Cellular and Molecular Neurobiology最新文献

Sex and gender (SG) differences in the human brain are of interest to society and science as numerous processes are impacted by them, including brain development, behavior, and diseases. By collecting publicly available single-cell data from the in-utero to elderly age in healthy, Alzheimer's disease and multiple sclerosis samples, we identified and characterized SG-biased genes in ten brain cell types across 9 age and disease groups. Sex and gender differences in the transcriptome were present throughout the lifespan and across all cell types. Although there was limited overlap among SG-biased genes across different age and disease groups, we observed significant functional overlap. Female-biased genes are consistently enriched for brain-related processes, while male-biased genes are enriched for metabolic pathways. Additionally, mitochondrial genes showed a consistent female bias across cell types. We also found that androgen response elements (not estrogen) were significantly enriched in both male- and female-biased genes, and thymosin hormone targets being consistently enriched only in male-biased genes. We systematically characterised SG differences in brain development and brain-related disorders at a single-cell level, by analysing a total of publicly available 419,885 single nuclei from 161 human brain samples (72 females, 89 males). The significant enrichment of androgen (not estrogen) response elements in both male- and female-biased genes suggests that androgens are important regulators likely establishing these SG differences. Finally, we provide full characterization of SG-biased genes at different thresholds for the scientific community as a web resource.

Epigenetic alterations have emerged as critical factors in the pathogenesis of brain cancer, particularly gliomas. This article explores the impact of organochlorine pesticides (OCPs) on the hypermethylation of key tumor suppressor genes, and some histone modifications in primary brain tumor (PBT) patients. This study involved 73 patients diagnosed with PBT and 15 non-cancerous brain tissue samples as contol. DNA extracted from tumor specimens was used to evaluate the methylation status of tumor suppressor genes, P16 and RRP22, using the methylation-specific PCR (MSP) technique and four histone marks (H4K16ac, H3K9ac, H4K20me3, and H3k4me2) to investigate by western blotting. The results of MSP revealed the methylation of RRP22 and P16 promoter regions and western blot analysis demonstrated significantly low levels of H3K9ac, H4K20me3, and H3K4me2 in PBT patients in comparison with the controls. The results of regression analysis revealed direct and significant correlations between serum OCPs concentration and methylation of RRP22 and P16. Furthermore, a direct and significant association was observed between hypomethylation of histones H3K4 and H4K20, as well as hypoacetylation of H3K9, with OCPs levels. This study revealed that epigenetic modifications play a significant role in the development of brain tumors, with OCPs identified as key contributors to these changes. Our research indicated that in patients with PBT, hypermethylation of the RRP22 and P16 gene and histone modifications correlates directly and significantly with the levels of OCPs found in their serum.

Neuropathic pain, a prevalent complication following spinal cord injury (SCI), severely impairs the life quality of patients. No ideal treatment exists due to incomplete knowledge on underlying neural processes. To explore the SCI-induced effect on nociceptive circuits, the protein expression of c-Fos was analyzed as an indicator of neuronal activation in a rat contusion model exhibiting below-level pain. Additional stimuli were delivered to mimic the different peripheral sensory inputs in daily life. Following noxious rather than innocuous or no stimulation, a greater number of spinal dorsal horn (DH) neurons were activated after SCI, mainly in the deep DH. SCI facilitated the activation of excitatory but not inhibitory DH neurons. Moreover, excitatory interneurons expressing protein kinase C gamma (PKCγ) in laminae II-III, which are known to play a role in mechanical allodynia after peripheral nerve injury, responded in larger amounts to both innocuous and noxious stimulation following SCI. Accordingly, more spinal projection neurons in lamina I were activated. Within supraspinal nuclei processing pain, differentially enhanced activation in response to noxious stimulation was detected after SCI, with a significant increase in the locus coeruleus and medial thalamus, a slight increase in the periaqueductal gray and dorsal raphe, and no change in the lateral parabrachial nucleus or primary sensory cortex. These findings indicated differential hyperexcitability along the sensory neuroaxis following SCI, with a particular emphasis on the involvement of specific neuron subtypes, such as spinal PKCγ interneurons and locus coeruleus noradrenergic neurons, which may serve as crucial targets for potential therapies.

Tetrameric AMPA-type ionotropic glutamate receptors are primary transducers of fast excitatory synaptic transmission in the central nervous system, and their properties and abundance at the synaptic surface are crucial determinants of synaptic efficacy in neuronal communication across the brain. The induction of long-term potentiation (LTP) leads to the insertion of GluA1-containing AMPA receptors at the synaptic surface, whereas during long-term depression (LTD), these receptors are internalized into the cytoplasm of the spine. Disruptions in the trafficking of AMPA receptors to and from the synaptic surface attenuate both forms of synaptic plasticity. Homeostatic scaling up and scaling down, which are additional types of plasticity similar to LTP and LTD, are also regulated by the insertion and removal of GluA1-containing AMPA receptors from the synaptic surface. The trafficking of AMPA receptors is an intricate process assisted by various proteins. Furthermore, AMPA receptors are critical for the formation and consolidation of various types of memory, and alterations in their function are intimately associated with cognitive dysfunction in aging and several neurological and psychiatric diseases. In this review, we will provide an overview of the current understanding of how AMPA receptors regulate various forms of synaptic plasticity, their contribution to memory functions, and their role in aging and brain diseases.

Immune and metabolic factors play an important role in the onset and development of insomnia. This study aimed to investigate the causal relationship between insomnia and immune cells and metabolites. Data for 731 immune cell phenotypes, 1400 metabolites, and insomnia in this study were obtained from the GWAS open-access database. Two-way Mendelian randomization was used to (1) detect the causal relationship between immune cells and insomnia and (2) identify potential mediating metabolites. Mendelian randomization analysis identified eight immune cell phenotypes with a causal relationship to insomnia, and two immune cell phenotypes were protective factors for insomnia, namely CD8br %T cells and CD80 on CD62L + myeloid dendritic cells. The other six immune cell phenotypes were risk factors for insomnia, i.e., CD4/CD8br, CD16-CD56 on NKT, CCR2 on myeloid dendritic cells, CD40 on monocytes, CD38 on CD3-CD19-, and CD25 on CD45RA + CD4 not Treg. Further Mendelian randomization revealed 11 metabolites that were causally related to insomnia. Five metabolites were protective factors for insomnia, i.e., 3-hydroxy-3-methylglutarate, cholate, dodecanedioate, N-formylmethionine, and x-26054. Six metabolites were risk factors for insomnia, 3-amino-2-piperidone, 6-oxopiperdine-2-carboxylate, caffeine to theophylline ratio, leucine, maltose, and x-24736. In addition, our analysis showed that leucine mediated the association between CD4/CD8br and insomnia. From genetic information, we confirmed the causal relationship between insomnia, eight immune cell phenotypes, and eleven metabolite levels. Notably, we found a relationship between leucine-mediated CD4/CD8br and insomnia, providing evidence supporting the causal relationship between immune cell and insomnia, with plasma metabolites serving as mediators.

Both astroglia and microglia show region-specific distribution in CNS and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra (SN) of Parkinson's disease (PD) patients and experimental models propose gliosis as a trigger for neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites. Similarly, different mice strains are variably sensitive to MPTP. We had earlier likened divergent MPTP sensitivity of C57BL/6 J and CD-1 mice with differential susceptibility to PD, based on the numbers of SN neurons. We examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6 J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of normal C57BL/6 J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains suggest their involvement in pathogenesis. ELISA of pro-inflammatory cytokines in the ventral-midbrain revealed augmentation of TNF-α and IL-6 at middle age in both strains that reduced at old age, suggesting middle age as a critical, inflamm-aging-associated time point. TNF-α levels were high in C57BL/6 J, through aging and post-MPTP, while IL-6 and IL-1β were upregulated at old age. CD-1 had higher levels of anti-inflammatory cytokine TGF-β. MPTP challenge caused upregulation of enzymes MAO-A, MAO-B, and iNOS in both strains. Post-MPTP enhancement in fractalkine and hemeoxygenase-1 may be neuron-associated compensatory signals. Ultrastructural observations of elongated astroglial/microglial mitochondria vis-à-vis the shrunken ones in neurons suggest a scale-up of their functions with neurotoxic consequences. Thus, astroglia and microglia may modulate aging and PD susceptibility.