The Journal of neuroscience : the official journal of the Society for Neuroscience
-
Peripheral sensory neurons in the dorsal root ganglia (DRG) are the initial transducers of sensory stimuli, including painful stimuli, from the periphery to central sensory and pain-processing centers. Small- to medium-diameter non-peptidergic neurons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of ionotropic glutamate receptors, as well as the putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2). Neto2 alters recombinant KAR function markedly but has yet to be confirmed as an auxiliary subunit that assembles with and alters the function of endogenous KARs. ⋯ The putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2) is also expressed in DRG. We show here that it is a developmentally downregulated but dynamic component of KARs in these neurons, that it contributes to regulated neurite regrowth in adult neurons, and that it is increased in adult mice after nerve injury. Our data confirm Neto2 as a KAR auxiliary subunit and expand our knowledge of the molecular composition of KARs in nociceptive neurons, a key piece in understanding the mechanistic contribution of KAR signaling to pain-processing circuits.
-
Transcranial magnetic stimulation (TMS) of human occipital and posterior parietal cortex can give rise to visual sensations called phosphenes. We used near-threshold TMS with concurrent EEG recordings to measure how oscillatory brain dynamics covary, on single trials, with the perception of phosphenes after occipital and parietal TMS. Prestimulus power and phase, predominantly in the alpha band (8-13 Hz), predicted occipital TMS phosphenes, whereas higher-frequency beta-band (13-20 Hz) power (but not phase) predicted parietal TMS phosphenes. ⋯ We probed cortical excitability directly in human occipital and parietal cortex and observed that, whereas alpha-band dynamics indeed reflect excitability of occipital areas, beta-band activity was most predictive of parietal cortex excitability. Differences in the state of cortical excitability predicted perceptual outcomes (phosphenes), which were manifest in both early and late patterns of evoked activity, revealing the time course of phosphene perception. Our findings prompt revision of the notion that alpha activity reflects excitability across all of cortex and suggest instead that excitability in different regions is reflected in distinct frequency bands.
-
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.
-
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.
-
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.