Neuroscience
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Intranasal insulin reduces lesion size and enhances memory capacity in traumatic brain injury (TBI) models, but the molecular mechanisms behind this neuroprotective action not yet understood. Here we used Feeney's free-falling method to construct TBI mouse models and administrated intranasal insulin, rapamycin, insulin and rapamycin, or normal saline to assess their effects on neurological functions, cerebral edema, and the expression of Iba1 in microglia through immunofluorescence assay. We also measured concentrations of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the brain using enzyme immunosorbent assay, investigated apoptosis with TUNEL staining and Western blotting, and evaluated autophagy, endoplasmic reticulum (ER) stress, and PI3K/Akt/mTOR signaling pathway with Western blotting. ⋯ TUNEL assay and Western blotting also indicated that intranasal insulin inhibited ER stress-mediated apoptosis. Interestingly, the mTOR inhibitor rapamycin partially blocked the pro-autophagy and anti-apoptosis effects of intranasal insulin both on days 1 and 3 post TBI. Our results suggest that intranasal insulin can ameliorate TBI by regulating autophagy and ER stress-mediated apoptosis through the PI3K/AKT/mTOR signaling pathway, providing a promising therapeutic strategy for TBI.
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Oxidative stress is heavily involved in several pathological features of Multiple Sclerosis (MS), such as myelin destruction, axonal degeneration, and inflammation. Different therapies have been shown to reduce the oxidative stress that occurs in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Some of these therapies are transcranial magnetic stimulation (TMS), extra virgin olive oil (EVOO) and S-allyl cysteine (SAC). ⋯ All treatments were maintained for 51 days. TMS, EVOO and SAC, alone or in combination, reduce oxidative stress, increasing antioxidant defenses and also lowering the clinical score. Combination therapies do not appear to be more potent than individual therapies against the oxidative stress of EAE or its clinical symptoms.
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Mir125b-1 is not imprinted in human brain and shows developmental expression changes in mouse brain.
Genomic imprinting is a predominantly brain and placenta-specific epigenetic process that contributes to parent-of-origin-specific gene expression. While microRNAs are highly expressed in the brain, their imprinting status in this tissue remains poorly studied. Previous research demonstrated that Mir125b-2 is imprinted in the human brain and regulates hippocampal circuits and functions in mice. ⋯ Specifically, miR-125b-1 displayed preferential expression in the olfactory bulb, thalamus, and hypothalamus of the mouse brain. Notably, miR-125b-1 was enriched in GABAergic neurons, particularly somatostatin-expressing GABAergic neurons, compared with glutamatergic neurons. Taken together, our findings provide the imprinting status and comprehensive spatiotemporal expression profiling of Mir125b-1 in the brain.
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Ischemic stroke (IS) is one of the leading causes of disability and death worldwide. Long-chain fatty-acid-coenzyme A ligase 4 (ACSL4) is a critical isozyme for ferroptosis that participates in the progression of IS. RING finger protein 146 (RNF146) is an E3 ligase predicted to interact with ACSL4 and regulated by activating transcription factor 3 (ATF3). ⋯ RNF146 overexpression could prevent the stimulation of OGD/R-induced LDH, MDA, and Fe2+ levels and ferroptosis-related gene expression. ATF3 could activate the transcription and expression of RNF146, leading to the inhibition of OGD/R-induced neuron ferroptosis. The ATF3-mediated RNF146 could alleviate neuronal damage in IS by regulating ACSL4 ubiquitination and ferroptosis, providing a novel theoretical basis for exploring therapeutic targets and strategies.
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While the functional and behavioral role of the medial habenula (MHb) is still emerging, recent data indicate an involvement of this nuclei in regulating mood, aversion, and addiction. Unique to the MHb is a large cluster of cholinergic neurons that project to the interpeduncular nucleus and densely express acetylcholine receptors (AChRs) suggesting that the activity of these cholinergic neurons may be regulated by ACh itself. Whether endogenous ACh from within the habenula regulates cholinergic neuron activity has not been demonstrated. ⋯ To test this hypothesis, we expressed channelrhodopsin in a portion of MHb cholinergic neurons while recording from non-opsin-expressing neurons. Light pulses progressively increased activity of MHb cholinergic neurons indicating feed-forward activation driven by MHb ACh release. These data indicate MHb cholinergic neurons may utilize a unique feed-forward mechanism to synchronize and increase activity by releasing local ACh.