Neuroscience
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The use of the existing endogenous neural progenitor cells (NPCs) in the brains of adult mammalian animals is challenging for cell therapy in treating Parkinson's disease (PD). Previous studies have indicated that there is a low level of neurogenesis in the substantia nigra (SN) of adult mice. To assess the regenerative/neurogenic capacity of NPCs following an intranigral injection of 6-hydroxydopamine (6-OHDA), the proliferation and differentiation of subventricular zone (SVZ)- and midbrain-derived NPCs were investigated, and the origin of SN newborn dopaminergic neurons was traced by using Nestin-CreER(TM)::ROSA26-LacZ mice and constructing a plasmid CD133-Promoter2-Cre. ⋯ The SN newly generated dopaminergic neurons might contribute a little to an incomplete recovery of the nigrostriatal system. In addition, we found that SN newborn dopaminergic neurons were mainly derived from the migration and differentiation of the NPCs in the 3V- and Aq-SVZ and their adjacent regions. Thus, it will become an ideal strategy to treat PD by promoting the proliferation and differentiation of endogenous NPCs.
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Huntington's disease (HD) is a hereditary neurodegenerative disorder resulting from N-terminal polyglutamine expansion in the huntingtin protein. A relatively selective and early loss of medium spiny neurons in the striatum is a hallmark of HD neuropathology. Although the exact mechanism of mutant huntingtin-mediated neurodegeneration is unclear, recent evidence suggests that NMDA-receptor-mediated excitotoxicity is involved. ⋯ Our findings demonstrate that deletion of a single allele of p35 in the B6 YAC128 mice results in an upregulation of Akt activity, and increases phosphorylation of mutant huntingtin at Ser421. Longitudinal behavioral analysis showed that this 50% reduction in p35 and p25 levels did not improve accelerating Rotarod performance in these YAC128 mice. However, a complete deletion of p35 normalized the accelerating Rotarod performance relative to their non-transgenic littermates at four months of age.
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Exposure to chronic stress following stroke has been shown, both clinically and pre-clinically, to impact negatively on the recovery process. While this phenomenon is well established, the specific mechanisms involved have remained largely unexplored. One obvious signaling pathway through which chronic stress may impact on the recovery process is via corticosterone, and its effects on microglial activity and vascular remodeling. ⋯ We also identified that corticosterone administration significantly altered the expression of the key microglial complement receptor, CD11b after stroke. Corticosterone administration did not alter the expression of the vessel basement membrane protein, Collagen IV after stroke. Together, these results suggest that corticosterone is likely to represent only one of the major stress signals responsible for driving the negative impacts of chronic stress on recovery.
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A number of studies have shown that sensory inputs from the hand can have a profound effect in stabilizing upright posture. This suggests that the central nervous system can extract information about body motion and external forces acting on the body from cutaneous sensory signals. ⋯ In this study we investigate whether this rapid change in activation of lower limb muscles is an invariant response determined by the pattern of somatosensory information arising from sensory receptors in the hand or whether it adapts to changes in postural stability. We manipulated lateral stability of upright stance by changing stance width which had no effect on the activation of upper limb muscles or hand kinematics, but produced profound changes in the activation patterns of lower limb muscles when perturbations were in the medial/lateral direction without affecting the activation patterns of muscles when perturbations were in the anterior/posterior direction.
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The immune/inflammatory signaling molecule tumor necrosis factor α (TNFα) is an important mediator of both constitutive and plastic signaling in the brain. In particular, TNFα is implicated in physiological processes, including fever, energy balance, and autonomic function, known to involve the hypothalamic paraventricular nucleus (PVN). Many critical actions of TNFα are transduced by the TNFα type 1 receptor (TNFR1), whose activation has been shown to potently modulate classical neural signaling. ⋯ Dendritic profiles expressing TNFR1 were contacted by axon terminals, which formed non-synaptic appositions, as well as excitatory-type and inhibitory-type synaptic specializations. A smaller population of TNFR1-labeled axon terminals making non-synaptic appositions, and to a lesser extent synaptic contacts, with unlabeled dendrites was also identified. These findings indicate that TNFR1 is structurally positioned to modulate postsynaptic signaling in the PVN, suggesting a mechanism whereby TNFR1 activation contributes to cardiovascular and other autonomic functions.