Neuroscience
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The cochlear nucleus, located in the brainstem, receives its afferent auditory input exclusively from the auditory nerve fibers of the ipsilateral cochlea. Noise-induced neurodegenerative changes occurring in the auditory nerve stimulate a cascade of neuroplastic changes in the cochlear nucleus resulting in major changes in synaptic structure and function. To identify some of the key molecular mechanisms mediating this synaptic reorganization, we unilaterally exposed rats to a high-intensity noise that caused significant hearing loss and then measured the resulting changes in a synaptic plasticity gene array targeting neurogenesis and synaptic reorganization. ⋯ Significant gene expression changes occurred more frequently in the VCN than the DCN and more changes were seen at 28 d versus 2 d post-exposure. We confirmed the PCR findings by in situ hybridization for Brain-derived neurotrophic factor (Bdnf), Homer-1, as well as the glutamate NMDA receptor Grin1, all involved in neurogenesis and plasticity. These results suggest that Bdnf, Homer-1 and Grin1 play important roles in synaptic remodeling and homeostasis in the cochlear nucleus following severe noise-induced afferent degeneration.
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Despite extensive literature showing damages in the sensorimotor projection fibers of children with hemiplegic cerebral palsy (HCP), little is known about how these damages affect the global brain network. In this study, we assess the relationship between the structural integrity of sensorimotor projection fibers and the integrity of intergyral association white matter connections in children with HCP. Diffusion tensor imaging was performed in 10 children with HCP and 16 typically developing children. ⋯ Using the whole-brain parcellation method, we tracked the short-, middle-, and long-range association fibers. We observed for the more affected hemisphere of children with HCP: (i) an increase in axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) for the STh and ThC fibers; (ii) a decrease in fractional anisotropy (FA) and an increase in MD and RD for the CST and SMU fibers; in (iii) a decrease in FA and an increase in AD, MD, and RD for the middle- and long-range association fibers; and (iv) an association between the integrity of sensorimotor projection and intergyral association fibers. Our findings indicate that altered structural integrity of the sensorimotor projection fibers disorganizes the intergyral association white matter connections among local and distant regions in children with HCP.
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Resilience to stress can be obtained by adjusting the stress-response set point during postnatal sensory development. Recent studies have implemented epigenetic mechanisms to play leading roles in improving resilience. We previously found that better resilience to heat stress in chicks can be achieved by conditioning them to moderate heat stress during their critical developmental period of thermal control establishment, 3 days posthatch. ⋯ The observed changes in DNA methylation can be explained by decreased activity of the enzyme DNA methyltransferase as a result of the PARPi injection. Furthermore, evaluation of the DNA-methylation pattern along the CRH intron showed a reduction in 5mC% as a result of PARPi treatment, alongside a reduction in CRH mRNA expression. Thus, PARPi treatment can affect DNA methylation, which can alter hypothalamic-pituitary-adrenal (HPA) axis anchors such as CRH, thereby potentially enhancing long-term resilience to heat stress.
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Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The proapoptotic BH3-only protein Bim has been reported to be involved in dopaminergic neurodegeneration of experimental PD. However, an in situ expression profile of Bim in PD has not been performed, and the cell types of which Bim accounts for PD pathogenesis is unclear. ⋯ Bim△Dat mice are shown to be resistant to MPTP-induced neurotoxicity, confirming that the induction of Bim in dopaminergic neurons is responsible for parkinsonian neurodegeneration. Furthermore, we demonstrated with dopaminergic neuron-specific c-Jun knockout (c-Jun△Dat) that the transcriptional upregulation of Bim of nigral dopaminergic neurons was c-Jun-dependent and further validated the detrimental role of c-Jun in dopaminergic neurodegeneration. Together, these data specify that c-Jun-mediated Bim upregulation in nigral dopaminergic neurons contributes to parkinsonian neurodegeneration.
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MicroRNAs have been reported to be an important pathophysiological factor in neuropathic pain. However, the potential mechanism through which miRNAs function in neuropathic pain remains unclear. The purpose of this study was to explore the potential role of mir-34c in neuropathic pain in a mouse model of chronic constriction injury (CCI). ⋯ We also demonstrated that miR-34c suppressed the expression of NLRP3 by directly binding the 3'-untranslated region. Overexpression of miR-34c decreased the protein levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in the spinal cord in CCI mice. Together, our results indicated that miR-34c may inhibit neuropathic pain development in CCI mice through inhibiting NLRP3-mediated neuroinflammation.