Developmental Neurobiology最新文献

This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.

Ischemic stroke is a prominent cause of morbidity and mortality, affecting numerous people worldwide. The exact role of Maixuekang capsule in cerebral ischemia/reperfusion injury (CI/RI) remains elusive. The present study aimed to delve into the neuroprotective potential of Maixuekang in CI/RI rats. Utilizing the HREB database, leech ingredients were retrieved, while GeneCards, therapeutic target database (TTD), and DisGeNET databases were used to predict cerebral infarction targets. Search tool for the retrieval of interacting genes/proteins (STRING) database was adopted to identify overlapping genes, and Cytoscape 3.9.1 to analyze core targets. The gene ontology (GO)/ Kyoto encyclopedia of genes and genomes (KEGG) pathway were analyzed and neurological function was assessed via Longa scoring. The 2,3,5-triphenyltetrazolium chloride (TTC), Golgi, hematoxylin and eosin (H&E), and Nissl stains were adopted to observe cerebral infarction and pathological changes. The neuronal apoptosis, hypoxia inducible factor 1 alpha (HIF1A), myeloperoxidase (MPO) and inflammatory factors in rat were measured. Results suggested Maixuekang reduced the neurological function score and the cerebral infarction incidence in CI/RI rats. After taking Maixuekang, the number of dendritic spines of CI/RI rats increased, the neuronal damage degree in the ischemic cortical area reduced, and the neurons morphology improved. In addition, Maixuekang reduced the blood–brain barrier (BBB) damage and brain tissue water content by decreasing neuronal apoptosis rate, Bax expression, neutrophil infiltration, inflammatory factor levels, and increasing Bcl2 by decreasing HIF1A in CI/RI rat tissues. Collectively, Maixuekang could reduce neurological function, cerebral infarction rate, blood–brain barrier damage, neuroinflammation and downregulates HIF1A in tissues of CI/RI rats.

The capacity for enhanced experience, modeled as environmental enrichment (EE) in laboratory animals, to drive positive changes in brain circuitry presents a promising avenue in the development of therapies for neurodevelopmental conditions. Less understood are the underlying mechanisms, or potential interactions of EE with other therapeutic approaches. We have previously shown that early exposure to EE can drive the partial repair of miswired uncrossed retinal projections, and the concomitant rescue of a visual behavior, in the Ten-m3 knockout (KO) mouse. This was associated with a highly spatiotemporally localized upregulation of microglial reactivity in the region where the correction was occurring which peaked around postnatal day (P)25. Aiming to confirm a causal role for microglial-mediated engulfment in this process, we assessed the effect of daily injections of minocycline or vehicle saline from P18 to P24 (inclusive) on measures of microglial reactivity and anatomical corrective pruning in P25 Ten-m3 KO mice. While an effect of EE was confirmed at this timepoint, intriguingly, we found that both the vehicle- and minocycline-treated mice had a similar lack of microglial reactivity and showed a marked absence of corrective pruning of their miswired retinal projections. This suggests that the injection procedure itself disrupted the experience-induced microglial-mediated circuit repair. These results underscore the highly sensitive nature of EE-driven corrective pruning actions of microglia and the critical importance of considering and controlling for all aspects of experience.

The retinotectal projection in Xenopus laevis is topographically organized. During the early development of the Xenopus visual system, the optic tectum increases considerably in volume, and retinotectal axons and dendrites undergo extensive activity-dependent remodeling. We have previously observed marked changes in the three-dimensional layout of the tectal retinotopic functional map over the course of a few days. This raised the question of whether such functional reorganization might be attributable to the migration and structural remodeling of tectal neurons as the brain grows. To examine changes in map topography in the context of individual tectal neuron morphology and location, we performed calcium imaging in the optic tecta of GCaMP6s-expressing tadpoles in parallel with structural imaging of tectal cells that were sparsely labeled with Alexa 594-dextran dye. We performed functional and structural imaging of the optic tectum at two developmental time points, recording the morphology of the dextran-labeled cells and quantifying the changes in their positions and the spanning volume of their dendritic fields. Comparing anatomical growth to changes in the functional retinotopic map at these early stages, we found that dendritic arbor growth kept pace with the overall growth of the optic tectum and that individual neurons continued to receive widespread visual field input, even as the tectal retinotopic map evolved markedly over time. This suggests a period of initial growth during which inputs to individual tectal neurons maintain diffuse connectivity and broad topographic integration.

The clustered protocadherins (cPcdhs) are a family of ∼60 homophilic cell adhesion molecules expressed across three gene clusters (Pcdha, Pcdhb, and Pcdhg) with a variety of essential roles in the developing nervous system. Some of these roles rely on specific isoforms, whereas others are more consistent with a model of isoform redundancy or a requirement for diversity. The γ-Pcdhs (expressed from the Pcdhg gene cluster) are particularly important for neuronal self-avoidance in starburst amacrine cells in the mouse retina. Here, we used mouse mutants to test two of the C-type isoforms—γC4 and γC5—and found that neither was required for normal self-avoidance. Conversely, when we analyzed a mutant with only γC4 intact, we found significant failures in self-avoidance that could not be completely rescued by overexpression of this isoform from a transgene. We have recently found that this isoform is essential for normal neuronal survival during development, and our new findings here support the hypothesis that γC4 is specialized for the survival function at the expense of a significant role in self-avoidance.

One hallmark of brain maturation in adolescence is increased myelination (fractional anisotropy [FA]) of the axons, although the epigenetic drivers of this stage of neurodevelopment are as yet poorly understood. Our previous study of a longitudinal cohort of normally developing adolescents, aged nine to fourteen, established the connections between changes in DNA methylation (DNAm) at seven cytosine–phosphate–guanine (CpG) sites in genes highly expressed in the brain to grey matter maturation as well as cognitive improvement. Continuing that work, we investigate the relationships between the changes in DNAm of these genes (GRIN2D, GABRB3, KCNC1, SLC12A9, CHD5, STXBP5, and NFASC), four networks of FA change, and scores from seven cognitive tests. The demethylation of the CpGs over time was significantly related to a brain network highlighting FA increases in regions associated with maturation of interhemispheric connectivity. Mediation analysis found that this same network mediated the relationship between decreases in DNAm of four of these genes and increases in overall cognitive performance. These relationships suggest that changes in DNAm of genes involved in myelination and the excitatory/inhibitory balance in the brain might be driving maturation of white matter, which in turn is implicated in the improved cognitive performance seen in adolescents.