What Do Microglia Really Do in Healthy Adult Brain?

Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease.

Effects of 50 Hz magnetic fields on circadian rhythm control in mice.

Artificial light and power frequency magnetic fields are ubiquitous in the built environment. Light is a potent zeitgeber but it is unclear whether power frequency magnetic fields can influence circadian rhythm control. To study this possibility, 8-12-week-old male C57BL/6J mice were exposed for 30 min starting at zeitgeber time 14 (ZT14, 2 h into the dark period of the day) to 50 Hz magnetic fields at 580 µT using a pair of Helmholtz coils and/or a blue LED light at 700 lux or neither. Our experiments revealed an acute adrenal response to blue light, in terms of increased adrenal per1 gene expression, increased serum corticosterone levels, increased time spent sleeping, and decreased locomotor activity (in all cases, P < 0.0001) compared to an unexposed control group. There appeared to be no modulating effect of the magnetic fields on the response to light, and there was also no effect of the magnetic fields alone (in both cases, P > 0.05) except for a decrease in locomotor activity (P < 0.03). Gene expression of the cryptochromes cry1 and cry2 in the adrenals, liver, and hippocampus was also not affected by exposures (in all cases, P > 0.05). In conclusion, these results suggest that 50 Hz magnetic fields do not significantly affect the acute light response to a degree that can be detected in the adrenal response. Bioelectromagnetics. 2019;9999:XX-XX. © 2019 Bioelectromagnetics Society.

Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels.

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3ß (GSK-3ß) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent stress-induced inhibition of hippocampal neurogenesis and accompanying physiological changes. The present data suggest that thiamine precursors with high bioavailability might be useful as a complementary therapy in several neuropsychiatric disorders.

Neonatal prebiotic (BGOS) supplementation increases the levels of synaptophysin, GluN2A-subunits and BDNF proteins in the adult rat hippocampus.

Compelling data suggest that perturbations in microbial colonization of the gut in early-life, influences neurodevelopment and adult brain function. If this is the case, then ensuring the growth of beneficial bacteria at an early age will lead to optimal brain development and maturation. We have tested whether feeding neonatal rats daily (from post-natal days 3-21) with a galacto-oligosaccharide prebiotic (Bimuno®, BGOS) or a control solution, alters the levels of hippocampal N-Methyl-D-Aspartate receptor (NMDAR) subunits (GluN1, GluN2A, GluN2B), synaptic proteins (synaptophysin, MAP2, and GAP43) and brain-derived-neurotrophic factor (BDNF), at post-natal days 22 and 56. The administration of BGOS significantly elevated GluN2A subunits, synaptophysin and BDNF in the hippocampus of 22 day old rats. The effect was also observed on day 56 (26 days after the feeding ceased). The levels of all other proteins (GluN1, GluN2B, MAP2, GAP43) remained unaltered. Increased GluN2A, synaptophysin, BDNF, but not MAP2, may suggest that neonatal BGOS feeding alters neurotransmission rather than synaptic architecture. Although the functional consequences of our findings require further investigation, the current study confirms that the manipulation of gut bacteria in early-life, has central effects that persist until at least young adulthood.

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients.

OBJECTIVES: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients. DESIGN: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening. METHODS: The metabolic composition of CSF was analysed using H nuclear magnetic resonance (H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features. RESULTS: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, ß-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%. CONCLUSION: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.

Anti-IL-17A treatment reduces clinical score and VCAM-1 expression detected by in vivo magnetic resonance imaging in chronic relapsing EAE ABH mice.

IL-17 is argued to play an important role in the multiple sclerosis-like disease experimental autoimmune encephalitis (EAE). We investigated the therapeutic effects of anti-IL-17A in a chronic relapsing EAE ABH mouse model using conventional scoring, quantitative behavioral outcomes, and a novel vascular cell adhesion molecule 1 (VCAM-1)-targeted magnetic resonance imaging (MRI) contrast agent [anti-VCAM-microparticles of iron oxide (MPIO)] to identify conventionally undetectable neuropathology. Mice were administered prophylactic or treatment regimens of anti-IL-17A or IgG and two injections of anti-VCAM-MPIO before undergoing T2*-weighted three-dimensional and gadolinium-diethylenetriamine pentaacetic acid T1-weighted MRI. Rotarod, inverted screen, and open field motor function tests were performed, conventional clinical scores calculated, and central IL-17A mRNA expression quantified during acute disease, remission, and relapse. Prophylactic anti-IL-17A prevents acute disease and relapse and is associated with reduced clinical and functional severity. Treatment regimens delay relapse, improve functional scores, and are associated with reduced VCAM-MPIO lesions during remission. No significant alteration was detectable in levels of gadolinium-diethylenetriamine pentaacetic acid- or VCAM-MPIO-positive lesions during relapse. Prophylactic and treatment anti-IL-17A were therapeutically effective in chronic relapsing EAE, improving clinical and quantifiable functional outcomes. IL-17A expression seems significant during acute disease but less important chronically. Disease-related immunoneuropathology is more sensitively detected using VCAM-MPIO MRI, which may, therefore, be used to monitor therapy meaningfully.

Study of cytokine induced neuropathology by high resolution proton NMR spectroscopy of rat urine.

Multiple sclerosis is a major cause of non-traumatic neurological disability. The identification of markers that differentiate disease progression is critical to effective therapy. A combination of NMR spectroscopic metabolic profiling of urine and statistical pattern recognition was used to detect focal inflammatory central nervous system (CNS) lesions induced by microinjection of a replication-deficient recombinant adenovirus expressing TNF-alpha or IL1-beta cDNA into the brains of Wistar rats. These animals were compared with a group of naïve rats and a group of animals injected with an equivalent null adenovirus. Urine samples were collected 7 days after adenovirus injection, when the inflammatory lesion is maximally active. Principal components analysis and Partial Least Squares-Discriminate analysis of the urine (1)H NMR spectra revealed significant differences between each of the cytokine adenovirus groups and the control groups; for the TNF-alpha group the main differences lay in citrate and succinate, while for the IL-1beta group the predominant changes occurred in leucine, isoleucine, valine and myo-inositol. Thus, we can identify urinary metabolic vectors that not only separate rats with inflammatory lesions in the brain from control animals, but also distinguish between different types of CNS inflammatory lesions.