Developmental Neurobiology最新文献

The transcription factors Olig2 and Sox10 jointly define oligodendroglial identity. Because of their continuous presence during development and in the differentiated state they shape the oligodendroglial regulatory network at all times. In this review, we exploit their eminent role and omnipresence to elaborate the central principles that organize the gene regulatory network in oligodendrocytes in such a way that it preserves its identity, but at the same time allows defined and stimulus-dependent changes that result in an ordered lineage progression, differentiation, and myelination. For this purpose, we outline the multiple functional and physical interactions and intricate cross-regulatory relationships with other transcription factors, such as Hes5, Id, and SoxD proteins, in oligodendrocyte precursors and Tcf7l2, Sip1, Nkx2.2, Zfp24, and Myrf during differentiation and myelination, and interpret them in the context of the regulatory network.

Glia are widely distributed in the central nervous system and are closely related to cell metabolism, signal transduction, support, cell migration, and other nervous system development processes and functions. Glial development is complex and essential, including the processes of proliferation, differentiation, and migration, and requires precise regulatory networks. Noncoding RNAs (ncRNAs) can be deeply involved in glial development through gene regulation. Here, we review the regulatory roles of ncRNAs in glial development. We briefly describe the classification and functions of noncoding RNAs and focus on microRNAs (miRNAs) and long ncRNAs (lncRNAs), which have been reported to participate extensively during glial formation. The highlight of this summary is that miRNAs and lncRNAs can participate in and regulate the signaling pathways of glial development. The review not only describes how noncoding RNAs participate in nervous system development but also explains the processes of glial development, providing a foundation for subsequent studies on glial development and new insights into the pathogeneses of related neurological diseases.

Early-life stress (ELS) is considered a relevant etiological factor for neurodegenerative and mental disorders. In the present study, we hypothesized that ELS may persistently and sex dependently influence blood–brain barrier (BBB) integrity and function during critical periods of brain development and consequently determine susceptibility to and sex-related prevalence of chronic diseases in adult life. We used the maternal separation (MS) procedure in rats to model ELS and evaluated BBB permeability and gene expression of selected tight junction (TJ) proteins, glucose transporter type 1 (Slc2a1) and aquaporin 4 (Aqp4) in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR) and hippocampus of juvenile and adult rats. Serum concentrations of a peripheral marker of BBB function (S100β) and proinflammatory cytokines were also assessed. We observed developmental sealing of the BBB and sex differences in the permeability of the BBB and the mRNA expression of TJ proteins and Slc2a1. Adult females showed lower BBB permeability and higher levels of Cldn3, Cldn5, Ocln, and Slc2a1 in the mPFC and dSTR than males. MS temporarily increased BBB permeability in the dSTR of juvenile males and affected mRNA expression of the majority of studied proteins related to BBB function in age-, region- and sex-dependent manners. Additionally, MS sex dependently decreased serum S100β levels and did not affect proinflammatory cytokine concentrations. In general, our study did not reveal a clear or strong negative effect of MS on BBB integrity. However, the results suggest that ELS may induce adaptive/maladaptive changes or compensatory mechanisms within the BBB of unknown yet consequences.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to women at risk for preterm birth during a critical period of fetal development for mesocortical pathways. Yet, little information is available regarding the potential effects of 17-OHPC on the developing fetal brain. In rat models, the mesocortical serotonin pathway is sensitive to progestins. Progesterone receptor (PR) is expressed in layer 3 pyramidal neurons of medial prefrontal cortex (mPFC) and in serotonergic neurons of the dorsal raphe. The present study tested the hypothesis that exposure to 17-OHPC during development disrupts serotonergic innervation of the mPFC in adolescence and impairs behavior mediated by this pathway in adulthood. Administration of 17-OHPC from postnatal days 1–14 decreased the density of SERT-ir fibers within superficial and deep layers and decreased the density of synaptophysin-ir boutons in all layers of prelimbic mPFC at postnatal day 28. In addition, rats exposed to 17-OHPC during development were less likely to make impulsive choices in the Delay Discounting task, choosing the larger, delayed reward more often than controls at moderate delay times. Interestingly, 17-OHPC exposed rats were more likely to fail to make any choice (i.e., increased omissions) compared to controls at longer delays, suggesting disruptions in decision-making. These results suggest that further investigation is warranted in the clinical use of 17-OHPC to better inform a risk/benefit analysis of progestin use in pregnancy.

The avian basilar papilla is a valuable model system for exploring the developmental determination and differentiation of sensory hair cells and their innervation. In the mature basilar papilla, hair cells form a well-known continuum between two extreme types—tall and short hair cells—that differ strikingly in their innervation. Previous work identified Wnt9a as a crucial factor in this differentiation. Here, we quantified the number and volume of immunolabelled presynaptic ribbons in tall and short hair cells of chickens, from developmental stages shortly after ribbons first appear to the mature posthatching condition. Two longitudinal locations were sampled, responding to best frequencies of approximately 1 kHz and approximately 5.5 kHz when mature. We found significant reductions of ribbon number during normal development in the tall-hair-cell domains, but stable, low numbers in the short-hair-cell domains. Exposing developing hair cells to continuous, excessive Wnt9a levels (through virus-mediated overexpression) led to transiently abnormal high numbers of ribbons and a delayed reduction of ribbon numbers at all sampled locations. Thus, (normally) short-hair-cell domains also showed tall-hair-cell like behaviour, confirming previous findings (Munnamalai et al., 2017). However, at 3 weeks posthatching, ribbon numbers had decreased to the location-specific typical values of control hair cells at all sampled locations. Furthermore, as shown previously, mature hair cells at the basal, high-frequency location harboured larger ribbons than more apically located hair cells. This was true for both normal and Wnt9a-overexposed basilar papillae.

New neurons are generated throughout life in distinct regions of the mammalian brain due to the proliferation and differentiation of neural stem cells (NSCs). Ubiquitin, a post-translational modification of cellular proteins, is an important factor in regulating neurogenesis. Deubiquitination is a biochemical process that mediates the removal of ubiquitin moieties from ubiquitin-conjugated substrates. Recent studies have provided growing evidence that deubiquitylases (DUBs) which reverse ubiquitylation process play critical roles in NSCs maintenance, differentiation and maturation. This review mainly focused on the relationship of DUBs and NSCs, and further summarized recent advances in our understanding of DUBs on regulating NSCs biological behaviors.

Fetal alcohol spectrum disorder patients suffer from many cognitive disabilities. These include impaired auditory, visual, and tactile sensory information processing, making it more difficult for these patients to learn to navigate social scenarios. Rodent studies have shown that alcohol exposure during the brain growth spurt (BGS) can lead to acute neuronal apoptosis and an immunological response by microglia in the somatosensory cortex. Since microglia have critical physiological functions, including the support of excitatory synapse remodeling via interactions with dendritic spines, we sought to understand whether BGS alcohol exposure has long-term effects on microglial or dendritic spine dynamics. Using in vivo two-photon microscopy in 4–5 week old mice, we evaluated microglial functions such as process motility, the response to tissue injury, and the dynamics of physical interactions between microglial processes and dendritic spines. We also investigated potential differences in the morphology, density, or dynamics of dendritic spines in layer I/II primary sensory cortex of control and BGS alcohol exposed mice. We found that microglial process motility and contact with dendritic spines were not altered after BGS alcohol exposure. While the response of microglial processes toward tissue injury was not significantly altered by prior alcohol exposure, there was a trend suggesting that alcohol early in life may prime microglia to respond more quickly to secondary injury. Spine density, morphology, stability, and remodeling over time were not perturbed after BGS alcohol exposure. We demonstrate that after BGS alcohol exposure, the physiological functions of microglia and excitatory neurons remain intact in early adolescence.

Leucine-rich repeat (LRR) transmembrane proteins have been directly linked to neurodevelopmental and cognitive disorders. We have previously shown that the LRR transmembrane protein, leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), is a physiological regulator of dendrite complexity of hippocampal pyramidal neurons and social behavior. In this study, we performed a battery of behavioral tests to evaluate spatial memory and cognitive capabilities in Lrig1 mutant mice. The cognitive assessment demonstrated deficits in recognition and spatial memory, evaluated by novel object recognition and object location tests. Moreover, we found that Lrig1-deficient mice present specific impairments in the processing of similar but not dissimilar locations in a spatial pattern separation task, which was correlated with an enhanced dendritic growth and branching of Doublecortin-positive immature granule cells of the dentate gyrus. Altogether, these findings indicate that Lrig1 plays an essential role in controlling morphological and functional plasticity in the hippocampus.

It is now well established that aging is associated with emotional and cognitive changes. Although the basis of such changes is not fully understood, ultrastructural alterations in key brain areas are likely contributing factors. Recently, we reported that aging-related anxiety in male Wistar rats is associated with ultrastructural changes in the central nucleus of amygdala, an area that plays important role in emotional regulation. In this study, we evaluated the cognitive performance of adolescent, adult, and aged male Wistar rats in multi-branch maze (MBM) as well as in Morris water maze (MWM). We also performed ultrastructural analysis of the CA1 region of the hippocampus, an area intimately involved in cognitive function. The behavioral data indicate significant impairments in few indices of cognitive functions in both tests in aged rats compared to the other two age groups. Concomitantly, a total number of presynaptic vesicles as well as vesicles in the resting pool were significantly lower, whereas postsynaptic mitochondrial area was significantly higher in aged rats compared to the other age groups. No significant differences in presynaptic terminal area or postsynaptic mitochondrial number were detected between the three age groups. These results indicate that selective ultrastructural changes in specific hippocampal region may accompany cognitive decline in aging rats.

Glial cells play essential roles in the nervous system. Although glial populations are tightly regulated, the mechanisms regulating the population size remain poorly understood. Since Drosophila glial cells are similar to the human counterparts in their functions and shapes, rendering them an excellent model system to understand the human glia biology. Lipid phosphate phosphatases (LPPs) are important for regulating bioactive lipids. In Drosophila, there are three known LPP-encoding genes: wunen, wunen-2, and lazaro. The wunens are important for germ cell migration and survival and septate junction formation during tracheal development. Lazaro is involved in phototransduction. In the present study, we characterized a novel Drosophila LPP-encoding gene, CG11426. Suppression of CG11426 increased glial cell number in the eye imaginal disc during larval development, while ectopic CG11426 expression decreased it. Both types of mutation also caused defects in axon projection to the optic lobe in larval eye–brain complexes. Moreover, CG11426 promoted apoptosis via inhibiting ERK signaling in the eye imaginal disc. Taken together, these findings demonstrated that CG11426 gene product negatively regulates ERK signaling to promote apoptosis for proper maintenance of the glial population in the developing eye disc.