Journal of Neuroscience Research最新文献

It has been hypothesized that the rapid/long-lasting antidepressant action observed following medial forebrain bundle DBS in clinical trials of Treatment-Resistant Depression patients could partially be driven by modulation of the midbrain-to-forebrain dopaminergic fibers. The study investigated the spatial distribution and myelination status of dopaminergic fibers within the rodent equivalent structure in a preclinical depression model, the Flinders Sensitive Line (FSL). Fixed, sliced brain sections were double stained with anti-tyrosine hydroxylase/anti-dopamine-β-hydroxylase antibodies to distinguish dopaminergic from noradrenergic fibers, and with anti-tyrosine hydroxylase/anti-myelin antibodies to specifically investigate myelination. Quantification was done at six predefined segments. The dopaminergic fibers coursing through the medial forebrain bundle were small diameter, unmyelinated and mainly restricted to the dorsolateral quadrant on the AP axis. Analyses across six predefined planes revealed significantly fewer dopaminergic fibers in FSL males (vs control males, and vs. FSL females) at AP −2.8 mm, the segment corresponding to the medial forebrain bundle DBS target in the rat. No differences were observed elsewhere along the medial forebrain bundle. Previously reported differences in stimulation-evoked dopamine release in the FSLs could be due to differences in the numbers of recruited dopaminergic fibers.

North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disease that presents at an early age with progressive ataxia, myoclonus, and epilepsy. The disease is caused by a mutation in the Golgi SNAP receptor 2 gene (GOSR2). However, the consequences of this genetic defect at the cellular level are still unknown. Using a NS-PME Drosophila melanogaster model, it was previously found that knockdown of membrin, the fruit fly GOSR2 ortholog, in glial cells leads to progressive heat-induced seizure-like behavior in adult flies. Upon close inspection, we found NS-PME flies not only show progressive heat-induced seizures but also disrupted sleep architecture (higher number of shorter sleep bouts). Here we asked what glial cellular consequences could be underlying these phenotypes of membrin knockdown. First, we investigate whether these phenotypes are attributed to specific glial types; we found that these phenotypes were partly reproduced with specific knockdown of membrin in perineurial glia only. Next, we show that Innexin2, a gap junction protein specifically expressed in glia, is affected upon membrin knockdown, with an altered expression pattern and reduced protein levels. Finally, glial overexpression of Innexin2 in the background of glial membrin knockdown strongly ameliorates the heat-induced seizure phenotype, disrupted sleep architecture, as well as Innexin2 expression pattern, corroborating the importance of Innexin2 in maintaining neuronal homeostasis in NS-PME. These findings show that dysregulation of Innexin2 at least partially underlies the phenotypes of membrin knockdown in Drosophila melanogaster and could suggest a similar role of Innexin2-like proteins in the human disease NS-PME.

Epoxyeicosatrienoic acids (EETs), are known to possess potent anti-inflammatory and antioxidant neuroprotective properties. However, the molecular mechanisms responsible for these effects are not well understood. In this work, we aimed to evaluate the neuroprotective role of EETs in a hemorrhagic stroke model and the possible involvement of PPAR-α activation in this neuroprotection. Hemorrhagic damage was induced in mice through the intracerebral administration of collagenase VII in the striatum. The neuroprotective effect of EETs was tested in mice by pre-treatments of 2 h with TPPU, an inhibitor of the EETs metabolism. TPPU was administered intraperitoneally at a dose of 0.5, 1.0, or 2 mg/kg. Brain damage was evaluated based on measurements of motor activity, hematoma volume, brain water content, and blood–brain barrier (BBB) permeability. Additionally, the levels of enzymes involved in the oxidative stress balance, such as NADPH oxidase 2 (NOX-2) and superoxide dismutase (SOD), were determined by Western blot analysis. Our results showed that EETs exert neuroprotective effects by significantly decreasing all parameters related to brain damage, improving motor function and promoting an antioxidant state, as evidenced by increased levels of SOD and reduced levels of NOX enzymes. Subsequently, PPAR-α involvement was evaluated through the administration of GW6471, a PPAR-α antagonist. Pre-treating mice with GW6471 for 30 min, reverted all neuroprotective effects, including the observed changes in SOD and NOX levels. Our results demonstrate that EETs confer neuroprotection in hemorrhagic brain injury, and this effect is dependent on PPAR-α activation.

Spinal cord injury (SCI) triggers complex secondary injury mechanisms, resulting in long-term impacts on sensory and motor function. Rolipram, a phosphodiesterase-4 inhibitor, has shown promise in preserving/restoring cyclic adenosine monophosphate (cAMP) to reduce secondary injury responses, but its clinical application is hindered by poor solubility and systemic side effects. To overcome these challenges, we developed rolipram-loaded poly(lactide-co-glycolide)-graft-polyethylenimine (PgP) nanoparticles (Rm-PgP) to enable localized and sustained drug delivery. In our previous findings, Rm-PgP administered via intraspinal injection restored cAMP levels at the lesion site, and reduced secondary injury after moderate, contusive SCI. In this study, we investigated the effect of single and repeat administration of Rm-PgP by the clinically relevant intrathecal route immediately after injury. We observed that the hydrophobic dye, DiR-loaded PgP (DiR-PgP) was retained in the CNS over 7 days post-injury (DPI). In addition, we observed that both single and repeat Rm-PgP treatment groups showed higher cAMP levels compared to those in the untreated SCI group and only the single treatment group showed a significant difference compared to the untreated SCI group. Lastly, we observed that cAMP restoration in both single and repeat Rm-PgP treatment groups showed higher levels of activated cAMP-response element-binding protein (pCREB) relative to the untreated control. We also observed that both Rm-PgP treatment groups showed reduced inflammatory response, reduced astrogliosis and apoptosis, and increased neuronal survival and spared tissue volume. These findings highlight the neuroprotective efficacy of Rm-PgP by intrathecal administration in mitigating secondary injury during the critical early phase of recovery after SCI.

Exercise has been reported to improve outcomes in patients with Parkinson's disease, but the exact biological mechanisms remain incompletely understood. This study was conducted to determine whether chronic moderate treadmill exercise prevents dopaminergic neuron loss and Lewy body-like inclusion burden in a preclinical model of PD. This study also sought to identify plasma exosome bound “exerkines” with potential to induce neuroprotective brain adaptations. Benefits of exercise are thought to be achieved in part through nucleic acids, lipids, and peptides termed exerkines abundant during exercise. These exerkines can induce cell-specific exercise adaptations culminating in neuroprotection. Membrane-free exerkines are subject to degradation in blood and may not effectively cross the blood-brain barrier to induce brain adaptations to exercise, limiting their inter-organ signaling potential. This led us to hypothesize that exerkines, bioactive RNAs in particular, may be selectively packaged into exosomes and released into plasma during exercise. Exosomes are small extracellular vesicles, selectively packaged and released by cells, with likely important differences in composition at rest, during injury and disease, and in response to exercise. Exosomes have been demonstrated to play a major role in inter-organ communication. Chronic exercise was found to provide neuroprotection to dopaminergic neurons in the substantia nigra pars compacta, without affecting Lewy body-like inclusion burden in the nigra or the striatum. Plasma exosomal RNA was isolated from age-matched exercising and sedentary non-PD rats and sequenced. We report 27 unique RNAs upregulated in the exosomes of exercisers, 3 mRNAs with clear neuroprotective potential.