Neuroscience
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The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though, that studies reporting no effect of propranolol on memory reconsolidation could be due to a failure to engage the memory destabilisation process, which is necessary for the memory to become susceptible to disruption with amnestic agents. ⋯ Following a failure to replicate, we manipulated the parameters of the memory reactivation session to enhance prediction error in an attempt to overcome the boundary conditions of reconsolidation. On finding no disruption of memory despite these manipulations, we examined the expression of the post-synaptic density protein Shank in the basolateral amygdala. Degradation of Shank has been shown to correlate with the induction of memory lability, but we found no effect on Shank expression, consistent with the lack of observed behavioural effects.
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Microglia cells are activated after cerebral ischemia-reperfusion injury (CIRI), playing a dual role in aggravating the injury or promoting tissue repair by polarization. Translocator protein (TSPO) is a biomarker of neuroinflammation or microglia activation. Its expression is significantly increased while brain injury and neuroinflammation occur. ⋯ In vitro studies showed that shRNA-mediated TSPO knock-down promoted M1 polarization but inhibited M2 polarization, accompanied by a significant decrease in cell viability. On the contrary, overexpression of TSPO inhibited M1 polarization, promoted M2 polarization, and significantly improved cell viability. In summary, TSPO plays a neuroprotective role in CIRI by inhibiting M1 polarization and promoting M2 polarization, which suggests that TSPO may have the potential to serve as a therapeutic target for stroke.
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Decreased levels of Brain-Derived Neurotrophic Factor (BDNF) are a common finding in schizophrenia. Another well-documented protein linked to schizophrenia is intracellular Ca2+-independent Phospholipase (PLA2). However, the potential association between PLA2 and BDNF with regard to schizophrenia has yet to be examined. ⋯ The cognitive impairment of BDNF heterozygous mice as well as their increased PLA2 activity in plasma is consistent with findings in schizophrenia patients. The particular elevation of PLA2 activity in females may partly explain sex differences of clinical symptoms in schizophrenia (e.g. age of onset, severity of symptoms). Additionally, PLA2 was significantly correlated with body and adrenal weight after weaning, whereby the latter emphasizes the possible connection of PLA2 with steroidogenesis.
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P2Y purinoceptor 2 (P2RY2) is involved in the regulation of cell proliferation and apoptosis. The aim of this study was to explore the effects of P2RY2 on cerebral ischemia/reperfusion (I/R) injury and its molecular mechanism. Middle cerebral artery occlusion (MCAO) model in rats and OXYGEN and oxygen-glucose deprivation/reoxygenation (OGD/R) model in PC12 cells were established. ⋯ The addition of PI3K/AKT inhibitor LY294002 could reverse the decrease of YAP phosphorylation level and cell apoptosis, and the increase of nuclear translocation caused by P2RY2 overexpression. Further in vivo studies validated that interference with P2RY2 increased the cerebral infarction area, decreased AKT expression, enhanced YAP phosphorylation, and inhibited the nuclear translocation of YAP. In conclusion, P2RY2 can alleviate cerebral I/R injury by inhibiting YAP phosphorylation and reducing mitochondrial fission.
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Therapeutic hypothermia with modest results is the only treatment currently available for neonatal hypoxic ischemic encephalopathy (HIE). Endothelin B (ETB) receptors in the brain are shown to have neural restorative capacity. ETB receptors agonist sovateltide alone or as an adjuvant therapy may enhance neurovascular remodeling in HIE. ⋯ Animals receiving sovateltide demonstrated a significant (p < 0.0001) upregulation of ETB receptor, VEGF, and NGF expression in the brain compared to vehicle-treated animals. Additionally, sovateltide alone or in combination with therapeutic hypothermia significantly (p < 0.001) reduced cell death when compared to vehicle or therapeutic hypothermia alone, demonstrating that sovateltide is neuroprotective and attenuates neural damage following HIE. These findings are important and merit additional studies for development of new interventions for improving neurodevelopmental outcomes after HIE.