scholarly journals Anatomical development of the cerebellothalamic tract in embryonic mice

2019 ◽  
Author(s):  
Daniël B. Dumas ◽  
Simona V. Gornati ◽  
Youri Adolfs ◽  
Tomomi Shimogori ◽  
R. Jeroen Pasterkamp ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
Light Sheet ◽  
Autism Spectrum ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Wide Field ◽  
Thalamic Nuclei ◽  
Cortical Regions

AbstractCerebellar projections to the thalamus are a pivotal connection in cerebello-cerebral interactions. Apart from its role in coordinating sensorimotor integration in the adult brain, the cerebello-thalamic projection has also been implemented in developmental disorders, such as autism spectrum disorders. Although the development of the cerebellum, thalamus and cerebral cortex have been studied in many species, a detailed description of the ontogeny of the mammalian cerebello-thalamic tract (CbT) is currently missing. Here we investigated the development of the CbT at embryonic stages using transgenic Ntsr1-Cre/Ai14 mice and in utero electroporation (IUE) of wild type mice. Wide-field, confocal and 3D light-sheet imaging of immunohistochemical stainings showed that CbT fibers arrive in the prethalamus between E14.5 and E15.5, but only invade the thalamus after E16.5. We quantified the spread of CbT fibers throughout the various thalamic nuclei and found that at E17.5 and E18.5 the ventrolateral, ventromedial and parafascicular nuclei, but also the mediodorsal and posterior complex become increasingly innervated. Several CbT fiber varicosities colocalize with vGluT2, indicating that already from E18.5 the CbT synapse in various thalamic nuclei. Our results contribute to the construction of a frame of reference on the anatomical development of the CbT, which will help to guide future experiments investigating neurodevelopmental disorders.Significance statementUsing various microscopic approaches, we investigated the anatomical development of the fiber tract between the cerebellum and thalamus, one of the major mammalian brain connections. Our results show that in mice cerebellar axons wait outside of the thalamus from embryonic day (E)15.5 until E17.5 before invading the thalamic complex. Cerebellar axons establish vGluT2-positive synapses at E18.5 throughout various thalamic nuclei, each of which subsequently develops its connections with dedicated cerebral cortical regions. Our data thereby advocate the cerebellar influence on the maturation of the thalamus and connected cerebral cortex. This knowledge can help to guide future experiments into neurodevelopmental disorders affecting cerebello-thalamo-cortical networks.

scholarly journals The Expression and Distributions of ANP32A in the Developing Brain

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Shanshan Wang ◽  
Yunliang Wang ◽  
Qingshan Lu ◽  
Xinshan Liu ◽  
Fuyu Wang ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Fetal Brain ◽  
Tissue Expression ◽  
Developing Brain ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Dependent Manner ◽  
Growing Up ◽  
Embryonic Mouse ◽  
And Function

Acidic (leucine-rich) nuclear phosphoprotein 32 family, member A (ANP32A), has multiple functions involved in neuritogenesis, transcriptional regulation, and apoptosis. However, whether ANP32A has an effect on the mammalian developing brain is still in question. In this study, it was shown that brain was the organ that expressed the most abundant ANP32A by human multiple tissue expression (MTE) array. The distribution of ANP32A in the different adult brain areas was diverse dramatically, with high expression in cerebellum, temporal lobe, and cerebral cortex and with low expression in pons, medulla oblongata, and spinal cord. The expression of ANP32A was higher in the adult brain than in the fetal brain of not only humans but also mice in a time-dependent manner. ANP32A signals were dispersed accordantly in embryonic mouse brain. However, ANP32A was abundant in the granular layer of the cerebellum and the cerebral cortex when the mice were growing up, as well as in the Purkinje cells of the cerebellum. The variation of expression levels and distribution of ANP32A in the developing brain would imply that ANP32A may play an important role in mammalian brain development, especially in the differentiation and function of neurons in the cerebellum and the cerebral cortex.

scholarly journals Correlating Neuroimaging and CNVs Data: 7 Years of Cytogenomic Microarray Analysis on Patients Affected by Neurodevelopmental Disorders

2020 ◽  
Author(s):  
Roberta Milone ◽  
Claudia Cesario ◽  
Marina Goldoni ◽  
Rosa Pasquariello ◽  
Caterina Fusilli ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Neurodevelopmental Disorders ◽  
Detection Rate ◽  
Developmental Disorders ◽  
Brain Magnetic Resonance Imaging ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Brain Anomalies ◽  
Diagnostic Threshold ◽  
Diagnostic Potential

AbstractThe aim of this study was to evaluate the relationship between neurodevelopmental disorders, brain anomalies, and copy number variations (CNVs) and to estimate the diagnostic potential of cytogenomical microarray analysis (CMA) in individuals neuroradiologically characterized with intellectual developmental disorders (IDDs) isolated or associated with autism spectrum disorders (ASDs) and epilepsy (EPI), all of which were identified as a “synaptopathies.” We selected patients who received CMA and brain magnetic resonance imaging (MRI) over a 7-year period. We divided them into four subgroups: IDD, IDD + ASD, IDD + EPI, and IDD + ASD + EPI. The diagnostic threshold of CMA was 16%. The lowest detection rate for both CMA and brain anomalies was found in IDD + ASD, while MRI was significantly higher in IDD and IDD + EPI subgroups. CMA detection rate was significantly higher in patients with brain anomalies, so CMA may be even more appropriate in patients with pathological MRI, increasing the diagnostic value of the test. Conversely, positive CMA in IDD patients should require an MRI assessment, which is more often associated with brain anomalies. Posterior fossa anomalies, both isolated and associated with other brain anomalies, showed a significantly higher rate of CMA positive results and of pathogenic CNVs. In the next-generation sequencing era, our study confirms once again the relevant diagnostic output of CMA in patients with IDD, either isolated or associated with other comorbidities. Since more than half of the patients presented brain anomalies in this study, we propose that neuroimaging should be performed in such cases, particularly in the presence of genomic imbalances.

scholarly journals Supporting Bilingualism in Vulnerable Populations

2021 ◽  
Vol 13 (24) ◽  
pp. 13830
Author(s):  
Maria Vender ◽  
Mirta Vernice ◽  
Antonella Sorace
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
Language Disorder ◽  
State Of The Art ◽  
Autism Spectrum ◽  
Home Language ◽  
Developmental Language Disorder ◽  
Bilingual Speakers ◽  
The Family ◽  
Family Language

Although bilingualism is generally appraised and supported by society, many more doubts arise when it comes to children suffering from neurodevelopmental disorders. The concern that the exposure to two languages might deteriorate the linguistic development of children, together with the advice to simplify the linguistic environment and to adopt a monolingual approach, leads many families to abandon their home language and sacrifice bilingualism. Scientific research, however, has shown that this fear is ungrounded and that children with developmental disorders can become successful bilingual speakers, if they are provided with appropriate linguistic exposure. The aim of this paper is that of providing a state-of-the-art of the literature on this topic, by reviewing studies conducted on the interaction between bilingualism and neurodevelopmental disorders, focusing in particular on the interaction between bilingualism and developmental language disorder (DLD), developmental dyslexia and autism spectrum disorder. We discuss issues related to the early identification of DLD and dyslexia among bilinguals and we report the results of studies showing that bilingualism does not exacerbate the difficulties of children with developmental disorders, but on the contrary it can be beneficial for them, at the cognitive, linguistic and socio-cultural level. Finally, we provide some recommendations for parents, educators and practitioners, focusing on the importance of supporting the family language in all of its components, including literacy, for a complete and harmonic bilingual growth.

scholarly journals mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex

2021 ◽  
Vol 22 (11) ◽  
pp. 6034
Author(s):  
Martin Schüle ◽  
Tamer Butto ◽  
Sri Dewi ◽  
Laura Schlichtholz ◽  
Susanne Strand ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Neurodevelopmental Disorders ◽  
Cholesterol Biosynthesis ◽  
Single Gene ◽  
Autism Spectrum ◽  
Altered Expression ◽  
Mtorc1 Signaling ◽  
Mtor Activity

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.

scholarly journals PSA Depletion Induces the Differentiation of Immature Neurons in the Piriform Cortex of Adult Mice

2021 ◽  
Vol 22 (11) ◽  
pp. 5733
Author(s):  
Simona Coviello ◽  
Bruno Benedetti ◽  
Dominika Jakubecova ◽  
Maria Belles ◽  
Patrycja Klimczak ◽  
...  
Keyword(s):  
Piriform Cortex ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Extrinsic Factors ◽  
Factors Affecting ◽  
Neuronal Markers ◽  
Adult Mice ◽  
Immature Neurons ◽  
Cortical Regions ◽  
The Impact

Immature neurons are maintained in cortical regions of the adult mammalian brain. In rodents, many of these immature neurons can be identified in the piriform cortex based on their high expression of early neuronal markers, such as doublecortin (DCX) and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule plays critical roles in different neurodevelopmental events. Taking advantage of a DCX-CreERT2/Flox-EGFP reporter mice, we investigated the impact of targeted PSA enzymatic depletion in the piriform cortex on the fate of immature neurons. We report here that the removal of PSA accelerated the final development of immature neurons. This was revealed by a higher frequency of NeuN expression, an increase in the number of cells carrying an axon initial segment (AIS), and an increase in the number of dendrites and dendritic spines on the immature neurons. Taken together, our results demonstrated the crucial role of the PSA moiety in the protracted development of immature neurons residing outside of the neurogenic niches. More studies will be required to understand the intrinsic and extrinsic factors affecting PSA-NCAM expression to understand how the brain regulates the incorporation of these immature neurons to the established neuronal circuits of the adult brain.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Elliott Rees ◽  
Hugo D. J. Creeth ◽  
Hai-Gwo Hwu ◽  
Wei J. Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Increase Risk ◽  
Spectrum Disorders ◽  
Using Data ◽  
Shared Risk

AbstractPeople with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10−6). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo Creeth ◽  
Hai-Gwo Hwu ◽  
Wei Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

Abstract Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo D. J. Creeth ◽  
Hai-Gwo Hwu ◽  
Wei J. Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

AbstractGenes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Activity-Dependent Callosal Axon Projections in Neonatal Mouse Cerebral Cortex

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Yoshiaki Tagawa ◽  
Tomoo Hirano
Keyword(s):  
Cerebral Cortex ◽  
Ion Channels ◽  
Neuronal Activity ◽  
Intracellular Signaling ◽  
Developmental Disorders ◽  
Genetic Mutation ◽  
Mammalian Brain ◽  
Intracellular Signaling Pathway ◽  
Activity Dependent

Callosal axon projections are among the major long-range axonal projections in the mammalian brain. They are formed during the prenatal and early postnatal periods in the mouse, and their development relies on both activity-independent and -dependent mechanisms. In this paper, we review recent findings about the roles of neuronal activity in callosal axon projections. In addition to the well-documented role of sensory-driven neuronal activity, recent studies using in utero electroporation demonstrated an essential role of spontaneous neuronal activity generated in neonatal cortical circuits. Both presynaptic and postsynaptic neuronal activities are critically involved in the axon development. Studies have begun to reveal intracellular signaling pathway which works downstream of neuronal activity. We also review several distinct patterns of neuronal activity observed in the developing cerebral cortex, which might play roles in activity-dependent circuit construction. Such neuronal activity during the neonatal period can be disrupted by genetic factors, such as mutations in ion channels. It has been speculated that abnormal activity caused by such factors may affect activity-dependent circuit construction, leading to some developmental disorders. We discuss a possibility that genetic mutation in ion channels may impair callosal axon projections through an activity-dependent mechanism.

scholarly journals New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

2021 ◽  
Vol 14 ◽  
Author(s):  
Ana-Maria Oproescu ◽  
Sisu Han ◽  
Carol Schuurmans
Keyword(s):  
Stem Cells ◽  
Cerebral Cortex ◽  
Protein Interactions ◽  
Neural Progenitor Cells ◽  
Target Genes ◽  
Brain Regions ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Proneural Gene ◽  
Molecular Control

Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become ‘activated’ are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein–protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.

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