Neuroscience
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Whereas environmental challenges during gestation have been repeatedly shown to alter offspring brain architecture and behavior, exploration examining the consequences of paternal preconception experience on offspring outcome is limited. The goal of this study was to examine the effects of preconception paternal stress (PPS) on cerebral plasticity and behavior in the offspring. Several behavioral assays were performed on offspring between postnatal days 33 (P33) and 101 (P101). ⋯ Neuroanatomical measures revealed a heavier brain in stressed animals and dendritic changes in all regions measured, the precise effect varying with the measure and cerebral region. Thus, PPS impacted both behavior and neuronal morphology of offspring. These effects likely have an epigenetic basis given that in a parallel study of littermates of the current animals we found extensive epigenetic changes at P21.
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Preclinical and clinical studies support a promising, albeit not definitive, neuroprotective effect of emergent uric acid (UA) administration in ischemic stroke. We assessed the effects of UA in an ischemic stroke model relevant to the current treatment paradigm of mechanical thrombectomy within the STAIR/RIGOR recommendations. A cohort of male and female Wistar rats was subjected to ischemic stroke with mechanical recanalization under physiological monitoring. ⋯ After a 7-day follow-up, male rats subjected to UA treatment still showed reductions in neurofunctional impairment and infarct size, compared to vehicle treatment. In conclusion, UA treatment immediately after transient ischemia results in a sex-independent, maintained reduction of brain damage and neurological impairment, better manifested in hyperperfusion conditions. This synergistic effect of UA with mechanical recanalization supports additional clinical testing of UA as an adjunctive treatment to mechanical thrombectomy.
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Mutations in a ubiquitin (Ub)-binding adaptor protein optineurin have been found in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a prominent neuroinflammatory component. Unlike more frequent ALS mutations which cause disease by gaining toxic properties such as aggregation, mutated optineurin is thought to cause disease by loss-of-function, highlighting its neuroprotective role. Optineurin regulates inflammatory signaling by acting as a scaffold for Tank-binding kinase 1 (TBK1) activation and interferon (IFN)-β production in peripheral immune cells. ⋯ Notably, although optineurin was also reported to block proinflammatory transcription factor NF-κB, normal NF-κB activation and TNF production were found in Optn470T microglia. However, expression of both proinflammatory and anti-inflammatory factors distal to IFN-β was diminished, and could be restored upon IFN-β supplementation. Taken together with the recent discoveries of TBK1 mutations as an important genetic factor in ALS, our results open up the possibility that disruption of optineurin/TBK1-mediated IFN-β axis leads to an immune failure in containing neuronal damage, which could predispose to neurodegeneration.
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We have recently revealed that the proprioceptive signal from jaw-closing muscle spindles (JCMSs) is conveyed to the dorsal part of granular insular cortex rostroventrally adjacent to the rostralmost part of secondary somatosensory cortex (dGIrvs2) via the caudo-ventromedial edge (VPMcvm) of ventral posteromedial thalamic nucleus (VPM) in rats. However, it remains unclear to which cortical or subcortical structures the JCMS proprioceptive information is subsequently conveyed from the dGIrvs2. To test this issue, we injected an anterograde tracer, biotinylated dextranamine, into the electophysiologically identified dGIrvs2, and analyzed the resultant distribution profiles of labeled axon terminals in rats. ⋯ They were also observed in the central amygdaloid nucleus and extended amygdala (the interstitial nucleus of posterior limb of anterior commissure and the juxtacapsular part of lateral division of bed nucleus of stria terminalis). In the thalamus, they were seen in the reticular nucleus, ventromedial nucleus, core VPM, parvicellular part of ventral posterior nucleus, oval paracentral nucleus, medial and triangular parts of posterior nucleus, and zona incerta as well as the VPMcvm. These data suggest that the JCMS proprioceptive information through the dGIrvs2 is transmitted to the emotional 'limbic' regions as well as sensorimotor regions.
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Hypobaric Hypoxia (HH) is well-known to cause cognitive impairment and synaptic dysfunction which results in neurodegeneration. Although the role of small conductance calcium-activated potassium channels (SK channels) has been reported in synaptic plasticity, cognition and different neurological disorders; however, the precise role of SK channels in HH-induced memory impairment remains yet to be explored. We, therefore, hypothesized the pivotal role of SK channels in HH-induced cognitive decline and investigated the SK channel expression during different duration of HH exposure (Control, 1, 3, 7 and 14 days) at mRNA and protein level in male Sprague-Dawley rats. ⋯ Immunohistochemical analysis revealed similar pattern in different regions of the hippocampus. Additionally, SK channel inhibition with Apamin prevented HH-induced neurodegeneration and memory impairment as evident from decreased number of Fluoro Jade-positive cells, pyknotic cells, and caspase-3 expression and improved performance in the Morris water maze task. Thus, the present study demonstrates that SK channels play a crucial role in HH-induced cognitive decline and neurodegeneration.