fabrice,Leconte Claire,Besson Valérie C,Petretto Enrico G,Edwards A David,Hagberg Henrik,Soussi-Yanicostas Nadia,Fleiss Bobbi,Gressens Pierre Brain : a journal of neurology Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target. 10.1093/brain/awz319
    Markers of microglia in post-mortem brain samples from patients with Alzheimer's disease: a systematic review. Hopperton K E,Mohammad D,Trépanier M O,Giuliano V,Bazinet R P Molecular psychiatry Neuroinflammation is proposed as one of the mechanisms by which Alzheimer's disease pathology, including amyloid-β plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer's disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post-mortem brain samples from patients with Alzheimer's disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions. Nine studies were identified that included high pathology controls, patients who remained free of dementia despite Alzheimer's disease pathology. The majority (5/9) of these studies reported higher levels of microglial markers in Alzheimer's disease relative to controls, suggesting that these increases are not solely a consequence of Alzheimer's disease pathology. These results show that increased markers of microglia are a consistent feature of Alzheimer's disease, though this seems to be driven primarily by increases in activation-associated markers, as opposed to markers of all microglia. 10.1038/mp.2017.246
    Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals. Farokhnia M,Grodin E N,Lee M R,Oot E N,Blackburn A N,Stangl B L,Schwandt M L,Farinelli L A,Momenan R,Ramchandani V A,Leggio L Molecular psychiatry Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder. 10.1038/mp.2017.226
    Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology. Layé Sophie,Nadjar Agnès,Joffre Corinne,Bazinet Richard P Pharmacological reviews Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain. 10.1124/pr.117.014092
    Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. Sinha Bharati,Wu Qiaofeng,Li Wei,Tu Yanyang,Sirianni Ana C,Chen Yanchun,Jiang Jiying,Zhang Xinmu,Chen Wu,Zhou Shuanhu,Reiter Russel J,Manning Simon M,Patel Nirav J,Aziz-Sultan Ali M,Inder Terrie E,Friedlander Robert M,Fu Jianfang,Wang Xin Journal of pineal research The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation. 10.1111/jpi.12443
    Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety. McKim D B,Weber M D,Niraula A,Sawicki C M,Liu X,Jarrett B L,Ramirez-Chan K,Wang Y,Roeth R M,Sucaldito A D,Sobol C G,Quan N,Sheridan J F,Godbout J P Molecular psychiatry Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1β (IL-1β). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1 neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1 specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders. 10.1038/mp.2017.64
    Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning. Woo J,Kim J E,Im J J,Lee J,Jeong H S,Park S,Jung S-Y,An H,Yoon S,Lim S M,Lee S,Ma J,Shin E Y,Han Y-E,Kim B,Lee E H,Feng L,Chun H,Yoon B-E,Kang I,Dager S R,Lyoo I K,Lee C J Molecular psychiatry The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity. 10.1038/mp.2017.113
    Induction of a transmissible tau pathology by traumatic brain injury. Zanier Elisa R,Bertani Ilaria,Sammali Eliana,Pischiutta Francesca,Chiaravalloti Maria Antonietta,Vegliante Gloria,Masone Antonio,Corbelli Alessandro,Smith Douglas H,Menon David K,Stocchetti Nino,Fiordaliso Fabio,De Simoni Maria-Grazia,Stewart William,Chiesa Roberto Brain : a journal of neurology Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans. 10.1093/brain/awy193
    Mechanical stress increases brain amyloid β, tau, and α-synuclein concentrations in wild-type mice. Levy Nogueira Marcel,Hamraz Minoo,Abolhassani Mohammad,Bigan Erwan,Lafitte Olivier,Steyaert Jean-Marc,Dubois Bruno,Schwartz Laurent Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Exposure to traumatic brain injury is a core risk factor that predisposes an individual to sporadic neurodegenerative diseases. We provide evidence that mechanical stress increases brain levels of hallmark proteins associated with neurodegeneration. METHODS:Wild-type mice were exposed to multiple regimens of repetitive mild traumatic brain injury, generating a range of combinations of impact energies, frequencies, and durations of exposure. Brain concentrations of amyloid β 1-42 (Aβ), total tau, and α-synuclein were measured by sandwich enzyme-linked immunosorbent assay. RESULTS:There was a highly significant main effect of impact energy, frequency, and duration of exposure on Aβ, tau, and α-synuclein levels (P < .001), and a significant interaction between impact energy and duration of exposure for Aβ and tau (P < .001), but not for α-synuclein. DISCUSSION:Dose-dependent and cumulative influence of repetitive mild traumatic brain injury-induced mechanical stress may trigger and/or accelerate neurodegeneration by pushing protein concentration over the disease threshold. 10.1016/j.jalz.2017.11.003