Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure.
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 individuals beginning a resistance training program, small but detectable increases in hypertrophy may occur in the absence of eccentric muscle damage within seven training sessions.
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...
BackgroundA majority of indoor residential microbes originate from humans, pets, and outdoor air and are not adapted to the built environment (BE). Consequently, a large portion of the microbes identified by DNA-based methods are either dead or metabolically inactive. Although many exceptions have been noted, the ribosomal RNA fraction of the sample is more likely to represent either viable or metabolically active cells. We examined methodological variations in sample processing using a defined, mock BE microbial community to better understand the scope of technique-based vs. biological-based differences in both ribosomal transcript (rRNA) and gene (DNA) sequence community analysis. Based on in vitro tests, a protocol was adopted for the analysis of the genetic and metabolic pool (DNA vs. rRNA) of air and surface microbiomes within a residential setting.ResultsWe observed differences in DNA/RNA co-extraction efficiency for individual microbes, but overall, a greater recovery of rRNA using FastPrep (> 50%). Samples stored with various preservation methods at − 80°C experienced a rapid decline in nucleic acid recovery starting within the first week, although post-extraction rRNA had no significant degradation when treated with RNAStable. We recommend that co-extraction samples be processed as quickly as possible after collection. The in vivo analysis revealed significant differences in the two components (genetic and metabolic pool) in terms of taxonomy, community structure, and microbial association networks. Rare taxa present in the genetic pool showed higher metabolic potential (RNA:DNA ratio), whereas commonly detected taxa of outdoor origins based on DNA sequencing, especially taxa of the Sphingomonadales order, were present in lower relative abundances in the viable community.ConclusionsAlthough methodological variations in sample preparations are high, large differences between the DNA and RNA fractions of the total microbial community demonstrate that direct examination of rRNA isolated from a residential BE microbiome has the potential to identify the more likely viable or active portion of the microbial community. In an environment that has primarily dead and metabolically inactive cells, we suggest that the rRNA fraction of BE samples is capable of providing a more ecologically relevant insight into the factors that drive indoor microbial community dynamics.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0453-0) contains supplementary material, which is available to authorized users.
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