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1.
Nat Neurosci ; 24(10): 1392-1401, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34400844

RESUMO

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO's synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.


Assuntos
Cerebelo/crescimento & desenvolvimento , Glândulas Endócrinas/fisiologia , Placenta/fisiologia , Pregnanolona/deficiência , Pregnanolona/fisiologia , Comportamento Social , Aldeído Redutase/genética , Animais , Transtorno do Espectro Autista/etiologia , Cerebelo/fisiologia , Feminino , Agonistas GABAérgicos/farmacologia , Moduladores GABAérgicos , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Muscimol/farmacologia , Gravidez , Receptores de GABA-A/fisiologia , Caracteres Sexuais , Trofoblastos/metabolismo , Substância Branca/patologia
2.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193509

RESUMO

Retinal ganglion cells (RGCs) project topographically to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Spontaneous activity plays a critical role in retinotopic mapping in both regions; however, the molecular mechanisms underlying activity-dependent refinement remain unclear. Previous pharmacologic studies implicate NMDA receptors (NMDARs) in the establishment of retinotopy. In other brain regions, NMDARs are expressed on both the presynaptic and postsynaptic side of the synapse, and recent work suggests that presynaptic and postsynaptic NMDARs play distinct roles in retinotectal developmental dynamics. To directly test the role of NMDARs expressed by RGCs in retinofugal map formation, we took a conditional genetic knock-out approach to delete the obligate GluN1 subunit of NMDARs in RGCs. Here, we demonstrate reduced GluN1 expression in the retina of Chrnb3-Cre;GluN1flox/flox (pre-cKO) mice without altered expression in the SC. Anatomical tracing experiments revealed no significant changes in termination zone size in the SC and dLGN of pre-cKO mice, suggesting NMDAR function in RGCs is not an absolute requirement for topographic refinement. Further, we observed no change in the eye-specific organization of retinal inputs to the SC nor dLGN. To verify that NMDA induces activity in RGC terminals, we restricted GCaMP5 expression to RGCs and confirmed induction of calcium transients in RGC terminals. Together, these findings demonstrate that NMDARs expressed by RGCs are not required for retinofugal topographic map formation nor eye-specific segregation in the mouse.


Assuntos
Células Ganglionares da Retina , Vias Visuais , Animais , Corpos Geniculados , Camundongos , Receptores de N-Metil-D-Aspartato/genética , Retina , Colículos Superiores
3.
Semin Cell Dev Biol ; 116: 16-24, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34110985

RESUMO

Oligodendrocytes are highly specialized glial cells, responsible for producing myelin in the central nervous system (CNS). The multi-stage process of oligodendrocyte development is tightly regulated to ensure proper lineage progression of oligodendrocyte progenitor cells (OPCs) to mature myelin producing oligodendrocytes. This developmental process involves complex interactions between several intrinsic signaling pathways that are modulated by an array of extrinsic factors. Understanding these regulatory processes is of crucial importance, as it may help to identify specific molecular targets both to enhance plasticity in the normal CNS and to promote endogenous recovery following injury or disease. This review describes two major regulators that play important functional roles in distinct phases of oligodendrocyte development: OPC proliferation and differentiation. Specifically, we highlight the roles of the extracellular astrocyte/radial glia-derived protein Endothelin-1 in OPC proliferation and the intracellular Akt/mTOR pathway in OPC differentiation. Lastly, we reflect on how recent advances in neuroscience and scientific technology will enable greater understanding into how intrinsic and extrinsic regulators interact to generate oligodendrocyte diversity.

4.
Front Cell Dev Biol ; 9: 665409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981706

RESUMO

Postnatal neurodevelopment is profoundly influenced by environmental experiences. Environmental enrichment is a commonly used experimental paradigm that has uncovered numerous examples of experience-dependent plasticity in health and disease. However, the role of environmental enrichment in normal development, especially glial development, is largely unexplored. Oligodendrocytes, the myelin-forming glia in the central nervous system, provide metabolic support to axons and establish efficient saltatory conduction by producing myelin. Indeed, alterations in myelin are strongly correlated with sensory, cognitive, and motor function. The timing of developmental myelination is uniquely positioned to be influenced by environmental stimuli, as peak myelination occurs postnatally and continues into adulthood. To determine if developmental myelination is impacted by environmental experience, mice were housed in an enriched environment during peak myelination through early adulthood. Using translating ribosome affinity purification, oligodendrocyte-specific RNAs were isolated from subcortical white matter at various postnatal ages. RNA-sequencing revealed that differences in the oligodendrocyte translatome were predominantly evident after prolonged and continuous environmental enrichment. These translational changes corresponded with altered oligodendrocyte lineage cell dynamics and enhanced myelination. Furthermore, consistent with increased developmental myelination, enriched mice displayed enhanced motor coordination on a beam walking task. These findings indicate that protracted environmental stimulation is sufficient to modulate developmental myelination and to promote behavioral function.

5.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33688045

RESUMO

It is hypothesized that perinatal cerebellar injury leads to long-term functional deficits due to circuit dysmaturation. Using a novel integration of GCaMP6f fiber photometry with automated measurement of cerebellar behavior using the ErasmusLadder, we causally link cerebellar injury to altered Purkinje cell responses during maladaptive behavior. Chemogenetic inhibition of neonatal Purkinje cells is sufficient to phenocopy the effects of perinatal cerebellar injury. Our results uncover a direct link between perinatal cerebellar injury and activity-dependent maturation of cerebellar cortex.


Assuntos
Doenças Cerebelares/complicações , Deficiências da Aprendizagem/etiologia , Deficiências da Aprendizagem/fisiopatologia , Células de Purkinje/patologia , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Locomoção , Camundongos , Camundongos Endogâmicos C57BL
6.
Am J Orthod Dentofacial Orthop ; 159(4): e343-e362, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33653640

RESUMO

INTRODUCTION: Research on clear aligner treatment (CAT) has increased in recent years. In this study, we aimed to perform a bibliometric and visualized analysis to identify and critically assess the 50 most highly cited articles on CAT. METHODS: Web of Science was selected as a data source and consulted until March 2020 to identify all articles potentially relevant to the analysis. All the eligible articles were collected until 50 manuscripts were listed. Article-based parameters, journal-based parameters, and author-based parameters were registered to perform the bibliometric analysis. Keywords were automatically harvested from the selected articles to implement the visualized analysis. RESULTS: The search identified a total of 378 articles; the total number of citations of the selected articles varied from 15 to 112. The average number of citations per year varied from 1.15 to 13.83. The predominant study design was clinical (31.7%). Over the 15 journals in which the most cited articles were published, the American Journal of Orthodontics and Dentofacial Orthopedics published the majority of those included in the list (14) and also received the greatest number of citations (671). A total of 195 authors contributed to the 50 most cited articles; a significant portion of them (26) were unaffiliated with academic institutions. A total of 184 keywords were gathered from the article list. CONCLUSIONS: The number of citations on CAT is expected to grow steadily in parallel with the rising number of research projects. The present work identifies the most influential articles on CAT and their characteristics, placing emphasis on the journals, the authors, and the topics addressed.


Assuntos
Aparelhos Ortodônticos Removíveis , Ortopedia , Bibliometria
7.
Nat Neurosci ; 24(3): 312-325, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589835

RESUMO

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.


Assuntos
Envelhecimento/patologia , Astrócitos/patologia , Encéfalo/patologia , Medula Espinal/patologia , Animais , Encefalopatias/patologia , Lesões Encefálicas/patologia , Humanos , Traumatismos da Medula Espinal/patologia
8.
iScience ; 23(12): 101766, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33294779

RESUMO

Acute hypoxia (HX) causes extensive cellular damage in the developing human cerebral cortex. We found increased expression of activated-EGFR in affected cortical areas of neonates with HX and investigated its functional role in the piglet, which displays a highly evolved, gyrencephalic brain, with a human-like maturation pattern. In the piglet, HX-induced activation of EGFR and Ca2+/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR blockade inhibited CaMKIV activation, attenuated neuronal loss, increased oligodendrocyte proliferation, and reversed HX-induced astrogliosis. We performed for the first time high-throughput transcriptomic analysis of the piglet cortex to define molecular responses to HX and to uncover genes specifically involved in EGFR signaling in piglet and human brain injury. Our results indicate that specific molecular responses modulated by EGFR may be targeted as a therapeutic strategy for HX injury in the neonatal brain.

9.
iScience ; 23(10): 101592, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33083751

RESUMO

Signaling pathways that promote oligodendrocyte development improve oligodendrocyte regeneration and myelin recovery from demyelinating pathologies. Sox factors critically control myelin gene expression and oligodendroglial fate, but little is known about signaling events underlying Sox-mediated oligodendroglial regeneration. In this study of the SoxF member Sox17, we demonstrate that Sox17-induced oligodendrocyte regeneration in adult myelin lesions occurs by suppressing lesion-induced Wnt/beta-catenin signaling which is inhibitory to oligodendrocyte regeneration and by increasing Sonic Hedgehog/Smoothened/Gli2 activity. Hedgehog signaling through Smoothened critically supports adult oligodendroglial viability and is an upstream regulator of beta-catenin. Gli2 ablation in adult oligodendrocyte progenitor cells indicates that Gli2 regulates beta-catenin differentially in wild-type and Sox17-overexpressing white matter. Myelin lesions in Sox17-deficient mice show beta-catenin hyperactivation, regenerative failure, and loss of oligodendrogenesis, despite exogenous Hedgehog stimulation. These studies indicate the benefit of Sox17 signaling targets to enhance oligodendrocyte regeneration after demyelination injury by modulating both Hedgehog and Wnt/beta-catenin signaling.

10.
Neuron ; 107(1): 1-3, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32645303

RESUMO

Krabbe disease is characterized by GALC deficiency and Schwann cell impairment. In a recent issue of Neuron, Weinstock et al. (2020) show that hematopoietic stem cell transplantation, an established therapy, improves pathology in a mouse model through an unexpected GALC-dependent mechanism, i.e., by providing functional macrophages capable of phagocytosis, rather than by supplying GALC for Schwann cell function.


Assuntos
Leucodistrofia de Células Globoides , Animais , Modelos Animais de Doenças , Galactosilceramidase , Humanos , Recém-Nascido , Macrófagos , Camundongos , Células de Schwann
11.
Nat Commun ; 11(1): 2138, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358570

RESUMO

Signaling molecules that regulate neurodevelopmental processes in the early postnatal subventricular zone (SVZ) are critical for proper brain development yet remain poorly characterized. Here, we report that Endothelin-1 (ET-1), a molecular component of the postnatal SVZ, promotes radial glial cell maintenance and proliferation in an autocrine manner via Notch signaling. Loss of ET-1 signaling increases neurogenesis and reduces oligodendrocyte progenitor cell proliferation (OPC) in the developing SVZ, thereby altering cellular output of the stem cell niche. We also show that ET-1 is required for increased neural stem cell and OPC proliferation in the adult mouse SVZ following demyelination. Lastly, high levels of ET-1 in the SVZ of patients with Cathepsin A-related arteriopathy with strokes and leukoencephalopathy correlate with an increased number of SVZ OPCs, suggesting ET-1's role as a regulator of glial progenitor proliferation may be conserved in humans. ET-1 signaling therefore presents a potential new therapeutic target for promoting SVZ-mediated cellular repair.


Assuntos
Endotelina-1/metabolismo , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Nicho de Células-Tronco/fisiologia , Animais , Proliferação de Células/fisiologia , Endotelina-1/genética , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Nicho de Células-Tronco/genética
12.
Nat Commun ; 11(1): 964, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075970

RESUMO

Hypoxic damage to the developing brain due to preterm birth causes many anatomical changes, including damage to the periventricular white matter. This results in the loss of glial cells, significant disruptions in myelination, and thereby cognitive and behavioral disabilities seen throughout life. Encouragingly, these neurological morbidities can be improved by environmental factors; however, the underlying cellular mechanisms remain unknown. We found that early and continuous environmental enrichment selectively enhances endogenous repair of the developing white matter by promoting oligodendroglial maturation, myelination, and functional recovery after perinatal brain injury. These effects require increased exposure to socialization, physical activity, and cognitive enhancement of surroundings-a complete enriched environment. Using RNA-sequencing, we identified oligodendroglial-specific responses to hypoxic brain injury, and uncovered molecular mechanisms involved in enrichment-induced recovery. Together, these results indicate that myelin plasticity induced by modulation of the neonatal environment can be targeted as a therapeutic strategy for preterm birth.


Assuntos
Lesões Encefálicas/reabilitação , Meio Ambiente , Neuroproteção , Substância Branca/fisiologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Modelos Animais de Doenças , Hipóxia/patologia , Hipóxia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Bainha de Mielina/fisiologia , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , RNA-Seq , Recuperação de Função Fisiológica , Substância Branca/citologia , Substância Branca/lesões , Substância Branca/metabolismo
13.
Cell Rep ; 29(10): 3173-3186.e7, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31801081

RESUMO

Sox17, a SoxF family member transiently upregulated during postnatal oligodendrocyte (OL) development, promotes OL cell differentiation, but its function in white matter development and pathology in vivo is unknown. Our analysis of oligodendroglial- and OL-progenitor-cell-targeted ablation in vivo using a floxed Sox17 mouse establishes a dependence of postnatal oligodendrogenesis on Sox17 and reveals Notch signaling as a mediator of Sox17 function. Following Sox17 ablation, reduced numbers of Olig2-expressing cells and mature OLs led to developmental hypomyelination and motor dysfunction. After demyelination, Sox17 deficiency inhibited OL regeneration. OL decline was unexpectedly preceded by transiently increased differentiation and a reduction of OL progenitor cells. Evidence of a dual role for Sox17 in progenitor cell expansion by Notch and differentiation involving TCF7L2 expression were found. A program of progenitor expansion and differentiation promoted by Sox17 through Notch thus contributes to OL production and determines the outcome of white matter repair.


Assuntos
Diferenciação Celular/genética , Proliferação de Células/genética , Proteínas HMGB/genética , Células Precursoras de Oligodendrócitos/fisiologia , Fatores de Transcrição SOXF/genética , Animais , Ciclo Celular/genética , Células Cultivadas , Doenças Desmielinizantes/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator de Transcrição 2 de Oligodendrócitos/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética
14.
J Neurodev Disord ; 11(1): 35, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31839007

RESUMO

BACKGROUND: Down syndrome (DS), caused by the triplication of chromosome 21, results in a constellation of clinical features including changes in intellectual and motor function. Although altered neural development and function have been well described in people with DS, few studies have investigated the etiology underlying the observed motor phenotypes. Here, we examine the development, patterning, and organization of the spinal cord throughout life in the Ts65Dn mouse, a model that recapitulates many of the motor changes observed in people with DS. METHODS: Spinal cords from embryonic to adult animals were processed for gene and protein expression (immunofluorescence) to track the spatiotemporal development of excitatory and inhibitory neurons and oligodendroglia. Postnatal analyses were focused on the lumbar region due to the reflex and gait abnormalities found in Ts65Dn mice and locomotive alterations seen in people with DS. RESULTS: Between embryonic days E10.5 and E14.5, we found a larger motor neuron progenitor domain in Ts65Dn animals containing more OLIG2-expressing progenitor cells. These disturbed progenitors are delayed in motor neuron production but eventually generate a large number of ISL1+ migrating motor neurons. We found that higher numbers of PAX6+ and NKX2.2+ interneurons (INs) are also produced during this time frame. In the adult lumbar spinal cord, we found an increased level of Hb9 and a decreased level of Irx3 gene expression in trisomic animals. This was accompanied by an increase in Calretinin+ INs, but no changes in other neuronal populations. In aged Ts65Dn animals, both Calbindin+ and ChAT+ neurons were decreased compared to euploid controls. Additionally, in the dorsal corticospinal white matter tract, there were significantly fewer CC1+ mature OLs in 30- and 60-day old trisomic animals and this normalized to euploid levels at 10-11 months. In contrast, the mature OL population was increased in the lateral funiculus, an ascending white matter tract carrying sensory information. In 30-day old animals, we also found a decrease in the number of nodes of Ranvier in both tracts. This decrease normalized both in 60-day old and aged animals. CONCLUSIONS: We show marked changes in both spinal white matter and neuronal composition that change regionally over the life span. In the embryonic Ts65Dn spinal cord, we observe alterations in motor neuron production and migration. In the adult spinal cord, we observe changes in oligodendrocyte maturation and motor neuron loss, the latter of which has also been observed in human spinal cord tissue samples. This work uncovers multiple cellular perturbations during Ts65Dn development and aging, many of which may underlie the motor deficits found in DS.


Assuntos
Síndrome de Down/fisiopatologia , Neuroglia/fisiologia , Neurônios/fisiologia , Medula Espinal/crescimento & desenvolvimento , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos Transgênicos , Substância Branca/crescimento & desenvolvimento
16.
J Am Heart Assoc ; 8(15): e012711, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31331224

RESUMO

Background Reduced oxygen delivery in congenital heart disease causes delayed brain maturation and white matter abnormalities in utero. No treatment currently exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon NOS activation, such as during hypoxic conditions, and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and that BH4 replacement therapy mitigates the toxic effects of hypoxia on white matter. Methods and Results Transgenic mice were used to visualize oligodendrocytes. Hypoxia was introduced during a period of white matter development equivalent to the human third trimester. BH4 was administered during hypoxia. BH4 levels were depleted in the hypoxic brain by direct quantification (n=7-12). The proliferation (n=3-6), apoptosis (n=3-6), and developmental stage (n=5-8) of oligodendrocytes were determined immunohistologically. Total oligodendrocytes increased after hypoxia, consistent with hypoxia-induced proliferation seen previously; however, mature oligodendrocytes were less prevalent in hypoxia, and there was accumulation of immature oligodendrocytes. BH4 treatment improved the mature oligodendrocyte number such that it did not differ from normoxia, and accumulation of immature oligodendrocytes was not observed. These results persisted beyond the initial period of hypoxia (n=3-4). Apoptosis increased with hypoxia but decreased with BH4 treatment to normoxic levels. White matter myelin levels decreased following hypoxia by western blot. BH4 treatment normalized myelination (n=6-10). Hypoxia worsened sensory-motor coordination on balance beam tasks, and BH4 therapy normalized performance (n=5-9). Conclusions Suboptimal BH4 levels influence hypoxic white matter abnormalities. Repurposing BH4 for use during fetal brain development may limit white matter dysmaturation in congenital heart disease.


Assuntos
Biopterina/análogos & derivados , Doenças Fetais/fisiopatologia , Cardiopatias/congênito , Cardiopatias/fisiopatologia , Hipóxia/fisiopatologia , Substância Branca/efeitos dos fármacos , Substância Branca/crescimento & desenvolvimento , Animais , Biopterina/farmacologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos
17.
Nat Rev Neurosci ; 20(5): 298-313, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30923348

RESUMO

The human cerebellum has a protracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neurological disorders. As the cerebellum is critical for motor behaviour, it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However, evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non-motor function, including cognition and emotion. More recently, evidence indicates that major neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, attention-deficit hyperactivity disorder and Down syndrome have potential links to abnormal cerebellar development. Out of recent findings from clinical and preclinical studies, the concept of the 'cerebellar connectome' has emerged that can be used as a framework to link the role of cerebellar development to human behaviour, disease states and the design of better therapeutic strategies.


Assuntos
Cerebelo/crescimento & desenvolvimento , Cerebelo/fisiopatologia , Conectoma , Rede Nervosa/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Animais , Humanos
18.
Trends Neurosci ; 42(3): 192-204, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616953

RESUMO

Congenital heart disease (CHD) is among the most common birth defects. Children with CHD frequently display long-term intellectual and behavioral disability. Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact on the maturation of cerebral regions responsible for higher-order cognitive functions. In this review we focus on the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD. Further understanding of the mechanisms underlying cortical dysmaturation due to CHD will be necessary to identify strategies for neonatal neuroprotection and for mitigating developmental delays in this patient population.


Assuntos
Comportamento/fisiologia , Disfunção Cognitiva/fisiopatologia , Cardiopatias Congênitas/metabolismo , Neurogênese/fisiologia , Encéfalo/crescimento & desenvolvimento , Disfunção Cognitiva/complicações , Humanos , Neurônios/metabolismo
19.
Neurobiol Learn Mem ; 165: 106861, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-29723669

RESUMO

The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While there is a wealth of knowledge on the development of locomotor behavior in human infants, children, and adolescents, pre-clinical animal models have fallen behind on the study of the emergence of behavioral motifs in locomotor function across postnatal development. Since cerebellar development is protracted, it is subject to higher risk of genetic or environmental disruption, potentially leading to abnormal behavioral development. This highlights the need for more sophisticated and specific functional analyses of adaptive cerebellar behavior within the context of whole-body locomotion across the entire span of postnatal development. Here we review evidence on cerebellar contribution to adaptive locomotor behavior, highlighting methodologies employed to quantify and categorize behavior at different developmental stages, with the ultimate goal of following the course of early behavioral alterations in neurodevelopmental disorders. Since experimental paradigms used to study cerebellar behavior are lacking in both specificity and applicability to locomotor contexts, we highlight the use of the Erasmus Ladder - an advanced, computerized, fully automated system to quantify adaptive cerebellar learning in conjunction with locomotor function. Finally, we emphasize the need to develop objective, quantitative, behavioral tasks which can track changes in developmental trajectories rather than endpoint measurement at the adult stage of behavior.


Assuntos
Cerebelo/fisiologia , Locomoção/fisiologia , Animais , Cerebelo/crescimento & desenvolvimento , Humanos , Transtornos do Neurodesenvolvimento/fisiopatologia
20.
Nat Commun ; 9(1): 3235, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104642

RESUMO

Premature infants are more likely to develop locomotor disorders than term infants. In a chronic sub-lethal hypoxia (Hx) mouse model of neonatal brain injury, we recently demonstrated the presence of cellular and physiological changes in the cerebellar white matter. We also observed Hx-induced delay in Purkinje cell (PC) arborization. However, the behavioral consequences of these cellular alterations remain unexplored. Using the Erasmus Ladder to study cerebellar behavior, we report the presence of locomotor malperformance and long-term cerebellar learning deficits in Hx mice. Optogenetics experiments in Hx mice reveal a profound reduction in spontaneous and photoevoked PC firing frequency. Finally, treatment with a gamma-aminobutyric acid (GABA) reuptake inhibitor partially rescues locomotor performance and improves PC firing. Our results demonstrate a long-term miscoordination phenotype characterized by locomotor malperformance and cerebellar learning deficits in a mouse model of neonatal brain injury. Our findings also implicate the developing GABA network as a potential therapeutic target for prematurity-related locomotor deficits.


Assuntos
Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Aprendizagem , Células de Purkinje/patologia , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal , Cerebelo/efeitos dos fármacos , Feminino , Inibidores da Captação de GABA/farmacologia , Integrases/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Células de Purkinje/efeitos dos fármacos , Tiagabina/farmacologia
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