Developmental Neurobiology最新文献

Owing to the high prevalence of gastrointestinal dysfunction in patients, the gut-brain axis is considered to play a vital role in neurodevelopment diseases. Recent pieces of evidence have pointed to the usage of antibiotics at an early developmental stage to be a causative factor in autism due to its ability to induce critical changes in the gut microbiota. The purpose of the study is to determine the neuroprotective effect of capric acid (CA) on autism in antibiotic-induced gut dysbiosis in rodents. In this study, the effect of CA was observed in penicillin V (31 mg/kg, p.o.) exposed animals by evaluating their autism-like behavioral and biochemical parameters. The establishment of gut dysbiosis was confirmed by 16 RNA sequencing, and behavioral tests were performed. Subsequently, oxidative stress, cytokine levels, and mitochondrial complex activities in the hippocampus and prefrontal cortex were analyzed. It was observed that the administration of penicillin V during the perinatal period produced gut dysbiosis and long-lasting changes in social behavior with symptoms of anxiety and depression and impaired learning and memory. Treatment with penicillin V also produced oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus and prefrontal cortex. Treatment with CA produced a positive effect on the alterations with maximum effects evident at 400 mg/kg, p.o. through amelioration of behavioral as well as biochemical changes. The current study concluded that CA could act as a likely candidate for the treatment and management of autism via modulation of gut dysbiosis-induced neurobehavioral parameters, oxidative stress, mitochondrial dysfunction, and inflammatory markers.

Observational studies have found that elevated serum homocysteine (Hcy) levels during pregnancy may be associated with the occurrence of neural tube defects (NTDs). However, the effect of Hcy on fetal neural development and its underlying molecular mechanisms remains unclear. To uncover the molecular mechanism, we analyzed the serum Hcy concentration in pregnant women with normal and abnormal pregnancy outcomes and treated zebrafish model embryos with high Hcy. Our findings indicate that elevated serum Hcy levels during pregnancy are associated with adverse pregnancy outcomes. Using the zebrafish model and transcriptome analysis, we found that high Hcy levels led to developmental neural malformations in embryos and affected the expression of key genes at various stages of neural development. Interestingly, deep transcriptome analysis showed that dysregulated heat shock proteins (HSP) might play a key role in high Hcy-mediated alterations in neural development. Importantly, the inhibition of HSP significantly restored the embryonic neuroteratogenic effects induced by high Hcy levels in the zebrafish model. In summary, our findings provide a novel molecular pathogenic mechanism in which ectopic HSP is associated with neural development defects caused by high Hcy levels, suggesting potential prevention and targeted therapies for high Hcy level-related NTDs during pregnancy.

Acetylcholine (ACh), a vital neurotransmitter for both the peripheral (PNS) and central nervous systems (CNS), signals through nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChR). Here, we explore the expression patterns of three nAChR subunits, chrna3, chrnb4, and chrna5, which are located in an evolutionary conserved cluster. This close genomic positioning, in a range of vertebrates, may indicate co-functionality and/or co-expression. Through novel transgenic zebrafish lines, we observe widespread expression within both the PNS and CNS. In the PNS, we observed expression of chrna3^tdTomato, chrnb4^eGFP, and chrna5^tdTomato in the intestinal enteric nervous system; chrna5^tdTomato and chrnb4^eGFP in sensory ganglia of the lateral line; and chrnb4^eGFP in the ear. In the CNS, the expression of chrnb4^eGFP and chrna5^tdTomato was found in the retina, all three expressed in diverse regions of the brain, where a portion of chrna3^tdTomato and chrnb4^eGFP cells were found to be inhibitory efferent neurons projecting to the lateral line. Within the spinal cord, we identify distinct populations of chrna3^tdTomato-, chrnb4^eGFP-, and chrna5^tdTomato-expressing neurons within the locomotor network, including dmrt3a-expressing interneurons and mnx1-expressing motor neurons. Notably, three to four primary motor neurons per hemisegment were labeled by both chrna3^tdTomato and chrnb4^eGFP. Interestingly, we identified an sl-type secondary motor neuron per hemisegement that strongly expressed chrna5^tdTomato and co-expressed chrnb4^eGFP. These transgenic lines provide insights into the potential roles of nAChRs within the locomotor network and open avenues for exploring their role in nicotine exposure and addiction in a range of tissues throughout the nervous system.

Individuals diagnosed with autism spectrum disorder (ASD) frequently exhibit abnormalities in auditory perception, a phenomenon potentially attributed to alterations in the excitatory and inhibitory cells constituting cortical circuits. However, the exact genetic factors and cell types affected by ASD remain unclear. The present study investigated the balance of excitatory and inhibitory activity in the auditory cortex using BTBR T⁺ Itpr3^tf/J (BTBR) mice, a well-established model for autism research. Our investigation unveiled a reduction in parvalbumin-positive (PV⁺) neurons within the AC of BTBR mice. Remarkably, in vivo magnetic resonance spectroscopy studies disclosed an elevation in glutamate (Glu) levels alongside a decrement in γ-aminobutyric acid (GABA) levels in this cortical region. Additionally, transcriptomic analysis of the mouse model facilitated the classification of several ASD-associated genes based on their cellular function and pathways. By comparing autism risk genes with RNA transcriptome sequencing data from the ASD mouse model, we identified the recurrent target gene Scn1a and performed validation. Intriguingly, we uncovered the specific expression of Scn1a in cortical inhibitory neurons. These findings hold significant value for understanding the underlying neural mechanisms of abnormal sensory perception in animal models of ASD.

In vivo astrocyte-to-neuron (AtN) conversion induced by overexpression of neural transcriptional factors has great potential for neural regeneration and repair. Here, we demonstrate that a single neural transcriptional factor, Dlx2, converts mouse striatal astrocytes into neurons in a dose-dependent manner. Lineage-tracing studies in Aldh1l1-CreERT2 mice confirm that Dlx2 can convert striatal astrocytes into DARPP32⁺ and Ctip2⁺ medium spiny neurons (MSNs). Time-course studies reveal a gradual conversion from astrocytes to neurons in 1 month, with a distinct intermediate state in between astrocytes and neurons. Interestingly, when Dlx2-infected astrocytes start to lose astrocytic markers, the other local astrocytes proliferate to maintain astrocytic levels in the converted areas. Unexpectedly, although Dlx2 efficiently reprograms astrocytes into neurons in the gray matter striatum, it also induces partial reprogramming of astrocytes in the white matter corpus callosum. Such partial reprogramming of white matter astrocytes is associated with neuroinflammation, which can be suppressed by the addition of NeuroD1. Our results highlight the importance of investigating AtN conversion in both the gray matter and white matter to thoroughly evaluate therapeutic potentials. This study also unveils the critical role of anti-inflammation by NeuroD1 during AtN conversion.

Visual impairment caused by optic neuropathies is irreversible because retinal ganglion cells (RGCs), the specialized neurons of the retina, do not have the capacity for self-renewal and self-repair. Blindness caused by optic nerve neuropathies causes extensive physical, financial, and social consequences in human societies. Recent studies on different animal models and humans have established effective strategies to prevent further RGC degeneration and replace the cells that have deteriorated. In this review, we discuss the application of electrical stimulation (ES) and magnetic field stimulation (MFS) in optic neuropathies, their mechanisms of action, their advantages, and limitations. ES and MFS can be applied effectively in the field of neuroregeneration. Although stem cells are becoming a promising approach for regenerating RGCs, the inhibitory environment of the CNS and the long visual pathway from the optic nerve to the superior colliculus are critical barriers to overcome. Scientific evidence has shown that adjuvant treatments, such as the application of ES and MFS help direct thetransplanted RGCs to extend their axons and form new synapses in the central nervous system (CNS). In addition, these techniques improve CNS neuroplasticity and decrease the inhibitory effects of the CNS. Possible mechanisms mediating the effects of electrical current on biological tissues include the release of anti-inflammatory cytokines, improvement of microcirculation, stimulation of cell metabolism, and modification of stem cell function. ES and MFS have the potential to promote angiogenesis, direct axon growth toward the intended target, and enhance appropriate synaptogenesis in optic nerve regeneration.

The Pcdhg gene cluster encodes 22 γ-Protocadherin (γ-Pcdh) cell adhesion molecules that critically regulate multiple aspects of neural development, including neuronal survival, dendritic and axonal arborization, and synapse formation and maturation. Each γ-Pcdh isoform has unique protein domains—a homophilically interacting extracellular domain and a juxtamembrane cytoplasmic domain—as well as a C-terminal cytoplasmic domain shared by all isoforms. The extent to which isoform-specific versus shared domains regulate distinct γ-Pcdh functions remains incompletely understood. Our previous in vitro studies identified protein kinase C (PKC) phosphorylation of a serine residue within a shared C-terminal motif as a mechanism through which γ-Pcdh promotion of dendrite arborization via myristoylated alanine-rich C-kinase substrate (MARCKS) is abrogated. Here, we used CRISPR/Cas9 genome editing to generate two new mouse lines expressing only non-phosphorylatable γ-Pcdhs, due either to a serine-to-alanine mutation (Pcdhg^S/A) or to a 15-amino acid C-terminal deletion resulting from insertion of an early stop codon (Pcdhg^CTD). Both lines are viable and fertile, and the density and maturation of dendritic spines remain unchanged in both Pcdhg^S/A and Pcdhg^CTD cortex. Dendrite arborization of cortical pyramidal neurons, however, is significantly increased in both lines, as are levels of active MARCKS. Intriguingly, despite having significantly reduced levels of γ-Pcdh proteins, the Pcdhg^CTD mutation yields the strongest phenotype, with even heterozygous mutants exhibiting increased arborization. The present study confirms that phosphorylation of a shared C-terminal motif is a key γ-Pcdh negative regulation point and contributes to a converging understanding of γ-Pcdh family function in which distinct roles are played by both individual isoforms and discrete protein domains.