Neuroscience
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The mitogen-activated protein kinases (MAPK) are major signaling components of intracellular pathways required for memory consolidation. Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) mediate signal transduction downstream of MAPK. MSKs are activated by Extracellular-signal Regulated Kinase 1/2 (ERK1/2) and p38 MAPK. ⋯ Loss of Msk1, but not of Msk2, affected excitatory synaptic transmission at perforant path-to-dentate granule cell synapses, altered short-term presynaptic plasticity, impaired selectively long-term spatial recognition memory, and decreased basal levels of CREB and its activated form. LTP in vivo and LTP-induced CREB phosphorylation and EGR1 expression were unchanged after Msk1 or Msk2 deletion. Our findings demonstrate a dissimilar contribution of MSKs proteins in cognitive processes and suggest that Msk1 loss-of-function only has a deleterious impact on neuronal activity and hippocampal-dependent memory consolidation.
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Radiation-induced cognitive dysfunction is a common complication associated with cranial radiation therapy. Inhibition of hippocampal neurogenesis and proliferation plays a critical role in this complication. Relieving hippocampal apoptosis may significantly protect hippocampal neurogenesis and proliferation. ⋯ Additionally, this treatment suppressed the expression of cleaved caspase-3. We further demonstrated that p5-TAT treatment reduced hippocampal dysfunction and improved behavioral performance. Therefore, Cdk5 inhibition by the small peptide p5-TAT is a promising therapeutic strategy for radiation-induced cognitive dysfunction.
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Estrogen produces a beneficial role in animal models of multiple sclerosis (MS). The effect of 17β-estradiol therapy on microglia polarization and neuroinflammation in the corpus callosum of the cuprizone-induced demyelination model has not been elucidated. In this study, mice were given 0.2% cuprizone (CPZ) for 5 weeks to induce demyelination during which they received 50 ng of 17β-estradiol (EST), injected subcutaneously in the neck region, twice weekly. ⋯ Moreover, administration of 17β-estradiol resulted in a significant reduction (∼3-fold) in transcript levels of NLRP3 inflammasome and its downstream product IL-18, compared to controls. In summary, this study demonstrated for the first time that exogenous 17β-estradiol therapy robustly leads to the reduction of M1 phenotype, stimulation of polarized M2 microglia, and repression of NLRP3 inflammasome in the corpus callosum of CPZ demyelination model of MS. The positive effects of 17β-estradiol on microglia and inflammasome seems to facilitate and accelerate the remyelination process.
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The Wechsler Adult intelligence scale-Revised (WAIS-R) Block design test (BDT) is a neuropsychological test widely used to assess cognitive declines in aging population. Previous studies suggest parietal lobe is the key region to influence the performance on the BDT; yet, it has not been clearly identified. The aim of the current study, therefore, is to identify the functional neural correlates of the BDT in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia patients. ⋯ The same analyses were conducted on the subgroups categorized by clinical severity based on the Clinical Dementia Rating (CDR). Significant positive correlations between performance on the BDT and regional cerebral glucose metabolism were found bilaterally in the inferior parietal lobules, right thalamus and right middle frontal gyrus. Our results suggest that performance on the BDT in MCI and AD patients functionally relies on the brain regions known to be associated with motor and executive functions in addition to visuospatial function.
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Activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. ⋯ Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF.