Journal of Neuroscience Research最新文献

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social deficits, restricted interest, and repetitive behaviors. The prevalence is higher in males (4:1). FDA-approved drugs, Aripiprazole, and risperidone, only target comorbid conditions and have significant side effects. Dysregulation in cAMP-responsive element-binding protein (CREB) signaling is reported in autistic individuals. Forskolin is traditionally used in Ayurvedic medicine with lesser side effects. It is a potent adenylyl cyclase (AC) activator, increases intracellular cyclic adenosine monophosphate (cAMP) levels, thereby activating the protein kinase A (PKA)/CREB pathway with clinically proven benefits as an anticancer, anti-asthmatic, and in metabolic disorder, and crosses the blood–brain-barrier (BBB) junction. The present study aimed to investigate the impact of Forskolin and sought to explore the role of estrogen beta (ERβ/ESR2) receptors in a valproic acid (VPA) model of ASD. Pregnant Wistar rats received VPA or an equal volume of saline on gestational day (GD) 12.5. From postnatal day (PND) 23, male and female rats were divided separately into control, VPA, risperidone, and Forskolin (10–30 mg/kg) groups. Systemic administration of Forskolin ameliorated anxiety, social deficit, repetitive behavior, spatial recognition memory, motor coordination, gastrointestinal (GIT) motility, brain edema, and BBB permeability in a dose-dependent manner. Moreover, chronic Forskolin treatment significantly alleviated VPA-induced neuronal damage in the prefrontal cortex (PFC), hippocampus (HC), and cerebellum, and increased the intracellular CREB ser133 protein phosphorylation. Forskolin upregulated the mRNA expression of CREB signaling, which was altered by prenatal VPA administration. Our findings indicate that Forskolin provides neuroprotection through CREB signaling, suggesting its therapeutic potential for ASD.

Schwann cells (SCs) are required for supporting axons, forming myelin, and facilitating repair through remyelination after injury in the peripheral nervous system (PNS). Processes of differentiation, myelination, and remyelination of SCs are tightly modulated by a complex network of transcription factors and coregulators, including Sox10, Oct6/Pou3f1, Krox20/Egr2, Nab1/2, YY1, COUP-TFII/NR2F2, YAP/TAZ-TEAD1, c-Jun, Sox2, Zeb2, and Etv1/Er81. These factors can regulate the expression of essential target genes such as Mpz and Mbp in SC myelination and repair. Genetic mutations or dysregulation within this network can lead to peripheral neuropathies such as Charcot–Marie–Tooth disease. However, the transcriptional regulatory network of differentiation, myelination, and remyelination of SCs has not been fully understood yet. Thus, this review briefly introduces processes of differentiation, myelination, and remyelination of SCs and explores the role and molecular mechanisms of each transcription factor and coregulator in differentiation and myelination of SCs and their remyelination following nerve injury. Clinical implications for peripheral neuropathies associated with specific gene mutations and variations of transcription factors and coregulators affecting SC biology are also discussed.

In sleep apnea, repeated hypovolemic ventilation or apnea in sleep leads to intermittent hypoxia (IH) of the brain. Thus, the impacts of sleep apnea on the brain need to be investigated. In this study, a mouse model with sleep-associated chronic IH and behavior tests was used to evaluate how IH impacts brain function and the expression of tyrosine hydroxylase (TH)-containing neurons in the substantia nigra, ventral tegmental area (VTA), and locus coeruleus. In an open-field test, mice subjected to chronic IH (5%–21% oxygen) for 10 and 20 days exhibited a significant decrease in spontaneous locomotor activity compared to the room air (RA, 21% oxygen) control mice. In the Y-maze test, the ability to recognize novel and familiar arms was similar between groups. In immunostaining of the brains of IH mice, TH-positive neurons in the substantia nigra, VTA, and locus coeruleus were significantly reduced compared to RA mice. Furthermore, in the brains of mice with decreased TH-positive neurons induced by IH, the expression of hippocampal neurons has not been affected. In the analysis of glial cells, in IH group mice, a significant increase of microglia was found in the substantia nigra, VTA, locus coeruleus, and hippocampus compared to the RA mice. These findings suggest that there is a loss of TH-containing neurons and neuronal inflammation in the substantia nigra, VTA, and locus coeruleus under chronic IH. Our findings provide precise evidence for the loss of TH-containing neurons in the setting of chronic IH mouse models, which can provide relevant empirical observations for clinicians.

Heat Shock Protein 60 (HSP60) plays a critical role in maintaining mitochondrial function in astrocytes and has a significant impact on central nervous system (CNS) health. However, how HSP60 regulates the mitochondrial function of astrocytes to inhibit neuroregeneration remains unknown. In this study, we generated astrocyte-specific HSP60 knockout male mice to investigate the consequences of HSP60 deficiency. Firstly, our results confirmed that HSP60 deficiency caused abnormal expression of mitochondrial function-related genes, causing significant mitochondrial dysfunction, which triggered cellular senescence in astrocytes. Moreover, the alterations of 5-hydroxytryptamine 2A receptor (5-HT2AR), glucocorticoid receptor (GR), dopamine D2 receptor (D2R), and N-methyl-D-aspartate receptor subunit 2A (NR2A) expression suggested a disruption in neurotransmission and synaptic plasticity. Additionally, the increased levels of site-1 protease (S1P), truncated brain-derived neurotrophic factor (truncated-BDNF), and synaptophysin indicate synaptic structural and functional impairments. Expectedly, our findings demonstrated mitochondrial dysfunction and cellular senescence in astrocytes, leading to altered expression of neurotransmitter receptors in the cortex, as well as reduced neuronal numbers and neurotransmitter levels in the hippocampus after the deletion of HSP60 in astrocytes of the male mice. Notably, Urolithin A (UA) and the S1P inhibitor, PF429242, were found to alleviate astrocyte senescence and promote neuronal regeneration by inhibiting truncated BDNF expression. In conclusion, our study revealed that HSP60 deficiency in astrocytes induces mitochondrial dysfunction and cellular senescence via the S1P/truncated-BDNF pathway, resulting in disrupted neurotransmitter receptor expression, synaptic protein alterations, and impaired neuroregeneration. These insights underscored the importance of HSP60 in CNS health and provided promising avenues for developing treatments for neurodegenerative disorders.

The neurobiology of human stress-related disorders remains poorly understood, necessitating novel models and new model organisms to advance translational research in this field. Complementing rodent studies, the zebrafish (Danio rerio) is a useful model species for stress-related disorders. Here, we develop two novel experimental models of stress-related brain disorders, based on repeated prolonged exposure to predators or on chronic unpredictable stress in adult zebrafish. The ability of both models to recapitulate human stress in these fish was assessed behaviorally, in the novel tank and the plus maze (anxiety, locomotor, and cognitive tests), as well as by analyzing the baseline levels of cortisol, a common neuroendocrine biomarker of stress. Overall, anxiety-like behavior in the novel tank test was seen in both stressed groups, whereas poor learning and higher anxiety were observed in the plus maze test in predator-exposed fish, paralleling clinical cognitive and affective symptoms. Elevated cortisol in both stressed zebrafish further resembled neuroendocrine deficits seen in stress-related disorders clinically. Finally, the evoked behavioral and endocrine stress symptoms were rescued by treatment with two popular, clinically active antidepressant drugs, fluoxetine and paroxetine. Collectively, these models successfully recapitulated in zebrafish several key aspects of clinical stress-related disorders, further supporting the utility of these fish for translational stress research and anti-stress drug development.

In this study, we aimed to investigate changes in the mean amplitude of low-frequency fluctuations (mALFF) in different frequency bands in flight trainees using resting-state functional magnetic resonance imaging (rs-fMRI) technology to explore the impact of flight training on brain functional changes. The study included 39 flight trainees and 37 well-matched healthy controls. MATLAB software was used to perform two-sample t-tests on the mALFF values of the subjects in different frequency bands to identify intergroup differences. SPSS software was used to perform correlation analysis between the different brain areas and the results of the Berg Card Sorting Test (BCST). The results revealed significant differences in mALFF values in multiple brain areas, including the left medial superior frontal gyrus and the left postcentral gyrus, between the two groups. Sub-bands revealed more differential brain areas compared to the classical band, and these differential brain areas were significantly correlated with the total accuracy of the BCST. Under resting conditions, flight trainees who underwent flight training showed significant differences from the control group in brain regions related to cognitive executive control, somatosensory function, memory function, and other functions. This may be related to the learning of critical flight skills, such as emergency operations, maneuvering the aircraft for takeoff, landing, and re-flight during executive flight training. Meanwhile, the sub-band is more sensitive to information about brain functional activities than the classical band, which provides a new perspective for further exploring the changes in pilot brain functional mechanisms in the future.