Neuroscience bulletin最新文献

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children, characterized by social interaction, communication difficulties, and repetitive and stereotyped behaviors. Existing intervention methods have limitations, such as requiring long treatment periods and needing to be more convenient to implement. Extended Reality (XR) technology offers a virtual environment to enhance children's social, communication, and self-regulation skills. This paper compares XR theoretical models, application examples, and intervention effects. The study reveals that XR intervention therapy is mainly based on cognitive rehabilitation, teaching, and social-emotional learning theories. It utilizes algorithms, models, artificial intelligence (AI), eye-tracking, and other technologies for interaction, achieving diverse intervention outcomes. Participants showed effective improvement in competency barriers using XR-based multimodal interactive platforms. However, Mixed Reality (MR) technology still requires further development. Future research should explore multimsodal interaction technologies combining XR and AI, optimize models, prioritize the development of MR intervention scenarios, and sustain an optimal intervention level.

Optogenetics, a technique that employs light for neuromodulation, has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type specificity. However, visible light, particularly blue and green light, commonly used in conventional optogenetics, has limited penetration in biological tissue. This limitation necessitates the implantation of optical fibers for light delivery, especially in deep brain regions, leading to tissue damage and experimental constraints. To overcome these challenges, the use of orange-red and infrared light with greater tissue penetration has emerged as a promising approach for tetherless optical neuromodulation. In this review, we provide an overview of the development and applications of tetherless optical neuromodulation methods with long wavelengths. We first discuss the exploration of orange-red wavelength-responsive rhodopsins and their performance in tetherless optical neuromodulation. Then, we summarize two novel tetherless neuromodulation methods using near-infrared light: upconversion nanoparticle-mediated optogenetics and photothermal neuromodulation. In addition, we discuss recent advances in mid-infrared optical neuromodulation.

Intellectual disability (ID) is a condition characterized by cognitive impairment and difficulties in adaptive functioning. In our research, we identified two de novo mutations (c.955C>T and c.732C>A) at the KDM2A locus in individuals with varying degrees of ID. In addition, by using the Gene4Denovo database, we discovered five additional cases of de novo mutations in KDM2A. The mutations we identified significantly decreased the expression of the KDM2A protein. To investigate the role of KDM2A in neural development, we used both 2D neural stem cell models and 3D cerebral organoids. Our findings demonstrated that the reduced expression of KDM2A impairs the proliferation of neural progenitor cells (NPCs), increases apoptosis, induces premature neuronal differentiation, and affects synapse maturation. Through ChIP-Seq analysis, we found that KDM2A exhibited binding to the transcription start site regions of genes involved in neurogenesis. In addition, the knockdown of KDM2A hindered H3K36me2 binding to the downstream regulatory elements of genes. By integrating ChIP-Seq and RNA-Seq data, we made a significant discovery of the core genes' remarkable enrichment in the MAPK signaling pathway. Importantly, this enrichment was specifically linked to the p38 MAPK pathway. Furthermore, disease enrichment analysis linked the differentially-expressed genes identified from RNA-Seq of NPCs and cerebral organoids to neurodevelopmental disorders such as ID, autism spectrum disorder, and schizophrenia. Overall, our findings suggest that KDM2A plays a crucial role in regulating the H3K36me2 modification of downstream genes, thereby modulating the MAPK signaling pathway and potentially impacting early brain development.

With the advancements in gene sequencing technologies, including genome-wide association studies, polygenetic risk scores, and high-throughput sequencing, there has been a tremendous advantage in mapping a detailed blueprint for the genetic model of bipolar disorder (BD). To date, intriguing genetic clues have been identified to explain the development of BD, as well as the genetic association that might be applied for the development of susceptibility prediction and pharmacogenetic intervention. Risk genes of BD, such as CACNA1C, ANK3, TRANK1, and CLOCK, have been found to be involved in various pathophysiological processes correlated with BD. Although the specific roles of these genes have yet to be determined, genetic research on BD will help improve the prevention, therapeutics, and prognosis in clinical practice. The latest preclinical and clinical studies, and reviews of the genetics of BD, are analyzed in this review, aiming to summarize the progress in this intriguing field and to provide perspectives for individualized, precise, and effective clinical practice.

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol.

GJB2 gene mutations are the most common causes of autosomal recessive non-syndromic hereditary deafness. For individuals suffering from severe to profound GJB2-related deafness, cochlear implants have emerged as the sole remedy for auditory improvement. Some previous studies have highlighted the crucial role of preserving cochlear neural components in achieving favorable outcomes after cochlear implantation. Thus, we generated a conditional knockout mouse model (Cx26-CKO) in which Cx26 was completely deleted in the cochlear supporting cells driven by the Sox2 promoter. The Cx26-CKO mice showed severe hearing loss and massive loss of hair cells and Deiter's cells, which represented the extreme form of human deafness caused by GJB2 gene mutations. In addition, multiple pathological changes in the peripheral auditory nervous system were found, including abnormal innervation, demyelination, and degeneration of spiral ganglion neurons as well as disruption of heminodes in Cx26-CKO mice. These findings provide invaluable insights into the deafness mechanism and the treatment for severe deafness in Cx26-null mice.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.

Senile plaque blue autofluorescence was discovered around 40 years ago, however, its impact on Alzheimer's disease (AD) pathology has not been fully examined. We analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain sections and also Aβ aggregation in vitro. In DAPI or Hoechst staining, the nuclear blue fluorescence could only be correctly assigned after subtracting the blue plaque autofluorescence. The flower-like structures wrapping dense-core blue fluorescence formed by cathepsin D staining could not be considered central-nucleated neurons with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was subtracted. Both Aβ self-oligomers and Aβ/hemoglobin heterocomplexes generated blue autofluorescence. The Aβ amyloid blue autofluorescence not only labels senile plaques but also illustrates red cell aggregation, hemolysis, cerebral amyloid angiopathy, vascular plaques, vascular adhesions, and microaneurysms. In summary, we conclude that Aβ-aggregation-generated blue autofluorescence is an excellent multi-amyloidosis marker in Alzheimer's disease.