Developmental Neuroscience最新文献

Hippo pathway is an evolutionarily conserved signaling pathway comprising a series of MST/LATS kinase complexes. Its key transcriptional coactivators YAP and TAZ regulate transcription factors such as TEAD family to direct gene expression. The regulation of Hippo pathway, especially the nuclear level change of YAP and TAZ, significantly influences the cell fate switching from proliferation to differentiation, regeneration, and postinjury repair. This review outlines the main findings of Hippo pathway in peripheral nerve development, regeneration, and tumorigenesis, especially the studies in Schwann cells. We also summarize other roles of Hippo pathway in damage repair of the peripheral nerve system and discuss the potential future research which probably contributes to novel therapeutic strategies.

Hypoxic-ischaemic encephalopathy (HIE) in the newborn baby is a major contributor to neonatal mortality and morbidity across the world. Therapeutic hypothermia (TH) is the current standard treatment for moderate to severe HIE, but not all babies benefit. Potential neuroprotective actions of progesterone (PROG) include anti-apoptotic, anti-inflammatory, and anti-oxidative effects and reduction of energy depletion, tissue/cellular oedema, and excitotoxicity. In pre-clinical studies of neonatal HIE, PROG has neuroprotective properties but has not been the subject of systematic review. Here, our objective was to evaluate the evidence base for PROG as a potential therapeutic agent in HIE. The PICO framework was used to define the following inclusion criteria. Population: human neonates with HIE/animal models of HIE; intervention: PROG +/- other agents; comparison: V.S. control; outcome: pathological, neurobehavioural, and mechanistic outcome measures. Medline, EMBASE, and CINHAL were then searched between August to October 2018 using pre-defined medical subject heading and keywords. Study inclusion, data extraction, and risk of bias (ROB) analysis using the SYRCLE ROB tool were carried out by two authors. 14 studies were included in the review. They typically displayed a high ROB. This systematic review suggests that PROG reduced neuropathology and reduced neurobehavioural deficits post-hypoxic-ischaemic (HI) insult in 8 and 3 studies, respectively. However, there was sex dimorphism in the effects of PROG. In addition, there are limitations and biases in these studies, and there remains a need for well-designed large pre-clinical studies with greater methodological quality to further inform the efficacy, safety, dose, timing, and frequency of PROG administration. With such data, large animal studies could be planned combining PROG administration with and without TH.

Cerebral ischemia is divided into local cerebral ischemia and diffuse cerebral ischemia. The etiology of localized cerebral ischemia includes middle cerebral artery embolism; stenosis, occlusion, or thrombosis of extracranial internal carotid artery or vertebral artery; and cerebral artery spasm. The causes of diffuse cerebral ischemia include cardiac arrest, hypotension, anemia, and hypoglycemia. However, the underlying mechanism is still unclear. In this study, we demonstrated that activator of transcription 3 (ATF3) is a hubgene in IS by bioinformatics analysis. The expression of ATF3 was increased in PC12 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ATF3 deficiency inhibited cell viability and induced cell apoptosis, whereas ATF3 overexpression showed the opposite role in cell viability and cell apoptosis. Moreover, Carvedilol as a compound targeting ATF3 also facilitated cell viability and reduced cell apoptosis. ATF3 deficiency retarded the increase in cell viability and inhibition of cell apoptosis in OGD/R-PC12 cells with Carvedilol treatment. Additionally, the decreased Bax and cleaved caspase-3 were released in OGD/R-PC12 cells with Carvedilol and siATF3 treatment, while Bcl-2 expression was inhibited in OGD/R-PC12 cells with Carvedilol and siATF3 treatment. In conclusion, Carvedilol may be a key compound targeting ATF3 in OGD/R-PC12 cells. Graphical Abstract: Carvedilol positively regulated cell viability and negatively regulated cell apoptosis in OGD/R-PC12 cells by inhibition of ATF3.

Macrocephaly has been associated with neurodevelopmental disorders; however, it has been mainly studied in the context of pathological or high-risk populations and little is known about its impact, as an isolated trait, on brain development in general population. Electroencephalographic (EEG) power spectral density (PSD) and signal complexity have shown to be sensitive to neurodevelopment and its alterations. We aimed to investigate the impact of macrocephaly, as an isolated trait, on EEG signal as measured by PSD and multiscale entropy during the first year of life. We recorded high-density EEG resting-state activity of 74 healthy full-term infants, 50 control (26 girls), and 24 macrocephalic (12 girls) aged between 3 and 11 months. We used linear regression models to assess group and age effects on EEG PSD and signal complexity. Sex and brain volume measures, obtained via a 3D transfontanellar ultrasound, were also included into the models to evaluate their contribution. Our results showed lower PSD of the low alpha (8-10 Hz) frequency band and lower complexity in the macrocephalic group compared to the control group. In addition, we found an increase in low alpha (8.5-10 Hz) PSD and in the complexity index with age. These findings suggest that macrocephaly as an isolated trait has a significant impact on brain activity during the first year of life.

Glioblastoma (GBM), the most common and lethal primary brain tumor in adults, requires multi-treatment intervention which unfortunately barely shifts the needle in overall survival. The treatment options after diagnosis and surgical resection (if possible) include irradiation, temozolomide (TMZ) chemotherapy, and now tumor treating fields (TTFields). TTFields are electric fields delivered locoregionally to the head/tumor via a wearable medical device (Optune®). Overall, the concomitant treatment of TTFields and TMZ target tumor cells but spare normal cell types in the brain. Here, we examine whether primary cilia, microtubule-based "antennas" found on both normal brain cells and GBM cells, play specific roles in sensitizing tumor cells to treatment. We discuss evidence supporting GBM cilia being exploited by tumor cells to promote their growth and treatment resistance. We review how primary cilia on normal brain and GBM cells are affected by GBM treatments as monotherapy or concomitant modalities. We also focus on latest findings indicating a differential regulation of GBM ciliogenesis by TTFields and TMZ. Future studies await arrival of intracranial TTFields models to determine if GBM cilia carry a prognostic capacity.

Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p < 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01-0.77, R2 = 0.18, p < 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p < 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

Background: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that may potentially be helpful for neuropsychiatric symptoms of developmental disorders with inflammatory aspects. TMS utilizes a varying magnetic field to induce electrical changes in the brain. Repetitive use of TMS modulates plasticity at multiple levels, particularly at the synapse and network level.

Summary: As inflammation can affect synaptic plasticity negatively, TMS may theoretically be a tool to address this inflammation-induced dysfunction. There are also data to suggest that TMS can directly downregulate inflammation. Neuropsychiatric consequences of multiple disorders with inflammatory aspects, particularly neurodevelopmental disorders like autism, Tourette syndrome, and obsessive-compulsive disorder (OCD), maybe treated effectively with TMS. Treatment of OCD, treatment-resistant major depression, and nicotine cessation (all in adults) are currently FDA-cleared indications, while migraine is cleared for ages 12 and above.

Key messages: TMS will likely continue to grow in terms of indications as research continues to assess what brain networks are dysfunctional in various disorders and it becomes clearer how to modulate these networks. TMS may thus be best understood as a technology platform that can be utilized to modulate different brain networks affected in neuropsychiatric disorders. TMS is likely to become an increasingly important tool in targeting brain networks that could become dysfunctional in part due to inflammation in the developing brain and addressing consequent neuropsychiatric symptoms.

Maternal immune activation (MIA) can result from a variety of maternal inflammatory factors, including metabolic disorders, nutritional deficits, infections, and psychosocial stress. MIA has been consistently recognized as a major risk factor for neurodevelopmental disorders, and this association seems to be especially important for viral infections as viral exposure during pregnancy was associated with a higher risk of developing neurodevelopmental disorders, such as schizophrenia. In MIA, the gestational parent's inflammatory response to an immune stimulus alters or interrupts fetal development, triggering neurodevelopmental consequences. As MIA can occur in any pregnancy, it is important to understand the many factors at play that contribute to altered brain development in the offspring, especially considering recent global events such as the COVID-19 pandemic. The underlying mechanisms by which MIA results in deleterious outcomes are not yet clear, but due to the inflammatory response it initiates, it is becoming apparent that microglia are critically involved. Through investigation of MIA animal models, the role of microglia in this field is becoming more evident. Compelling evidence from animal models indicates that MIA can disrupt synaptic pruning, neuronal progenitor cell proliferation/differentiation, oligodendrogenesis, and more. Microglia appear as an active player, assisting these neural-related functions during healthy development but also mediating MIA-induced disturbances in these critical processes when neurodevelopment is challenged. The present review illustrates this complex web by reviewing recent literature, focusing on the outcomes of MIA resulting from viral mimetic polyinosinic-polycytidylic acid in rodents, to provide a clear description of how MIA impacts microglial functions and what this means for the offspring's neurodevelopment. Moreover, we discuss the possible implications of the COVID-19 pandemic on the neurodevelopment of the current and next generations in the frame of MIA models and propose some putative pharmacological and non-pharmacological approaches to prevent or attenuate MIA consequences.

Early variations of fetal movements are the hallmark of a healthy developing central nervous system. However, there are no automatic methods to quantify the complex 3D motion of the developing fetus in utero. The aim of this prospective study was to use machine learning (ML) on in utero MRI to perform quantitative kinematic analysis of fetal limb movement, assessing the impact of maternal, placental, and fetal factors. In this cross-sectional, observational study, we used 76 sets of fetal (24-40 gestational weeks [GW]) blood oxygenation level-dependent (BOLD) MRI scans of 52 women (18-45 years old) during typical pregnancies. Pregnant women were scanned for 5-10 min while breathing room air (21% O2) and for 5-10 min while breathing 100% FiO2 in supine and/or lateral position. BOLD acquisition time was 20 min in total with effective temporal resolution approximately 3 s. To quantify upper and lower limb kinematics, we used a 3D convolutional neural network previously trained to track fetal key points (wrists, elbows, shoulders, ankles, knees, hips) on similar BOLD time series. Tracking was visually assessed, errors were manually corrected, and the absolute movement time (AMT) for each joint was calculated. To identify variables that had a significant association with AMT, we constructed a mixed-model ANOVA with interaction terms. Fetuses showed significantly longer duration of limb movements during maternal hyperoxia. We also found a significant centrifugal increase of AMT across limbs and significantly longer AMT of upper extremities <31 GW and longer AMT of lower extremities >35 GW. In conclusion, using ML we successfully quantified complex 3D fetal limb motion in utero and across gestation, showing maternal factors (hyperoxia) and fetal factors (gestational age, joint) that impact movement. Quantification of fetal motion on MRI is a potential new biomarker of fetal health and neuromuscular development.