Neural Plasticity最新文献

Cardiac arrest (CA)-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine CA and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal-dependent behavior to assess hippocampal function. LTP and contextual fear were impaired 7 days after GCI and endogenously recovered by 30 days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. This was confirmed with staining that revealed increased Cd68 expression in microglia within the hippocampus. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice, which differs mechanistically from juvenile males and does not occur in adults of either sex.

Objective: There currently lacks the prognosis assessment of hypertensive intracerebral hemorrhage (HICH) with acute disorders of consciousness (DoC) after early rehabilitation (ER). The present study aims to investigate the outcomes of consciousness and neurological and cognitive functions in HICH patients with acute DoC intervened with ER via a retrospective cohort study with propensity score matching (PSM). Methods: A total of 265 eligible HICH patients with acute DoC admitted to the First Affiliated Hospital with Nanjing Medical University from January 2021 to December 2023 were retrospectively recruited. They were randomly divided into the ER group (n = 115) and the nonER group (n = 150) before PSM. After the PSM at a ratio of 1:1, 96 patients were allocated to each group. Baseline characteristics before and after PSM were compared between the ER group and the nonER group. Outcome measures included the duration of mechanical ventilation, and proportions of participants with an emergence to a conscious state (eMCS), 0-3 points of the modified Rankin Scale (mRS), and cognitive impairment. Results: Baseline characteristics were comparable between the ER group and the nonER group after PSM (p ≥ 0.05). An ER significantly shortened the duration of mechanical ventilation (9 days vs. 10 days, p=0.022). The neurological prognosis at 3 months of HICH combined with acute DoC was significantly improved by the ER, with a significantly higher proportion of participants grading 0-3 points of the mRS in the ER group than the nonER group (57.3% vs. 40.6%, p=0.021). Among 174 participants who restored consciousness at 3 months of onset, a significantly lower proportion of cognitive impairment was detected in the ER group than the nonER group (25.8% vs. 53.2%, p=0.002). Conclusion: An ER shortens the duration of mechanical ventilation and improves the neurological prognosis in HICH patients with acute DoC. Although the outcome of consciousness is unable to be improved, an ER does reduce the risk of residual cognitive dysfunction in HICH patients with acute DoC.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder. The pathology of this disease is based on two basic mechanisms: amyloid-beta (Aβ) and tau fibrillation. Many genes and mechanisms have been identified as the primary causes of AD in clinical settings, and there have been exciting developments in drug treatments. Several molecules and biological structures regulate the genome outside of the standard DNA function. As in many diseases, circular RNAs (circRNAs), microRNAs (miRNAs), and exosomes (EXOs), investigated from different aspects of AD, are useful for treatment and diagnosis. This review examines two biological elements regarding their roles in the Aβ-tau pathology of AD and their potential as treatment targets. Importantly, the activities of miRNAs that play a role in these processes were evaluated. Trial Registration: ClinicalTrials.gov identifiers: NCT04120493, NCT04969172, NCT04388982.

Glutamate excitotoxicity is considered as the etiology of stroke and neurodegenerative diseases, namely, Parkinson's disease (PD), Alzheimer's disease (AD), and others. Meanwhile, substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc), a pivotal site in regulating orofacial nociceptive transmission via Aδ and C primary afferent fibers, majorly utilize glutamate as the principal excitatory neurotransmitter. Fucoxanthin (FCX), a carotenoid pigment extracted from brown seaweed, possesses various pharmaceutical properties including neuroprotective effect in multiple neuronal populations. To date, the direct activity of FCX on the SG of the Vc has not been extensively clarified. Consequently, we investigated the effect of FCX on excitatory signaling mediated by ionotropic glutamate receptors (iGluRs), using the patch-clamp technique recorded from SG neurons of the Vc. Here, FCX directly acted on glutamate receptors independent of voltage-gated sodium channel and γ-aminobutyric acid (GABA)_A/glycine receptors in the voltage-clamp mode. Specifically, the N-methyl-D-aspartic acid (NMDA)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced responses but not the kainic acid receptor (KAR)-mediated response were suppressed by FCX in standard extracellular solution. Additionally, the inhibitory effect of FCX on NMDA currents was repeatable and concentration-dependent. The FCX blockade of NMDA-mediated excitotoxicity was associated with the modulation of Ca²⁺ response without affecting Na⁺ ions. The Ca²⁺-dependent fluorescence intensity of brain slice was reduced in the presence of FCX. Notably, FCX significantly attenuated the spontaneous firing activity of SG neurons. Altogether, these results reveal that FCX may protect SG neurons against glutamate excitotoxicity via primarily regulating Ca²⁺ response, thereby inhibiting the excitatory signaling induced by NMDA and AMPA receptors (AMPARs).

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis, which has been extensively investigated, yet effective treatments remain lacking. Splicing factor proline and glutamine rich (SFPQ) is known to play a crucial role in neurodegenerative diseases, including antioxidant-related functions and regulating gene expression within brain neurons. However, the specific role of SFPQ in AD pathology is not well understood. In this study, an AD mouse model was established through lateral ventricular injection of amyloid-beta_1-42 (Aβ _1-42). Subsequently, adeno-associated virus was administered to overexpress SFPQ in the hippocampus of AD mice. The results demonstrate that SFPQ overexpression improves recognition and memory in AD mice, while reducing AD-related marker proteins such as amyloid precursor protein (APP) and Tau. Additionally, synaptic and memory-associated proteins, as well as antioxidant proteins like glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), were upregulated. The ratio of antiapoptotic protein Bcl-2 to proapoptotic protein Bax also increased. Furthermore, phosphorylated phosphoinositide 3-kinase (p-PI3K)/PI3K and phosphorylated protein kinase B (p-AKT)/AKT ratios were elevated, indicating activation of the PI3K/AKT signaling pathway. These findings suggest that SFPQ may serve as a promising molecular target for the prevention and treatment of AD.

Noise exposure is one of the most common causes of hearing loss and hyperacusis. Studies have shown that noise exposure can induce a cortical gain to compensate for reduced input of the cochlea, which may contribute to the increased sound sensitivity. However, many people with hyperacusis have no measurable cochlear lesion after being exposed to loud sound. In this experiment, we studied the neurological alterations in the cortical and subcortical areas following a prolonged moderate level of noise exposure (84 dB SPL, 8 h/day for 4 weeks) in the laboratory mice. The cochlear function was monitored by auditory brainstem responses (ABRs). The behavioral auditory sensitivity and temporal processing were evaluated using the acoustic startle response (ASR) and gap-induced prepulse inhibition (gap-PPI). The central auditory functions were determined by electrophysiological recordings of the inferior colliculus (IC) and the auditory cortex (AC). Our results showed that although there was no significant difference in the ABR thresholds, the noise group showed enhanced ASR and gap-PPI compared to the control group. Increased neural activity in both the IC and the AC was recorded in the noise-exposed mice compared to the control group, suggesting a central gain in both the subcortical and cortical regions. The current source density (CSD) analysis of the AC response revealed an increased columnar excitation and reduced corticocortical projection in the noise group, different from the central gain model of noise-induced hearing loss. Our results suggest that chronic "nondestructive" noise can increase the gain of the central auditory system by altering the balance of auditory thalamocortical and intracortical inputs, which may contribute to the increased sound sensitivity in people with normal hearing.

Objective: The investigation of brain functional network dynamics offers a promising approach to understanding network reorganization poststroke. This study aims to explore the dynamic network configurations associated with motor recovery in stroke patients and assess their predictive potential using multilayer network analysis. Methods: Resting-state functional magnetic resonance imaging data were collected from patients with subacute stroke within 2 weeks of onset and from matched healthy controls (HCs). Group-independent component analysis and a sliding window approach were utilized to construct dynamic functional networks. A multilayer network model was applied to quantify the switching rates of individual nodes, subnetworks, and the global network across the dynamic network. Correlation analyses assessed the relationship between switching rates and motor function recovery, while linear regression models evaluated the predictive potential of global network switching rate on motor recovery outcomes. Results: Stroke patients exhibited a significant increase in the switching rates of specific brain regions, including the medial frontal gyrus, precentral gyrus, inferior parietal lobule, anterior cingulate, superior frontal gyrus, and postcentral gyrus, compared to HCs. Additionally, elevated switching rates were observed in the frontoparietal network, default mode network, cerebellar network, and in the global network. These increased switching rates were positively correlated with baseline Fugl-Meyer assessment (FMA) scores and changes in FMA scores at 90 days poststroke. Importantly, the global network's switching rate emerged as a significant predictor of motor recovery in stroke patients. Conclusions: The reorganization of dynamic network configurations in stroke patients reveals crucial insights into the mechanisms of motor recovery. These findings suggest that metrics of dynamic network reorganization, particularly global network switching rate, may offer a robust predictor of motor recovery.

Although several adult rat models of medial temporal lobe epilepsy (mTLE) have been described in detail, our knowledge of mTLE epileptogenesis in infant rats is limited. Here, we present a novel infant rat model of mTLE (InfRPil-mTLE) based on a repetitive, triphasic injection regimen consisting of low-dose pilocarpine administrations (180 mg/kg. i.p.) on days 9, 11, and 15 post partum (pp). The model had a survival rate of >80% and exhibited characteristic spontaneous recurrent electrographic seizures (SRES) in both the hippocampus and cortex that persisted into adulthood. Using implantable video-EEG radiotelemetry, we quantified a complex set of seizure parameters that demonstrated the induction of chronic electroencephalographic seizure activity in our InfRPil-mTLE model, which predominated during the dark cycle. We further analyzed selected candidate genes potentially relevant to epileptogenesis using a RT-qPCR approach. Several candidates, such as the low-voltage-activated Ca²⁺ channel Ca_v3.2 and the auxiliary subunits β ₁ and β ₂, which were previously reported to be upregulated in the hippocampus of the adult pilocarpine mTLE model, were found to be downregulated (together with Ca_v2.1, Ca_v2.3, M₁, and M₃) in the hippocampus and cortex of our InfRPil-mTLE model. From a translational point of view, our model could serve as a blueprint for childhood epileptic disorders and further contribute to antiepileptic drug research and development in the future.

Hyperoside (Hyp), a kind of Chinese herbal medicine, exerts multiple therapeutic effects on many diseases. However, the role and mechanisms of Hyp in vascular pathophysiology in ischemic stroke need to be further established. The study aimed to investigate the role of (large-conductance Ca²⁺-activated K⁺) BK channels on the vasoprotection of Hyp against cerebral ischemia and reperfusion (I/R) injury in rats. The concentration gradient of Hyp was pretreated in both the middle cerebral artery occlusion and reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) model of primary vascular smooth muscle cells (VSMCs) in rats. A series of indicators were detected, including neurological deficit score, infarct volume, malondialdehyde (MDA), superoxide dismutase (SOD), cerebral blood flow (CBF), cell viability, membrane potential, and BK channels α- and β1-subunits expression. The results showed that Hyp significantly reduced infarct volume and ameliorated neurological dysfunction in I/R-injured rats. Besides, the effects of I/R-induced reduction of BK channels α- and β1-subunits expression were significantly reversed by Hyp in endothelial-denudated cerebral basilar arteries. Furthermore, the protective effect against I/R-induced increases of MDA and reduction of SOD as well as CBF induced by Hyp was significantly reversed by iberiotoxin (IbTX). In OGD/R-injured VSMCs, downregulated cellular viability and BK channels β1-subunits expression were remarkably reversed by Hyp. However, neither OGD/R nor Hyp affected BK channels α-subunits expression, and Hyp failed to induced hyperpolarization of VSMCs. Moreover, the protective effect against OGD/R-induced reduction of cell viability and SOD level and increases of MDA production induced by Hyp was significantly reversed by IbTX in VSMCs. The study indicates that Hyp has the therapeutic potential to improve vascular outcomes, and the mechanism is associated with suppressing oxidative stress and improving CBF through upregulating BK channels.