Neuroscience
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Activation of the M1 muscarinic acetylcholine receptor (M1R) may be an effective therapeutic approach for Alzheimer's disease (AD), dementia with Lewy bodies, and schizophrenia. Previously, the M1R/M4R agonist xanomeline was shown to improve cognitive function and exert antipsychotic effects in patients with AD and schizophrenia. However, its clinical development was discontinued because of its cholinomimetic side effects. ⋯ Other than in the orbital cortex and claustrum, TAK-071 induced similar c-Fos expression patterns. When donepezil was co-administered to increase the levels of acetylcholine, the number of TAK-071-induced c-Fos-positive cells in these brain regions was increased. TAK-071, through induction of similar neural activation as that seen with xanomeline, may produce procognitive and antipsychotic effects with improved cholinergic side effects.
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Substantial evidence has demonstrated that prenatal stress (PS) impairs spatial learning and memory in offspring. The neuron-specific protein kinase C gamma (PKCγ) has been proposed to be unique in spatial learning and memory. The present study proposes to determine whether hippocampal PKCγ is involved in the detrimental effects of PS on spatial learning and memory in offspring, and to further explore the effects of PS-induced PKCγ-dependent growth-associated protein 43 (GAP-43) and neurogranin (Ng) phosphorylation alteration on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. ⋯ Overexpression of PKCγ in the hippocampal CA1 area recovered the ability of spatial learning and memory in PS female offspring. Furthermore, enhancing PKCγ reversed PS-induced membrane and cytosolic PKCγ reduction, and restored levels of GAP-43 and Ng phosphorylation, and CaMKII activation in the hippocampus. In conclusion, PS possibly decreases hippocampal PKCγ activity, resulting in a reduction of p-GAP-43 and p-Ng, which underlies insufficient CaMKII activation, thereby impairing spatial learning and memory.
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Inflammation may result in periventricular leukomalacia, which is the leading cause of preterm brain encephalopathy. Moreover,
-3 polyunsaturated fatty acids ( -3 PUFAs) play a pivotal role against central nervous system injury, which is likely related to its anti-inflammatory effect. However, the mechanism regarding the remedial effects of -3 PUFA for LPS-induced neuro-injury has remained unclear. ⋯ Interestingly, this phenomenon became more noticeable with the combined application of -3 PUFA and a PI3K/AKT agonist. In conclusion, we confirm that -3 PUFA plays an important role in neuroprotection by activating the PI3K/AKT/β-catenin pathway. It may be a promising strategy against brain injury. -
The aim of this study was to investigate the effect of paradoxical sleep deprivation (PSD) on the BDNF-related miRNA expression in ovariectomized (OVX) rats. The animals were randomly divided into eight groups (control, PSD, wide platform, sham surgery, anti-miR-191, anti-miR-191/PSD, scrambled and PSD in intact). Bilateral-ovariectomy was performed one month before the experiment in the OVX rats. ⋯ Intracerebroventricular (ICV) injection of anti-miR-191a improved the down-regulation of BDNF and attenuated PSD-induced cognitive impairment. Hippocampal BDNF is probably one of the targets of miR-191a in sleep-deprived OVX rats. Our results suggest that miR-191a may be increased in the sleep-deprived OVX rats to regulate BDNF levels.
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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene. Random X-inactivation produces a mosaic of mutant (MT) and wild-type (WT) neurons in female Mecp2+/- (het) mice. Many RTT symptoms are alleviated by increasing activity in medial prefrontal cortex (mPFC) in RTT model mice (Howell et al., 2017). ⋯ At 6-7 months inhibitory charge in WT in het slices was increased compared to both MT in het and WT in WTf; however, in hets the excitatory/inhibitory charge ratio was still greater in WT compared to MT. nAChR currents were reduced in L6 of nulls and MT L6 in het slices compared to WT neurons of het, WTm and WTf. At 2-4 months, ACh perfusion increased frequency of inhibitory currents to L6 neurons equally in all genotypes but increased excitatory inputs to MT and WT in hets less than WT in WTfs. Unexpectedly ACh perfusion evoked greater sustained IPSC and EPSC input to L5 neurons of nulls compared to WTm.