Neuroscience
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Addiction to prescribed opioids including oxycodone has reached tragic levels. Herein, we investigated the relevance of fibroblast growth factors (FGFs) and immediate early genes (IEGs) to withdrawal-induced incubation of drug craving following escalated oxycodone self-administration (SA). Rats were trained to self-administer oxycodone for 4 weeks. ⋯ Similarly, striatal c-fos and junB mRNA levels showed greater increases in LgA rats. The observations that fgf mRNA levels were more altered in the dorsal striatum than in the NAc of LgA rats suggest that changes in striatal FGF expression may be more salient to incubation of oxycodone craving than alterations in the NAc. Targeting FGF signaling pathways might offer novel strategies against opioid addiction.
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Disruption of the blood-brain barrier (BBB) and subsequent neurological deficits are the most severe consequence of intracerebral hemorrhage (ICH). Minocycline has been wildly used clinically as a neurological protective agent in clinical practice. However, the underlying mechanisms by which minocycline functions remain unclear. ⋯ Moreover, minocycline decreased the production of inflammatory mediators including TNF, IL-6, and MMP-9, by microglia. Minocycline treatment decreased DKK1 expression but increased Wnt1, β-catenin and Occludin, a phenomenon mimicked by DKK1 silencing. These data suggest that minocycline improves the consequences of ICH by preserving BBB integrity and attenuating neurologic deficits in a DKK1-related manner that involves enhancement of the Wnt1-β-catenin activity.
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After myocardial infarction (MI), ovariectomized (OVX) female rats develop depression-like behaviors and an increase of pro-inflammatory cytokine (PIC) levels in the prefrontal cortex (PFC). We hypothesized that inhibition of neuroinflammation by the PIC synthesis inhibitor, pentoxifylline (PTX) would prevent depression-like behaviors induced by heart failure (HF) post-MI in OVX female rats. PTX treatment was initiated in female Wistar rats, 1 week after ovariectomy, and 1 week before MI by occlusion of the left anterior descending artery. ⋯ These findings show that OVX female rats post-MI exhibit an increase in both peripheral and central inflammation. PTX treatment prevents increases in PIC levels in plasma and PVN but does not attenuate the progression of cardiac dysfunction. In contrast, PTX prevents enhanced PIC production in the PFC, as well as limits depression-like behaviors induced by MI in OVX female rats.
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Stroke is a major life-threatening and disabling disease with a restricted therapeutic approach. Bone marrow stromal cells (BMSCs) possess proliferative ability and a multi-directional differentiation potential, and secrete a range of trophic/growth factors that can protect neurons after cerebral ischemia/reperfusion. Transient receptor potential canonical (TRPC) is a family of non-selective channels permeable to Ca2+, with several functions including neuronal survival. ⋯ In the present study, we report that over-expression of TRPC6 via a CRISPR-based synergistic activation mediator in BMSCs provided a greater reduction of brain injury in a rat model of ischemia/reperfusion. Further, the improved neurofunctional outcomes were associated with increased TRPC6 and brain derived neurotrophic factor expression levels. Overall, these data suggest that TRPC6 over-expressing BMSCs may be a promising therapeutic agent for ischemic stroke.
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Signal processing in the principal neurons of the anteroventral cochlear nucleus (AVCN) is modulated by glycinergic inhibition. The kinetics of IPSCs are specific to the target neurons. It remains unclear what glycine receptor subunits are involved in generating such target-specific IPSC kinetics in AVCN principal neurons. ⋯ To further identify the cell type-specific expression patterns of GlyRα subunits, we combined whole-cell patch clamp recording with immunohistochemistry by recording from all three types of AVCN principal neurons, characterizing the synaptic properties of their glycinergic inhibition, dye-filling the neurons, and processing the slice for immunostaining of different GlyRα subunits. We found that AVCN bushy neurons express both GlyRα1 and GlyRα4 subunits that underlie their slow IPSC kinetics, whereas both T-stellate and D-stellate neurons express only GlyRα1 subunit that underlies their fast IPSC kinetics. In conclusion, AVCN principal neurons express cell-type specific GlyRα subunits that underlie their distinct IPSC kinetics, which enables glycinergic inhibition from the same source to exert target cell-specific modulation of activity to support the unique physiological function of these neurons.