Microglia have diverse actions, ranging from synapse pruning in development to cytotoxic effects in disease. Brain energy metabolism and substrate availability vary under normal and disease states, but how these variations influence microglial function is relatively unknown. Microglia, like most other cell types, express the full complement of gene products required for both glycolytic and oxidative metabolism. Evidence suggests that microglia increase aerobic glycolysis and decrease respiration when activated by various stimuli. Mitochondrial function, glucose availability, and glycolytic rate influence pro-inflammatory gene expression at both transcriptional and post-translational levels. These effects are mediated through CtBP, an NADH-sensitive transcriptional co-repressor; through effects on NLRP3 inflammasome assembly and caspase-1 activation; through formation of advanced glycation end-products; and by less well-defined mechanisms. In addition to these transcriptional effects, microglial glucose metabolism is also required for superoxide production by NADPH oxidase, as glucose is the obligate substrate for regenerating NADPH in the hexose monophosphate shunt. Microglia also metabolize acetoacetate and β-hydroxybutyrate, which are generated during fasting or ketogenic diet, and respond to these ketones as metabolic signals. β-Hydroxybutyrate inhibits histone de-acetylases and activates microglial GRP109A receptors. These actions suppress microglia activation after brain injury and promote neuroprotective microglia phenotypes. As our understanding of microglial activation matures, additional links between energy metabolism and microglial function are likely to be identified.

The immune privileged nature of the CNS can make it vulnerable to chronic and latent infections. Little is known about the effects of lifelong brain infections, and thus inflammation, on the neurological health of the host. Toxoplasma gondii is a parasite that can infect any mammalian nucleated cell with average worldwide seroprevalence rates of 30%. Infection by Toxoplasma is characterized by the lifelong presence of parasitic cysts within neurons in the brain, requiring a competent immune system to prevent parasite reactivation and encephalitis. In the immunocompetent individual, Toxoplasma infection is largely asymptomatic, however many recent studies suggest a strong correlation with certain neurodegenerative and psychiatric disorders. Here, we demonstrate a significant reduction in the primary astrocytic glutamate transporter, GLT-1, following infection with Toxoplasma. Using microdialysis of the murine frontal cortex over the course of infection, a significant increase in extracellular concentrations of glutamate is observed. Consistent with glutamate dysregulation, analysis of neurons reveal changes in morphology including a reduction in dendritic spines, VGlut1 and NeuN immunoreactivity. Furthermore, behavioral testing and EEG recordings point to significant changes in neuronal output. Finally, these changes in neuronal connectivity are dependent on infection-induced downregulation of GLT-1 as treatment with the ß-lactam antibiotic ceftriaxone, rescues extracellular glutamate concentrations, neuronal pathology and function. Altogether, these data demonstrate that following an infection with T. gondii, the delicate regulation of glutamate by astrocytes is disrupted and accounts for a range of deficits observed in chronic infection.

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With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

Mild repetitive traumatic brain injury (rTBI) induces chronic behavioral and cognitive alterations and increases the risk for dementia. Currently, there are no therapeutic strategies to prevent or mitigate chronic deficits associated with rTBI. Previously we developed an animal model of rTBI that recapitulates the cognitive and behavioral deficits observed in humans. We now report that rTBI results in an increase in risk-taking behavior in male but not female mice. This behavioral phenotype is associated with chronic activation of the integrated stress response and cell-specific synaptic alterations in the type A subtype of layer V pyramidal neurons in the medial prefrontal cortex. Strikingly, by briefly treating animals weeks after injury with ISRIB, a selective inhibitor of the integrated stress response (ISR), we (1) relieve ISR activation, (2) reverse the increased risk-taking behavioral phenotype and maintain this reversal, and (3) restore cellspecific synaptic function in the affected mice. Our results indicate that targeting the ISR even at late time points after injury can permanently reverse behavioral changes. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat rTBI-induced behavioral dysfunction.

In the coming decade, astronauts will travel back to the moon in preparation for future Mars missions. Exposure to galactic cosmic radiation (GCR) is a major obstacle for deep space travel. Using multivariate principal components analysis, we found sex-dimorphic responses in mice exposed to accelerated charged particles to simulate GCR (GCRsim); males displayed impaired spatial learning, whereas females did not. Mechanistically, these GCRsiminduced learning impairments corresponded with chronic microglia activation and synaptic alterations in the hippocampus. Temporary microglia depletion shortly after GCRsim exposure mitigated GCRsim-induced deficits measured months after the radiation exposure. Furthermore, blood monocyte levels measured early after GCRsim exposure were predictive of the late learning deficits and microglia activation measured in the male mice. Our findings (i) advance our understanding of charged particle-induced cognitive challenges, (ii) provide evidence for early peripheral biomarkers for identifying late cognitive deficits, and (iii) offer potential therapeutic strategies for mitigating GCR-induced cognitive loss.

Small molecule cognitive enhancer reverses age-related memory decline in mice. 1 2SHORT TITLE (less than 40 characters): Reversing aging related deficits 3 4 ABSTRACT 49With increased life expectancy, age-associated cognitive decline becomes a growing 50 concern. The integrated stress response (ISR) is activated during aging and contributes 51 to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-52 molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by 53 decreased activating transcription factor 4 (ATF4) protein levels. Furthermore, ISRIB 54 treatment reverses spatial memory deficits and ameliorates working memory in old mice. 55At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal 56 electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, 57 specifically interferon and T cell-mediated responses. Thus, pharmacological interference 58 with the ISR emerges as a promising intervention strategy for combating age-related 59 cognitive decline. 60 61 INTRODUCTION 62 63 "Of the capacities that people hope will remain intact as they get older, perhaps the most 64 treasured is to stay mentally sharp" (1). 65 66The impact of age on cognitive performance represents an important quality-of-life and 67 societal concern, especially given our prolonged life expectancy. Decreases in executive 68 function as well as learning and memory decrements in older individuals are common (2, 69 3, 4 , 5). According to the US Department of Commerce the aging population is estimated 70 by 2050 to reach 83.7 million individuals above 65 years of age in the US; this represents 71 a rapidly growing healthcare and economic concern (6). 72 4 73Age-related decline in spatial memory has been recapitulated in preclinical studies with 74 old rodents (7-10). The hippocampus is the brain region associated with spatial learning 75 and memory formation and is particularly vulnerable to age-related changes in humans 76 and rodents (11)(12)(13)(14). Deficits in a number of cellular processes have been suggested as 77 underlying causes based on correlative evidence, including protein synthesis (15), 78 metabolism (16), inflammation (17), and immune responses (9,(18)(19)(20). While providing a 79 wealth of parameters to assess, by and large the causal molecular underpinnings of age-80 related memory decline have remained unclear. 81 82The principle that blocking protein synthesis prevents long-term memory storage was 83 discovered many years ago (21). With age there is a marked decline of protein synthesis 84 in the brain that correlates with defects in proper protein folding (22-24). Accumulation of 85 misfolded proteins can activate the integrated stress response (ISR) (25), an evolutionary 86 conserved pathway that decreases protein synthesis. In this way, the ISR may have a 87 causative role in age-related cognitive decline. We previously discovered that interference 88 with the drug-like small-molecule inhibitor (integ...

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