The Journal of neuroscience : the official journal of the Society for Neuroscience
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Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. ⋯ The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain.
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Targeting posttraumatic inflammation is crucial for improving locomotor function. SIRT1 has been shown to play a critical role in disease processes such as hepatic inflammation, rheumatoid arthritis, and acute lung inflammation by regulating inflammation. However, the role of SIRT1 in spinal cord injury (SCI) is unknown. ⋯ Here, new data show that administration of SRT1720, an SIRT1 agonist, to wild-type (WT) mice significantly improved outcomes after SCI, most likely by reducing the levels of inflammatory cytokines, the number of macrophages/microglia, perivascular macrophages, and M1 macrophages. In contrast, SIRT1 KO mice exhibited worse locomotor recovery than that of WT mice due to aggravated inflammation. Taken together, the results of this study expand upon the previous understanding of the functions and mechanisms of SIRT1 in neuroinflammation following injury to the CNS, suggesting that SIRT1 plays a critical role in regulating neuroinflammation following CNS injury and may be a novel therapeutic target for post-SCI intervention.
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Goal-directed behavior is sensitive to the current value of expected outcomes. This requires independent representations of specific rewards, which have been linked to orbitofrontal cortex (OFC) function. However, the mechanisms by which the human brain updates specific goals on the fly, and translates those updates into choices, have remained unknown. ⋯ Here we tested how identity-specific representations of food odor reward are updated by satiety. We found that fMRI pattern-based signatures of reward identity in lateral posterior OFC were modulated after selective devaluation, and that connectivity between this region and general value coding ventromedial prefrontal cortex (vmPFC) predicted choice behavior. These results provide evidence for a mechanism by which devaluation modulates a cognitive map of expected reward in OFC and thereby alters general value signals in vmPFC to guide goal-directed behavior.
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Transcriptional deregulation and changes in mitochondrial bioenergetics, including pyruvate dehydrogenase (PDH) dysfunction, have been described in Huntington's disease (HD). We showed previously that the histone deacetylase inhibitors (HDACIs) trichostatin A and sodium butyrate (SB) ameliorate mitochondrial function in cells expressing mutant huntingtin. In this work, we investigated the effect of HDACIs on the regulation of PDH activity in striatal cells derived from HD knock-in mice and YAC128 mice. ⋯ These results suggest that HDACIs, particularly SB, promote the activity of PDH in the HD brain, helping to counteract HD-related deficits in mitochondrial bioenergetics and motor function. SIGNIFICANCE STATEMENT The present work provides a better understanding of mitochondrial dysfunction in Huntington's disease (HD) by showing that the pyruvate dehydrogenase (PDH) complex is a promising therapeutic target. In particular, the histone deacetylase inhibitor sodium butyrate (SB) may indirectly (through reduced hypoxia-inducible factor 1 alpha stabilization) decrease the expression of the most abundant PDH kinase isoforms (e.g., PDK3), ameliorating PDH activity and mitochondrial metabolism and further affecting motor behavior in HD mice, thus constituting a promising agent for HD neuroprotective treatment.
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Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. ⋯ We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia.