Neuroscience
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Cholinergically differentiated SH-SY5Y neuroblastoma cells were treated with a pathophysiologically relevant, low (300 nM), and a high (3 μM) dose of amyloid beta 1-42 (Abeta) or 42-1 (revAbeta). At early (1 and 4h) and late (24h) time points, the pro- and anti-apoptotic factors--caspase-3 and p53, and B-cell lymphoma 2 protein (Bcl-2), respectively--were assessed together with lactate dehydrogenase (LDH) release as measure of cell viability and ATP levels as marker of mitochondrial activity. The low peptide dose significantly increased Bcl-2 and, time-delayed, caspase-3 and ATP levels, but barely impacted on LDH release, while the high concentration remarkably depressed Bcl-2 levels, depleted ATP and led to increased LDH release. ⋯ The low Abeta concentration drastically upregulated AChE-R and increased both ChAT and HACU, while the high dose caused cholinergic toxicity. We believe this study offers the first insight into the highly concentration-dependent effects of Abeta on cholinergic dynamics. In particular, it highlights the rescuing role of AChE-R as being, together with mitochondrial activity, involved in cholinergic adaptation to low doses of Abeta.
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Long-term potentiation (LTP) of synaptic transmission in the CA1 region of the hippocampus depends on the activation of N-methyl-D-aspartate receptors (NMDARs), which can be regulated by Ca²⁺-dependent release of D-serine from astrocytes. The detailed mechanism underlying astrocytic d-serine release is still unknown. In hippocampal slices prepared from Sprague-Dawley rats, we found that clamping astrocytic [Ca²⁺] at 100-150 nM or puffing artificial cerebrospinal fluid (ACSF) into the extracellular space (weak mechanical stimulation) enhanced the synaptic activation of NMDARs. ⋯ The formation of astrocytic large vesicles involved the intracellular fusion of small vesicles and/or other organelles. Spontaneous fusion of large vesicles occurred occasionally in astrocytes at rest, contributing to baseline D-serine levels, which increased the rising slope of NMDAR post-burst potentiation (PBP) without altering the PBP peak amplitude. Thus, under physiological conditions, astrocytic D-serine release by large vesicles facilitated weak theta-burst (TBS consisting of five bursts), but not strong TBS (TBS consisting of 10 bursts) stimulation-induced LTP.
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Investigations of local field potentials of the subthalamic nucleus of patients with Parkinson's disease have provided evidence for pathologically exaggerated oscillatory beta-band activity (13-30 Hz) which is amenable to physiological modulation by, e.g., voluntary movement. Previous functional magnetic resonance imaging studies in healthy controls have provided evidence for an increase of subthalamic nucleus blood-oxygenation-level-dependant signal in incremental force generation tasks. However, the modulation of neuronal activity by force generation and its relationship to peripheral feedback remain to be elucidated. ⋯ Granger-causality was computed with the squared partial directed coherence and showed no significant modulation during incremental isometric force generation. Our findings indicate that the upper beta- and gamma-band power of subthalamic nucleus local field potentials are modulated by the physiological task of force generation in patients with Parkinson's disease. This modulation seems to be not an effect of a modulation of peripheral feedback.
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Promoting neural stem/progenitor cell (NSC/NPC) survival in the pro-apoptotic environment is critical to stem cell replacement for neurodegenerative disease therapy. Paeoniflorin (PF), one of the principal bioactive components in Paeoniae Radix, has been used widely in central nervous system (CNS) diseases treatment and serves as an antioxidant to protect neurons against oxidative stress. The present study investigated the protective effects of PF on NPC injury induced by hydrogen peroxide (H₂O₂). ⋯ Furthermore, PF-mediated NPC protection was associated with an increase in phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt-1) phosphorylation in a time- and concentration-dependent manner. Selective inhibition of PI3K using LY294002 abolished PF-mediated phosphorylation of Akt-1 and NPC protection upon oxidative stress. These data suggest that PF-mediated NPC protection on H₂O₂ injury is reliant on the activation of the PI3K/Akt-1 pathway, giving insight to an essential role of PF in NPC protection.
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Precise mechanisms are required to coordinate the locomotor activity of fore- and hind-limbs in quadrupeds and similar mechanisms persist to coordinate movement of arms and legs in humans. Propriospinal neurons (PSNs) are major components of the networks that coordinate these mechanisms. The b subunit of cholera toxin (CTb) was injected unilaterally into either L1 or L3 segments in order to label ascending and descending propriospinal pathways. ⋯ The major finding of this study is the existence of a substantial excitatory propriospinal pathway that projects specifically to the VLM. Motoneurons in the VLM supply muscles of the axilla therefore this pathway is likely to have a profound influence on the activity of the shoulder joint. This pathway may synchronise lumbar and cervical pattern generators and hence the coordination of locomotor activity in the fore- and hind limbs.