Neuroscience
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Animals can suppress their behavioral response in advance according to changes in environmental context (proactive inhibition: delaying the start of response), a process in which several cortical areas may participate. However, it remains unclear how this process is adaptively regulated according to contextual changes on different timescales. To address the issue, we used an improved stop-signal task paradigm to behaviorally and electrophysiologically characterize the temporal aspect of proactive inhibition in head-fixed rats. ⋯ Subsequently, M1 activity was attenuated during motor decision/execution. Under trial-based proactive inhibition, the OFC activity was continuously enhanced, and PPC and M1 activity was also enhanced shortly during motor decision/execution. These results suggest that different cortical mechanisms underlie the two types of proactive inhibition in rodents.
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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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Genetic mutations of FOXP1 and FOXP2 are associated with neurodevelopmental diseases. It is important to characterize the cell types that express Foxp1 and Foxp2 in the brain. Foxp1 and Foxp2 are expressed at high levels in the striatum of mouse brains. ⋯ Neither Foxp1 nor Foxp2 was found to co-localize with parvalbumin, somatostatin, nNOS, calretinin and ChAT in interneurons of the striatum. Moreover, none of parvalbumin-, somatostatin-, nNOS-, and calretinin-positive interneurons co-expressed Foxp1 or Foxp2 in the cerebral cortex. As Foxp1 and Foxp2 can form heterodimers for transcriptional regulation, the differential and overlapping expression pattern of Foxp1 and Foxp2 in SPNs implicates coordinate and distinct roles of Foxp1 and Foxp2 in developmental construction and physiologic functions of striatal circuits in the brain.
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Subarachnoid hemorrhage (SAH) is a well-known hemorrhagic stroke with high rates of morbidity and mortality where patients frequently experience cognitive dysfunction. This study explores a potential treatment for cognitive dysfunction following SAH with the demonstration that multi-target drug cattle encephalon glycoside and ignotin (CEGI) can relieve cognitive dysfunction by decreasing hippocampal neuron apoptosis following SAH in rats. Experimentally, 110 male SD rats were separated at random into Sham (20), SAH + Vehicle (30), SAH + 4 ml/kg CEGI (30), and SAH + 1 ml/kg CEGI groups (30) and an endovascular perforation model was created to induce SAH. ⋯ This finding was associated with an observed decrease in Bax/Bcl-2 ratio, cytochrome-c and PUMA expression, and the suppression of caspase-3 activation following SAH. In Morris water maze tests, the SAH + 4 ml/kg CEGI group demonstrated a decreased escape latency time and increase in time spent in the target quadrant as well as crossing times of platform region. These results indicate that high doses of CEGI can decrease hippocampal neuron apoptosis and relieve cognitive dysfunction in rats, suggesting that multitarget-drug CEGI exhibits a neuroprotective effect in SAH via the mitochondrial apoptosis pathway.
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Alzheimer's disease (AD) is a debilitating neurodegenerative disease, characterized by extracellular deposition of senile plaques, mostly amyloid β-protein (Aβ) and neuronal loss. The neuroprotective effects of erythropoietin (EPO) have been reported in some models of neurodegenerative disease, but because of its hematopoietic side effects, its derivatives lacking hematopoietic bioactivity is recommended. In this study, the neuroprotective effects of carbamylated erythropoietin-Fc (CEPO-Fc) against beta amyloid-induced memory deficit were evaluated. ⋯ CEPO-Fc treatment prevented the elevation of hippocampal of P38, ERK, MMP-2 activity and also Akt/GSK-3β signaling impairment induced by Aβ25-35 but it had no effect on JNK. It seems that CEPO-Fc prevents Aβ-induced learning and memory deterioration, and also modulates hippocampal MAPKs, Akt/GSK-3β and MMP-2 activity. This study suggests that CEPO-Fc can be considered as a potential therapeutic strategy for memory deficits like AD.