Platelet factors attenuate inflammation and rescue cognition in ageing.

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans.

Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter oligodendrocytes contribute to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin basic protein (MBP) content in multiple brain areas. We found that oligodendrocyte cell density and MBP were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and MBP. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with MBP in the amygdala and spatial-processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species-independent relationship between region-specific, gray matter oligodendrocytes and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.

Lytic Cell Death in Specific Microglial Subsets Is Required for Preventing Atypical Behavior in Mice.

Microglial cells are known to contribute to brain development and behaviors, but the mechanisms behind such functions are not fully understood. Here, we show that mice deficient in inflammasome regulators, including caspase-1 (Casp1), NLR family pyrin domain containing 3 (Nlrp3), IL-1 receptor (Il-1r), and gasdermin D (Gsdmd), exhibit behavior abnormalities characterized by hyperactivity and low anxiety levels. Furthermore, we found that expression of Casp1 in CX3CR1+ myeloid cells, which includes microglia, is required for preventing these abnormal behaviors. Through tissue clearing and 3D imaging, we discovered that small numbers of Cx3cr1-GFP+ fetal microglial cells formed clusters and underwent lytic cell death in the primitive thalamus and striatum between embryonic day (E)12.5 and E14.5. This lytic cell death was diminished in Casp1-deficient mice. Further analysis of the microglial clusters showed the presence of Pax6+ neural progenitor cells (NPCs); thus, we hypothesized that microglial lytic cell death is important for proper neuronal development. Indeed, increased numbers of neurons were observed in the thalamic subset in adult Casp1-/- brains. Finally, injection of drug inhibitors of NLRP3 and CASP1 into wild-type (WT) pregnant mice from E12.5 to E14.5, the period when lytic cell death was detected, was sufficient to induce atypical behaviors in offspring. Taken together, our data suggests that the inflammasome cascade in microglia is important for regulating neuronal development and normal behaviors, and that genetic or pharmacological inhibition of this pathway can induce atypical behaviors in mice.