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INTRODUCTION: Our laboratory has been exploring the MRI detection of fetal brain injury, which previously provided a prognostic biomarker for newborn hypertonia in an animal model of cerebral palsy (CP). The biomarker relies on distinct patterns of diffusion-weighted imaging-defined apparent diffusion coefficient (ADC) in fetal brains during uterine hypoxia-ischemia (H-I). Despite the challenges posed by small brains and tissue acquisition, our objective was to differentiate between left and right brain ADC changes. METHODS: A novel aspect involved utilizing three-dimensional rendering techniques to refine ADC measurements within spheroids encompassing fetal brain tissue. 25-day gestation age of rabbit fetuses underwent global hypoxia due to maternal uterine ischemia. RESULTS: Successful differentiation of left and right brain regions was achieved in 28% of the fetal brains. Ordinal analysis revealed predominantly higher ADC on the left side compared to the right at baseline and across the entire time series. During H-I and reperfusion-reoxygenation, the right side exhibited a favored percentage change. Among these fetal brains, 73% exhibited the ADC pattern predictive of hypertonia. No significant differences between left and right sides were observed in patterns predicting hypertonia, except for one timepoint during H-I. This study also highlights a balance between left-sided and right-sided alterations within the population. CONCLUSION: This study emphasizes the importance of investigating laterality and asymmetric hemispheric lesions for early diagnosis of brain injury, leading to CP. The technological limitations in obtaining a clear picture of the entire fetal brain for every fetus mirror the challenges encountered in human studies.
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BACKGROUND: Fetal growth restriction (FGR) corresponds to the fetus's inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality. SUMMARY: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies. KEY MESSAGES: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients.
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It is well established that sevoflurane exposure leads to widespread neuronal cell death in the developing brain. Adenosine deaminase acting on RNA-1 (ADAR1) dependent adenosine-to-inosine (A-to-I) RNA editing is dynamically regulated throughout brain development. The current investigation is designed to interrogate the contributed role of ADAR1 in developmental sevoflurane neurotoxicity. Herein, we provide evidence to show that developmental sevoflurane priming triggers neuronal pyroptosis, apoptosis and necroptosis (PANoptosis), and elicits the release of inflammatory factors including IL-1ß, IL-18, TNF-α and IFN-γ. Additionally, ADAR1-P150, but not ADAR1-P110, depresses cellular PANoptosis and inflammatory response by competing with Z-DNA/RNA binding protein 1 (ZBP1) for binding to Z-RNA in the presence of sevoflurane. Further investigation demonstrates that ADAR1-dependent A-to-I RNA editing mitigates developmental sevoflurane-induced neuronal PANoptosis. To restore RNA editing, we utilize adeno-associated virus (AAV) to deliver engineered circular ADAR-recruiting guide RNAs (cadRNAs) into cells, which is capable of recruiting endogenous adenosine deaminases to promote cellular A-to-I RNA editing. As anticipated, AAV-cadRNAs diminishes sevoflurane-induced cellular Z-RNA production and PANoptosis, which could be abolished by ADAR1-P150 shRNA transfection. Moreover, AAV-cadRNAs delivery ameliorates developmental sevoflurane-induced spatial and emotional cognitive deficits without influence on locomotor activity. Taken together, these results illustrate that ADAR1-P150 exhibits a prominent role in preventing ZBP1-dependent PANoptosis through A-to-I RNA editing in developmental sevoflurane neurotoxicity. Application of engineered cadRNAs to rectify the compromised ADAR1-dependent A-to-I RNA editing provides an inspiring direction for possible clinical preventions and therapeutics.
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Adenosina Desaminasa , Adenosina , Edición de ARN , Proteínas de Unión al ARN , Sevoflurano , Animales , Adenosina/metabolismo , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Apoptosis/efectos de los fármacos , Inosina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/metabolismo , Piroptosis/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genéticaRESUMEN
Electroencephalography measures are of interest in developmental neuroscience as potentially reliable clinical markers of brain function. Features extracted from electroencephalography are most often averaged across individuals in a population with a particular condition and compared statistically to the mean of a typically developing group, or a group with a different condition, to define whether a feature is representative of the populations as a whole. However, there can be large variability within a population, and electroencephalography features often change dramatically with age, making comparisons difficult. Combined with often low numbers of trials and low signal-to-noise ratios in pediatric populations, establishing biomarkers can be difficult in practice. One approach is to identify electroencephalography features that are less variable between individuals and are relatively stable in a healthy population during development. To identify such features in resting-state electroencephalography, which can be readily measured in many populations, we introduce an innovative application of statistical measures of variance for the analysis of resting-state electroencephalography data. Using these statistical measures, we quantified electroencephalography features commonly used to measure brain development-including power, connectivity, phase-amplitude coupling, entropy, and fractal dimension-according to their intersubject variability. Results from 51 6-month-old infants revealed that the complexity measures, including fractal dimension and entropy, followed by connectivity were the least variable features across participants. This stability was found to be greatest in the right parietotemporal region for both complexity feature, but no significant region of interest was found for connectivity feature. This study deepens our understanding of physiological patterns of electroencephalography data in developing brains, provides an example of how statistical measures can be used to analyze variability in resting-state electroencephalography in a homogeneous group of healthy infants, contributes to the establishment of robust electroencephalography biomarkers of neurodevelopment through the application of variance analyses, and reveals that nonlinear measures may be most relevant biomarkers of neurodevelopment.
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Encéfalo , Electroencefalografía , Niño , Humanos , Lactante , Electroencefalografía/métodos , Encéfalo/fisiología , Entropía , BiomarcadoresRESUMEN
Understanding the intricate nanoscale architecture of neuronal myelin during central nervous system development is of utmost importance. However, current visualization methods heavily rely on electron microscopy or indirect fluorescent method, lacking direct and real-time imaging capabilities. Here, we introduce a breakthrough near-infrared emissive curcumin-BODIPY derivative (MyL-1) that enables direct visualization of myelin structure in brain tissues. The remarkable compatibility of MyL-1 with stimulated emission depletion nanoscopy allows for unprecedented super-resolution imaging of myelin ultrastructure. Through this innovative approach, we comprehensively characterize the nanoscale myelinogenesis in three dimensions over the course of brain development, spanning from infancy to adulthood in mouse models. Moreover, we investigate the correlation between myelin substances and Myelin Basic Protein (MBP), shedding light on the essential role of MBP in facilitating myelinogenesis during vertebral development. This novel material, MyL-1, opens up new avenues for studying and understanding the intricate process of myelinogenesis in a direct and non-invasive manner, paving the way for further advancements in the field of nanoscale neuroimaging.
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Compuestos de Boro , Curcumina , Animales , Ratones , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Neuronas , Microscopía ElectrónicaRESUMEN
Multifaceted microglial functions in the developing brain, such as promoting the differentiation of neural progenitors and contributing to the positioning and survival of neurons, have been progressively revealed. Although previous studies have noted the relationship between vascular endothelial cells and microglia in the developing brain, little attention has been given to the importance of pericytes, the mural cells surrounding endothelial cells. In this study, we attempted to dissect the role of pericytes in microglial distribution and function in developing mouse brains. Our immunohistochemical analysis showed that approximately half of the microglia attached to capillaries in the cerebral walls. Notably, a magnified observation of the position of microglia, vascular endothelial cells and pericytes demonstrated that microglia were preferentially associated with pericytes that covered 79.8% of the total capillary surface area. Through in vivo pericyte depletion induced by the intraventricular administration of a neutralizing antibody against platelet-derived growth factor receptor (PDGFR)ß (clone APB5), we found that microglial density was markedly decreased compared with that in control antibody-treated brains because of their low proliferative capacity. Moreover, in vitro coculture of isolated CD11b+ microglia and NG2+PDGFRα- cells, which are mostly composed of pericytes, from parenchymal cells indicated that pericytes promote microglial proliferation via the production of soluble factors. Furthermore, pericyte depletion by APB5 treatment resulted in a failure of microglia to promote the differentiation of neural stem cells into intermediate progenitors. Taken together, our findings suggest that pericytes facilitate microglial homeostasis in the developing brains, thereby indirectly supporting microglial effects on neural progenitors.SIGNIFICANCE STATEMENT This study highlights the novel effect of pericytes on microglia in the developing mouse brain. Through multiple analyses using an in vivo pericyte depletion mouse model and an in vitro coculture study of isolated pericytes and microglia from parenchymal cells, we demonstrated that pericytes contribute to microglial proliferation and support microglia in efficiently promoting the differentiation of neural stem cells into intermediate progenitors. Our present data provide evidence that pericytes function not only in the maintenance of cerebral microcirculation and blood brain barrier (BBB) integrity but also in microglial homeostasis in the developing cerebral walls. These findings will expand our knowledge and help elucidate the mechanism of brain development both in healthy and disease conditions.
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Corteza Cerebral/citología , Homeostasis/fisiología , Microglía/citología , Células-Madre Neurales/citología , Pericitos/citología , Animales , Anticuerpos Neutralizantes , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/embriología , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/embriología , Ácido Clodrónico/farmacología , Homeostasis/efectos de los fármacos , Liposomas , Ratones , Microglía/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Pericitos/efectos de los fármacos , Receptor beta de Factor de Crecimiento Derivado de PlaquetasRESUMEN
Throughout our lives, we are exposed to a variety of hazards, such as environmental pollutants and chemical substances that affect our health, and viruses and bacteria that cause infectious diseases. These external factors that are undesirable to an organism are called environmental stress. During the perinatal period, when neural networks are drastically reorganized and refined, the tolerance of the developing brain to various environmental stresses is lower than in adulthood. Thus, exposure to environmental stress during this vulnerable period is strongly associated with cognitive and behavioral deficits in later life. Recent studies have uncovered various mechanisms underlying the adverse impacts of environmental stress during the perinatal period on brain development. In this mini-review, we will present the findings from these studies, focusing on caspase-mediated apoptotic and nonapoptotic effects of environmental stress, and discuss several compounds that mitigate these caspase-mediated effects as examples of potential therapeutic approaches.
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Encéfalo , Etanol , Embarazo , Femenino , Humanos , Caspasa 3/farmacología , Caspasas/farmacologíaRESUMEN
While the majority of studies on the importance of parental caregiving on offspring behavioral and brain development focus on the role of the mother, the paternal contribution is still an understudied topic. We investigated if growing up without paternal care affects dendritic and synaptic development in the nucleus accumbens of male and female offspring and if replacement of the father by a female caregiver "compensates" the impact of paternal deprivation. We compared (a) biparental rearing by father and mother, (b) monoparental care by a single mother, and (c) biparental rearing by two female caregivers. Quantitative analysis of medium-sized neurons in the nucleus accumbens revealed that growing up without father resulted in reduced spine number in both male and female offspring in the core region, whereas spine frequency was only reduced in females. In the shell region, reduced spine frequency was only found in males growing up in a monoparental environment. Replacement of the father by a female caregiver did not "protect" against the effects of paternal deprivation, indicating a critical impact of paternal care behavior on the development and maturation of neuronal networks in the nucleus accumbens.
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Octodon , Humanos , Animales , Masculino , Femenino , Octodon/fisiología , Núcleo Accumbens , Privación Paterna , Neuronas , MadresRESUMEN
Alterations in the expression of genes encoding proteins involved in synapse formation, maturation, and function are a hallmark of many neurodevelopmental and psychiatric disorders. For example, there is reduced neocortical expression of the MET receptor tyrosine kinase (MET) transcript and protein in Autism Spectrum Disorder (ASD) and Rett syndrome. Preclinical in vivo and in vitro models manipulating MET signaling reveal that the receptor modulates excitatory synapse development and maturation in select forebrain circuits. The molecular adaptations underlying the altered synaptic development remain unknown. We performed a comparative mass spectrometry analysis of synaptosomes generated from the neocortex of wild type and Met null mice during the peak of synaptogenesis (postnatal day 14; data are available from ProteomeXchange with identifier PXD033204). The analyses revealed broad disruption of the developing synaptic proteome in the absence of MET, consistent with the localization of MET protein in pre- and postsynaptic compartments, including proteins associated with the neocortical synaptic MET interactome and those encoded by syndromic and ASD risk genes. In addition to an overrepresentation of altered proteins associated with the SNARE complex, multiple proteins in the ubiquitin-proteasome system and associated with the synaptic vesicle, as well as proteins that regulate actin filament organization and synaptic vesicle exocytosis/endocytosis, were disrupted. Taken together, the proteomic changes are consistent with structural and functional changes observed following alterations in MET signaling. We hypothesize that the molecular adaptations following Met deletion may reflect a general mechanism that produces circuit-specific molecular changes due to loss or reduction of synaptic signaling proteins.
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Trastorno del Espectro Autista , Neocórtex , Ratones , Animales , Sinaptosomas/metabolismo , Proteoma/metabolismo , Trastorno del Espectro Autista/genética , Proteómica/métodos , Sinapsis/metabolismoRESUMEN
The potential neurotoxic impact of anaesthetic agents has been the subject of sustained debate and continuing research. White matter, which comprises more than half of the brain volume and largely consists of myelinated axonal bundles, is critical for communication between diverse brain regions and for supporting neurobehavioural function. Evidence points to a correlation between exposure to anaesthesia and white matter alterations, which might underpin the ensuing cognitive and behavioural abnormalities. This review summarises the neuropathological and neuroimaging findings related to anaesthesia-induced white matter alterations in the developing brain. Future research is required to understand the effects of anaesthesia exposure on white matter development.
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Enfermedades del Sistema Nervioso , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Encéfalo/patología , Anestesia General , NeuroimagenRESUMEN
Normal visual development is supported by intrinsic neurobiological mechanisms and by appropriate stimulation from the environment, both of which facilitate the maturation of visual functions. However, an offset of this balance can give rise to visual disorders. Therefore, understanding the factors that support normal vision during development and in the mature brain is important, as vision guides movement, enables social interaction, and allows children to recognize and understand their environment. In this paper, we review fundamental mechanisms that support the maturation of visual functions and discuss and draw links between the perceptual and neurobiological impairments in autism spectrum disorder (ASD) and schizophrenia. We aim to explore how this is evident in the case of ASD, and how perceptual and neurobiological deficits further degrade social ability. Furthermore, we describe the altered perceptual experience of those with schizophrenia and evaluate theories of the underlying neural deficits that alter perception.
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Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Niño , Humanos , Encéfalo , Movimiento , Interacción SocialRESUMEN
The first documented pediatric use of Electroconvulsive therapy (ECT) occurred in Europe in 1941. Since then, predominantly successful treatments and reasonable side effects have been reported in severely ill minors. Nevertheless, a shy reluctance determines the controversy about ECT in young patients. This study describes the use of ECT in children and adolescents in Europe. We systematically searched the literature concerning the practice of ECT in minors in all 53 European countries. In addition, we surveyed European experts about national practices and compared guidelines for ECT in minors. The search yielded 79 publications from 18 European countries, mainly from Western Europe, Israel, and Turkey. National data were available from eight countries. These showed an interestingly high relationship between the number of minors treated with ECT and the general use of ECT. No persistent deficits or deaths were reported. On the other hand, no randomized clinical trial was found, and many publications lacked relevant information. Accordingly, the appraisal of the evidence in the guidelines varies considerably. Experts from 13 European countries consistently reported infrequent and unsystematic use of ECT in minors. ECT has been used successfully in minors in Europe with reasonable complications and side effects. Adverse effects on the developing brain, as often suspected, have not been scientifically supported in eight decades. Nevertheless, the use of ECT in Europe is sparse and dependent on accidental circumstances. High-quality evidence is needed, as well as improved knowledge and training of child and adolescent psychiatrists.
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Inhaled nitric oxide (iNO) is a therapy used in neonates with pulmonary hypertension. Some evidence of its neuroprotective properties has been reported in both mature and immature brains subjected to injury. NO is a key mediator of the VEGF pathway, and angiogenesis may be involved in the reduced vulnerability to injury of white matter and the cortex conferred by iNO. Here, we report the effect of iNO on angiogenesis in the developing brain and its potential effectors. We found that iNO promotes angiogenesis in the developing white matter and cortex during a critical window in P14 rat pups. This shift in the developmental program of brain angiogenesis was not related to a regulation of NO synthases by exogenous NO exposure, nor the VEGF pathway or other angiogenic factors. The effects of iNO on brain angiogenesis were found to be mimicked by circulating nitrate/nitrite, suggesting that these carriers may play a role in transporting NO to the brain. Finally, our data show that the soluble guanylate cyclase/cGMP signaling pathway is likely to be involved in the pro-angiogenetic effect of iNO through thrombospondin-1, a glycoprotein of the extracellular matrix, inhibiting soluble guanylate cyclase through CD42 and CD36. In conclusion, this study provides new insights into the biological basis of the effect of iNO in the developing brain.
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Óxido Nítrico , Roedores , Animales , Ratas , Óxido Nítrico/metabolismo , Animales Recién Nacidos , Roedores/metabolismo , Guanilil Ciclasa Soluble/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Encéfalo/metabolismo , Administración por InhalaciónRESUMEN
The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development could be a crucial factor in neurodevelopmental disorders of prematurity. Recent studies have focused on dexmedetomidine (DEX), which has been associated with potential neuroprotective properties and is used as an off-label application in neonatal units. Wistar rats (P6) were exposed to 80% hyperoxia for 24 h and received as pretreatment a single dose of DEX (5µg/kg, i.p.). Analyses in the immature rat cerebellum immediately after hyperoxia (P7) and after recovery to room air (P9, P11, and P14) included examinations for cell death and inflammatory and oxidative responses. Acute exposure to high oxygen concentrations caused a significant oxidative stress response, with a return to normal levels by P14. A marked reduction of hyperoxia-mediated damage was demonstrated after DEX pretreatment. DEX produced a much earlier recovery than in controls, confirming a neuroprotective effect of DEX on alterations elicited by oxygen stress on the developing cerebellum.
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Dexmedetomidina , Hiperoxia , Recién Nacido , Animales , Ratas , Humanos , Hiperoxia/complicaciones , Hiperoxia/tratamiento farmacológico , Ratas Wistar , Animales Recién Nacidos , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Recien Nacido Prematuro , Apoptosis , Estrés Oxidativo , Oxígeno/farmacología , InterneuronasRESUMEN
Burst discharges in the immature brain may contribute to its enhanced seizure susceptibility. The cellular mechanisms underlying burst discharges in the CA1 area of the immature versus adult hippocampus were investigated with simultaneous whole-cell and field-potential recordings. When GABAA receptors were blocked pharmacologically, bursts in CA1 were either graded or all-or-none (or mixed) as a function of electrical stimulation intensity. Most CA1 minislices from immature rats displayed all-or-none or mixed bursts, whereas the slices from adult rats predominantly elicited graded bursts. The frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) were greater in CA1 pyramidal cells from the immature than the adult slices. The developmental differences in CA1 bursting were also detected in slices adjusted for maturational changes in brain volume (i.e., 350 µm thick for immature vs. 450 µm thick for adult rats). Neither N-methyl-d-aspartate (NMDA) nor group I metabotropic glutamate (mGlu1) receptor antagonists blocked the network-driven bursts in immature CA1, but an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker abolished them. Robust excitatory postsynaptic potentials (EPSPs) occurred after bursts in some immature CA1 slices (23%) but never in slices from the adult. The input-output (amount of current injected vs. number of action potentials generated) relationship was markedly greater in CA1 pyramidal cells in the immature compared with the adult hippocampus. These data suggest that the CA1 area of the immature brain is capable of generating network-driven bursts, which declines in adult rats. The increased propensity of burst generation in immature CA1 appears to involve a greater AMPA receptor-mediated synaptic network and an increased intrinsic spike-generating ability.NEW & NOTEWORTHY Burst discharges in the developing brain can provide valuable insights into epileptogenesis. We show that the immature hippocampal CA1 area is capable of generating all-or-none (i.e., network) bursts, which transitions to graded (i.e., nonnetwork) bursts in the mature brain via both synaptic and intrinsic mechanisms. Our results provide new clues to help understand possible mechanisms that may be shared in the immature and epileptic brain and how the normal brain becomes seizure prone (i.e., epileptogenesis).
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Región CA1 Hipocampal , Convulsiones , Animales , Ratas , Región CA1 Hipocampal/fisiología , Región CA1 Hipocampal/fisiopatología , Potenciales Postsinápticos Excitadores , Células Piramidales , Factores de EdadRESUMEN
Early-life experiences are critical modifiers of development. An important component of early-life experience is the nature of maternal interactions, which can be modified by stress. During rearing, mothers are typically allocated to single-level cages where they are readily accessible to pups, a potentially stressful scenario not reflective of nature. Accordingly, mothers regularly removed from the rearing environment interact differently with their offspring, leading to long-term changes in offspring physiology and behavior. Such changes commonly include modifications within the hypothalamic-pituitary-adrenal axis, of which corticosterone is a major component. Modifications in the hypothalamic-pituitary-adrenal axis may also be manifested through changes in affective behavior and assessed via tests such as the open field and elevated plus maze as well as via ultrasonic vocalization (USV) analysis. As a means of assessing the impact of rearing in a shelved environment, we allocated mothers to standard single-level cages or cages with an integrated shelf, which allowed the mother to temporarily escape pups. While there were no differences in fecal cortico-sterone, behavior in the elevated plus maze, or USVs, male rats reared in standard cages weighed more, and all standard single-level housed rats spent more time in the center of the open field. The observed differences indicate that allocating nursing mothers to shelved environments throughout the postnatal period has long-lasting effects on offspring behavior that must be considered when establishing dam enrichment protocols.
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Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Ratas , Animales , Masculino , Humanos , Femenino , Corticosterona , Conducta Animal/fisiología , Conducta Materna/fisiología , Estrés PsicológicoRESUMEN
Intrauterine hypoxia is a common cause of brain injury in children resulting in a broad spectrum of long-term neurodevelopmental sequela, including life-long disabilities that can occur even in the absence of severe neuroanatomic damage. Postnatal hypoxia-ischemia rodent models are commonly used to understand the effects of ischemia and transient hypoxia on the developing brain. Postnatal models, however, have some limitations. First, they do not test the impact of placental pathologies on outcomes from hypoxia. Second, they primarily recapitulate severe injury because they provoke substantial cell death, which is not seen in children with mild hypoxic injury. Lastly, they do not model preterm hypoxic injury. Prenatal models of hypoxia in mice may allow us to address some of these limitations to expand our understanding of developmental brain injury. The published rodent models of prenatal hypoxia employ multiple days of hypoxic exposure or complicated surgical procedures, making these models challenging to perform consistently in mice. Furthermore, large animal models suggest that transient prenatal hypoxia without ischemia is sufficient to lead to significant functional impairment to the developing brain. However, these large animal studies are resource-intensive and not readily amenable to mechanistic molecular studies. Therefore, here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia (5% inspired oxygen) on long-term anatomical and neurodevelopmental outcomes in mice. Late gestation transient prenatal hypoxia increased hypoxia-inducible factor 1 alpha protein levels (a marker of hypoxic exposure) in the fetal brain. Hypoxia exposure predisposed animals to decreased weight at postnatal day 2, which normalized by day 8. However, hypoxia did not affect gestational age at birth, litter size at birth, or pup survival. No differences in fetal brain cell death or long-term gray or white matter changes resulted from hypoxia. Animals exposed to prenatal hypoxia did have several long-term functional consequences, including sex-dichotomous changes. Hypoxia exposure was associated with a decreased seizure threshold and abnormalities in hindlimb strength and repetitive behaviors in males and females. Males exposed to hypoxia had increased anxiety-related deficits, whereas females had deficits in social interaction. Neither sex developed any motor or visual learning deficits. This study demonstrates that late gestation transient prenatal hypoxia in mice is a simple, clinically relevant paradigm for studying putative environmental and genetic modulators of the long-term effects of hypoxia on the developing brain.
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Lesiones Encefálicas , Placenta , Animales , Animales Recién Nacidos , Encéfalo/patología , Lesiones Encefálicas/patología , Modelos Animales de Enfermedad , Femenino , Hipoxia , Masculino , Ratones , Embarazo , ConvulsionesRESUMEN
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant with high mortality and morbidity. Children who survive NEC have been shown to demonstrate neurodevelopmental delay, with significantly worse outcomes than from prematurity alone. The pathways leading to NEC-associated neurological impairments remain unclear, limiting the development of preventative and protective strategies. This review aims to summarize the existing clinical and experimental studies related to NEC-associated brain injury. We describe the current epidemiology of NEC, reported long-term neurodevelopmental outcomes among survivors, and proposed pathogenesis of brain injury in NEC. Highlighted are the potential connections between hypoxia-ischemia, nutrition, infection, gut inflammation, and the developing brain in NEC.
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Lesiones Encefálicas , Enterocolitis Necrotizante , Enfermedades del Recién Nacido , Enfermedades del Prematuro , Niño , Enterocolitis Necrotizante/etiología , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/etiologíaRESUMEN
Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the life span have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains, we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice, we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice, the distalmost apical branches were missing or reduced in number, but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.
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Síndrome de Down , Neocórtex , Animales , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis , Células Piramidales/patologíaRESUMEN
Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and a significant contributor to Autism Spectrum Disorder. Individuals with FXS are subject to developing numerous comorbidities, one of the most prevalent being seizures. In the present study, we investigated how seizures affected neonatal communicative behavior in the FXS mouse model. On postnatal day (PD) 7 through 11, we administered 3 flurothyl seizures per day to both Fmr1 knockout and wild-type C57BL/6J male mice. Ultrasonic vocalizations were recorded on PD12. Statistically significant alterations were found in both spectral and temporal measurements across seizure groups. We found that induction of seizures across PD7-11 resulted in an increased fundamental frequency (pitch) of ultrasonic vocalizations produced (p < 0.05), a longer duration of calls (p < 0.05), and a greater cumulative duration of calls (p < 0.05) in both genotypes. Induction of seizures across PD7-11 also resulted in a decreased latency to the first emitted vocalization (p < 0.05) and a decrease in mean power (loudness) for their vocalizations (p < 0.05). Early-life seizures also resulted in an increase in the number of downward and frequency step call types (p < 0.05). There was a significant increase in the number of chevron calls emitted from the Fmr1 knockout mice that received seizures compared to knockout control and wild-type seizure mice (p < 0.05). Overall, this study provides evidence that early-life seizures result in communication impairments and that superimposing seizures in Fmr1 knockout mice does produce an additional deficit in vocalization.