Developmental Neurobiology最新文献

Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround certain neurons and play a critical role in protecting neurons from oxidative stress and maintaining synaptic stability in the central nervous system. They have roles in memory formation, and their loss has been linked to various mental alterations, such as anxiety, depression, and schizophrenia. While immune activation is known to degrade PNNs, it remains unclear whether inflammasomes are involved in PNN formation dynamics during neuronal development, where cases of sepsis are particularly high. In this study, we investigated how activation of the NLRP3 inflammasome in neonatal mouse brains influences PNNs. To explore this, neonatal wild-type and Nlrp3 knockout mice were injected with lipopolysaccharide (LPS) or phosphate-buffered saline (PBS) on postnatal day (PND) 9, and PNNs were visualized at early adulthood (PND60). In addition, NLRP3 inflammasome activation was confirmed on PND10, and behavioral tests were performed on PND60. LPS treatment in wild-type mice reduced PNN-positive neurons in the hippocampus and cortex compared to the PBS group, whereas Nlrp3 knockout mice showed no differences between treatment groups. Moreover, behavioral tests revealed that neonatal LPS injection resulted in anxiety- and depressive-like behavior and that NLRP3 deficiency restrained this effect. These results highlight the key role of NLRP3 inflammasome activation in inflammation-driven PNN reduction during neuronal development. NLRP3 inhibitors could thus serve as potential therapeutic agents to protect the neuronal extracellular matrix from inflammatory damage in early life.

The cochlea's cellular architecture plays a critical role in auditory perception, yet is highly susceptible to degenerative factors. While melatonin is known for its antioxidative properties in the adult cochlea, its expression during early development remains understudied. This study used immunohistochemical staining of melatonin and its synthesizing enzymes (AANAT, HIOMT) to explore the self-synthesis and spatial distribution of melatonin in the cochlea of postnatal and adult rats. Postnatal rats exhibited low levels of intracellular marker expression in the lateral wall and the undifferentiated sensory epithelia, with no expression observed in the spiral ganglion. They showed mainly extracellular marker expression near the stria vascularis, in the stria vascularis interspace, and above undifferentiated sensory epithelia. In contrast, adults exhibited widespread intracellular marker presence in spiral ligament fibrocytes, spiral ganglion neurons, satellite glia, and epithelial supporter cells, except in hair cells. Fibrocytes in the spiral limbus expressed AANAT and HIOMT at both developmental stages. The present findings indicate melatonin's complex involvement in cochlear protection and development. Detailed knowledge of melatonin synthesis locations and intensity across different age stages within the auditory system holds the key to pioneering novel treatments, preventive strategies, and a deeper understanding of hearing processes.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders characterized by the accumulation of amyloid-β (Aβ) peptide and phosphorylated tau protein in the brain. Despite intensive efforts, early diagnosis and monitoring of AD remain challenging due to the lack of reliable biomarkers that can detect the disease in its preclinical stages. As a result, there exists a requirement for novel approaches to the diagnosis and treatment of the disease. Extracellular vesicles provide the transfer of Aβ peptides and tau proteins between the cells and participates in the spreading/propagation of disease pathology. Neuron-derived extracellular vesicles (NDEVs) that are found in plasma have emerged as promising candidates, especially for biomarker studies on neurodegenerative diseases because they are reachable and comparable with cerebrospinal fluid (CSF) studies. In addition to known proteins, synaptic proteins, transcription factors, or microRNAs have been suggested as new biomarkers, aiming to help differential or early diagnosis. Beyond their involvement in AD pathology, NDEVs also play essential roles in neurodevelopment and aging by mediating cell-to-cell communication and regulating processes such as synaptic formation, neuronal differentiation, and neuroinflammation. Age-related alterations in EV composition and secretion may contribute to the decline in neuroplasticity, thereby increasing susceptibility to neurodegenerative diseases like AD. Several challenges such as heterogeneous isolation of NDEVs limit the widespread clinical application of them as biomarkers for AD. Furthermore, the lack of standardized protocols for vesicle isolation and molecular analysis poses a barrier to reproducibility and clinical validation. The aim of this review is to elucidate the role of NDEVs in AD pathogenesis in comparison with their functions in neurodevelopment and aging, evaluate their potential as biomarkers for early diagnosis, while addressing the challenges in their isolation, characterization, and clinical application.

Although the early signs of autism spectrum disorder (ASD) are widely studied, the significant ambiguity and heterogeneity in symptoms require the comparison of available models, approaches, and the search for common denominators and key indicators. Early ASD symptoms in animal models include impaired somatic development (e.g., delayed eye opening), alterations in primitive motor reflexes, disrupted sensory function as well as communication deficits, such as reduced ultrasonic vocalization. This review aims to summarize early ASD-related symptoms based on studies involving transgenic or neurotoxic rodent models (postnatal days 1–21) and to compare these with human resemblance. The key brain areas (subventricular zone, cortex, hippocampus, cerebellum, etc.) as well as relevant neurotransmitter systems (GABA-glutamate imbalance, developmental GABA shift, serotonin, dopamine, oxytocin [OT], etc.) were identified as potential targets for intervention. OT, although a promising candidate, exemplifies the translational challenges inherent in ASD research. Therefore, it is recommended to monitor a wide range of behavioral signs simultaneously and employ diverse models (e.g., genetic, developmental, environmental, or combination) in preclinical studies to more accurately reflect the complexity of the disorder.

Reduced expression of the serotonin transporter (5-hydroxytryptamine transporter, 5-HTT) in early life has been associated with a delay in postnatal brain development and endophenotypes of a variety of neuropsychiatric and neurodevelopmental disorders in adolescence and adulthood. How a reduction in functional 5-HTT can disrupt neurodevelopment is still largely unknown. Here, we studied genome-wide gene expression using transcriptome analysis (RNA-seq) and global levels of DNA (hydroxy)methylation (5(h)mC) using high-performance liquid chromatography-tandem mass spectrometry in 5-HTT wild-type (5-HTT^+/+) and 5-HTT homozygous knockout (5-HTT^−/−) rats across life (postnatal day [PND] 8, 14, 21, 35, and 70) in the medial prefrontal cortex (mPFC); a brain region with an extensive serotonergic innervation involved in several neuropsychiatric endophenotypes. We observed most gene expression changes in the mPFC during early postnatal life (PND8) and found at this time point an enrichment of genes linked to neuronal and developmental processes like neurotransmission, neuropeptide signaling, and cell migration. Genome-wide DNA 5(h)mC analysis showed a global increase in 5-hydroxymethylcytosine (5hmC) in the mPFC during development in both genotypes and a significant increase in global 5hmC in 5-HTT^−/− compared to 5-HTT^+/+ rats at PND35. The differences in the regulation of gene expression in 5-HTT^−/− versus 5-HTT^+/+ rats during early postnatal life can dysregulate neurodevelopmental processes resulting in aberrant brain wiring and functioning. This can result in lifelong consequences for prefrontal context-dependent executive functioning.