Neuroscience
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Parkinson's disease (PD) is a motor disorder charactertised by altered neural activity throughout the basal ganglia-thalamocortical circuit. Electrical deep brain stimulation (DBS) is efficacious in alleviating motor symptoms, but has several notable side-effects, most likely reflecting the non-specific nature of electrical stimulation and/or the brain regions targeted. We determined whether specific optogenetic activation of glutamatergic motor thalamus (Mthal) neurons alleviated forelimb akinesia in a chronic rat model of PD. ⋯ Blue light (control) stimulation failed to alter behaviours. Activation of Chrimson using complex patterns in the Mthal may be an alternative treatment to recover movement in PD. These vector and opsin changes are important steps towards translating optogenetic stimulation to humans.
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Here, we studied the neuroinflammation- and ischemia-related glial markers chitotriosidase 1 (CHIT1) and chitinase-3-like protein 1 (CHI3L1, alias YKL-40) in the human striate cortex and cerebellum at different time points after global hypoxic-ischemic brain injury (HIBI). Both regions differ considerably in their glial cell population but are supplied by the posterior circulation. CHIT1 and CHI3L1 expression was compared to changes in microglial (IBA1, CD68), astrocytic (GFAP, S100β), and neuronal markers (H&E, neurofilament heavy chain, NfH; calretinin, CALR) using immunohistochemistry and multiple-label immunofluorescence. ⋯ Furthermore, enlarged GFAP- and S100β-positive astroglia emerged in both regions around 9-10 d post-HIBI, i.e., along with clearance of dead neurons from the neuropil, although GFAP-/S100β-positive gemistocytic astrocytes that co-expressed CHI3L1 were found only in the striate cortex. Thus, only GFAP-/S100β-positive astrocytes in the striate cortex, but not cerebellar Bergmann glia, differentiated into CHI3L1-positive gemistocytes. CHIT1 was co-expressed almost entirely in macrophages in the striate cortex and not cerebellum of long-term survivors, thereby indicating that CHIT1 and CHI3L1 could be valuable biomarkers for monitoring the outcome of global HIBI.
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Major depressive disorder is a burdensome condition with few treatment options, and traditional antidepressants are characterized by slow onset. Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD), the mechanisms of which remain elusive. In this study, we explored whether neuroplasticity, autophagy, and ferroptosis in the habenular nucleus are involved in the rapid antidepressant process of ketamine. ⋯ Electron microscopy observed that ketamine triggered autophagy, with increased levels of autophagy-related proteins. Ferroptosis was inhibited by ketamine by electron microscopy, with increased FTH1 and GPX4 levels and decreased Tfr1 levels. In conclusion, our findings demonstrate that ketamine may exert rapid antidepressant effects by improving neuroplasticity, activating autophagy, and inhibiting ferroptosis in the nuclear complex.
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Increased expression of alpha-synuclein (ASYN) and decreased expression of Nurr1 are associated with Parkinson's disease (PD) pathogenesis. These two proteins interact functionally and ASYN overexpression suppresses Nurr1 levels. ASYN pan-neuronal overexpression coupled with Nurr1 hemizygosity followed by Nurr1 repression in aging mice results in the manifestation of a typical PD-related phenotype and pathology. ⋯ However, they displayed increased energy expenditure, reduced striatal dopamine (DA) and prolonged hyperactivity to a novel environment indicating impaired habituation. This DA-ergic dysfunction was observed in young adult '2-hit-DA' mice, persisted throughout life and it was associated with ASYN and Nurr1 synergistic alterations of DAT levels and function. Our experiments indicate that the expression levels of ASYN and Nurr1 are critical in the dysregulation of the nigrostriatal DA system and may be involved in neuropsychiatric aspects of PD.
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Acetylcholine plays a pivotal role in the regulation of functions such as pain and the sleep and wake cycle by modulating neural activities of the ventrolateral periaqueductal gray (vlPAG). Electrophysiological studies have shown that cholinergic effects are inconsistent among recorded neurons, particularly in the depolarization and hyperpolarization of the resting membrane potential (RMP). This discrepancy may be due to the neural subtype-dependent cholinergic modulation of the RMP. ⋯ Intracellular application of GDP-β-S blocked the carbachol-induced hyperpolarization of the RMP. Neostigmine slowly hyperpolarized the RMP in cholinergic neurons. These results suggest that neural firing of vlPAG cholinergic neurons is suppressed by GIRK currents induced via M2 receptor activation, and this negative feedback regulation of cholinergic neuronal activities can be induced by acetylcholine, which is intrinsically released in the vlPAG.