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BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.
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Anestesia General , Encéfalo , Electroencefalografía , Red Nerviosa , Humanos , Lactante , Masculino , Femenino , Encéfalo/crecimiento & desarrollo , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Anestesia General/efectos adversos , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Red Nerviosa/crecimiento & desarrollo , Desarrollo Infantil/efectos de los fármacos , Desarrollo Infantil/fisiologíaRESUMEN
We examine the efficiency of information processing in a balanced excitatory and inhibitory (E-I) network during the developmental critical period, when network plasticity is heightened. A multimodule network composed of E-I neurons was defined, and its dynamics were examined by regulating the balance between their activities. When adjusting E-I activity, both transitive chaotic synchronization with a high Lyapunov dimension and conventional chaos with a low Lyapunov dimension were found. In between, the edge of high-dimensional chaos was observed. To quantify the efficiency of information processing, we applied a short-term memory task in reservoir computing to the dynamics of our network. We found that memory capacity was maximized when optimal E-I balance was realized, underscoring both its vital role and vulnerability during critical periods of brain development.
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An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI) can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil, a commercially available AChEI, can enable recovery in older children and adults with residual amblyopia. In this open-label pilot efficacy study, 16 participants (mean age 16 years; range 9-37 years) with residual anisometropic and/or strabismic amblyopia were treated with daily oral donepezil for 12 weeks. Donepezil dosage was started at 2.5 or 5.0 mg based on age and increased by 2.5 mg if the amblyopic eye visual acuity did not improve by 1 line from the visit 4 weeks prior for a maximum dosage of 7.5 or 10 mg. Participants < 18 years of age further patched the dominant eye. The primary outcome was visual acuity in the amblyopic eye at 22 weeks, 10 weeks after treatment was discontinued. Mean amblyopic eye visual acuity improved 1.2 lines (range 0.0-3.0), and 4/16 (25%) improved by ≥ 2 lines after 12 weeks of treatment. Gains were maintained 10 weeks after cessation of donepezil and were similar for children and adults. Adverse events were mild and self-limited. Residual amblyopia improves in older children and adults treated with donepezil, supporting the concept that the critical window of visual cortical plasticity can be pharmacologically manipulated to treat amblyopia. Placebo-controlled studies are needed.
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Ambliopía , Animales , Ratones , Acetilcolinesterasa , Ambliopía/tratamiento farmacológico , Donepezilo/uso terapéutico , Agudeza VisualRESUMEN
Early-life experience enduringly sculpts thalamocortical (TC) axons and sensory processing. Here, we identify the very first synaptic targets that initiate critical period plasticity, heralded by altered cortical oscillations. Monocular deprivation (MD) acutely induced a transient (<3 h) peak in EEG γ-power (~40 Hz) specifically within the visual cortex, but only when the critical period was open (juvenile mice or adults after dark-rearing, Lynx1-deletion, or diazepam-rescued GAD65-deficiency). Rapid TC input loss onto parvalbumin-expressing (PV) inhibitory interneurons (but not onto nearby pyramidal cells) was observed within hours of MD in a TC slice preserving the visual pathway - again once critical periods opened. Computational TC modeling of the emergent γ-rhythm in response to MD delineated a cortical interneuronal gamma (ING) rhythm in networks of PV-cells bearing gap junctions at the start of the critical period. The ING rhythm effectively dissociated thalamic input from cortical spiking, leading to rapid loss of previously strong TC-to-PV connections through standard spike-timing-dependent plasticity rules. As a consequence, previously silent TC-to-PV connections could strengthen on a slower timescale, capturing the gradually increasing γ-frequency and eventual fade-out over time. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after MD. Taken together, our findings reveal the initial synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe developmental trajectories.
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Ritmo Gamma , Interneuronas , Ratones , Animales , Ritmo Gamma/fisiología , Interneuronas/fisiología , Células Piramidales/fisiología , Uniones Comunicantes , Parvalbúminas , Plasticidad Neuronal/fisiologíaRESUMEN
Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.
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Acetilcisteína , Lesiones Traumáticas del Encéfalo , Ratas , Animales , Acetilcisteína/farmacología , Acetilcisteína/metabolismo , Parvalbúminas/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Estrés Oxidativo/fisiología , Interneuronas/metabolismoRESUMEN
BACKGROUND: Tactile sensitivity in the infant period is poorly characterized, particularly among children with prior surgery, anaesthesia or critical illness. The study aims were to investigate tactile sensitivity of the foot and the associated coordination of lower limb motor movement in typically developing infants with and without prior hospital experience, and to develop feasible bedside sensory testing protocols. MATERIALS AND METHODS: A prospective, longitudinal study in 69 infants at 2 and 4 months-old, with and without prior hospital admission. Mechanical stimuli were applied to the foot at graded innocuous and noxious intensities. Primary outcome measures were tactile and nociceptive threshold (lowest force required to evoke any leg movement, or brisk leg withdrawal, respectively), and specific motor flexion threshold (ankle-, knee-, hip-flexion). Secondary analysis investigated (i) single vs multiple trials reliability, and (ii) the effect of age and prior surgery, anaesthesia, or critical illness on mechanical threshold. RESULTS: Magnitude of evoked motor activity increased with stimulus intensity. Single trials had excellent reliability for knee and hip flexion at age 1-3m and 4-7m (ICC range: 0.8 to 0.98, p >0.05). Nociceptive threshold varied as a function of age. Tactile sensitivity was independent of age, number of surgeries, general anaesthesia and ICU stay. CONCLUSIONS: This brief sensory testing protocol may reliably measure tactile and nociceptive reactivity in human infants. Age predicts nociceptive threshold which likely reflects ongoing maturation of spinal and supraspinal circuits. Prior hospital experience has a negligible global effect on sensory processing demonstrating the resilience of the CNS in adverse environments.
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Enfermedad Crítica , Tacto , Niño , Humanos , Lactante , Preescolar , Reproducibilidad de los Resultados , Estudios Longitudinales , Estudios Prospectivos , Tacto/fisiología , Anestesia GeneralRESUMEN
As the science of adversity and resilience advances, and public awareness of the health consequences of stress grows, primary care providers are being increasingly asked to address the effects of adverse experiences on child wellbeing. Given limited tools for assessing these effects early in life, the authors explore how enhanced capacity to measure stress activation directly in young children could transform the role and scope of pediatric practice. When employed within a trusted relationship between caregivers and clinicians, selective use of biological measures of stress responses would help address the documented limitations of rating scales of adverse childhood experiences as a primary indicator of individual risk and strengthen the ability to focus on variation in intervention needs, assess their effectiveness, and guide ongoing management. The authors provide an overview of the potential benefits and risks of such expanded measurement capacity, as well as an introduction to candidate indicators that might be employed in an office setting. The ultimate value of such measures for both pediatricians and parents will require vigilant attention to the ethical responsibilities of assuring their correct interpretation and minimizing the harm of inappropriate labeling, especially for children and families experiencing the hardships and threats of racism, poverty, and other structural inequities. Whereas much work remains to be done to advance measurement development and ensure its equitable use, the potential of validated markers of stress activation and resilience to strengthen the impact of primary health care on the lives of young children facing significant adversity demands increased attention.
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Experiencias Adversas de la Infancia , Cuidadores , Biología , Niño , Salud Infantil , Protección a la Infancia , Preescolar , HumanosRESUMEN
Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.
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Depresión , Estudio de Asociación del Genoma Completo , Encéfalo , Preescolar , Depresión/genética , Humanos , Lactante , Acontecimientos que Cambian la Vida , Factores de RiesgoRESUMEN
Spontaneous pupil size fluctuations in humans and mouse models are noninvasively measured data that can be used for early detection of neurodevelopmental spectrum disorders. While highly valuable in such applied studies, pupillometry dynamics and dynamical characteristics have not been fully investigated, although their understanding may potentially lead to the discovery of new information, which cannot be readily uncovered by conventional methods. Properties of pupillometry dynamics, such as determinism, were previously investigated for healthy human subjects; however, the dynamical characteristics of pupillometry data in mouse models, and whether they are similar to those of human subjects, remain largely unknown. Therefore, it is necessary to establish a thorough understanding of the dynamical properties of mouse pupillometry dynamics and to clarify whether it is similar to that of humans. In this study, dynamical pupillometry characteristics from 115 wild-type mouse datasets were investigated by methods of nonlinear time series analysis. Results clearly demonstrated a strong underlying determinism in the investigated data. Additionally, the data's trajectory divergence rate and predictability were estimated.
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Pupila , Animales , Voluntarios Sanos , Humanos , RatonesRESUMEN
Brain α2-containing GABAA receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of α2-containing GABAA receptors following chronic social defeat stress using male mice deficient in the α2 subunit globally or conditionally in dopamine D1- or D2-receptor-expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of the lack of the α2 subunit on intermediates of the glutathione synthesis pathway. We found that α2-containing GABAA receptors on D2-receptor-positive but not on D1-receptor-positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of α2-containing GABAA receptors on D2-receptor-positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the elevated plus-maze, light-dark box, and novel open field tests. Increases in indices of oxidative stress-reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios-were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking α2-containing GABAA receptors. We conclude that α2-containing GABAA receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that α2-containing GABAA receptors provide against oxidative stress in NAc and the prefrontal cortex.
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Ansiedad , Receptores de GABA-A/metabolismo , Receptores de GABA , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Dopamina D1/metabolismo , Ácido gamma-AminobutíricoRESUMEN
Experience-dependent plasticity within visual cortex is controlled by postnatal maturation of inhibitory circuits, which are both morphologically diverse and precisely connected. Gene-targeted disruption of the voltage-dependent potassium channel Kv3.1 broadens action potentials and reduces net inhibitory function of parvalbumin (PV)-positive GABA subtypes within the neocortex. In mice lacking Kv3.1, the rate of input loss from an eye deprived of vision was slowed two-fold, despite otherwise normal critical period timecourse and receptive field properties. Rapid ocular dominance plasticity was restored by local or systemic enhancement of GABAergic transmission with acute benzodiazepine infusion. Diazepam instead exacerbated a global suppression of slow-wave oscillations during sleep described previously in these mutant mice, which therefore did not account for the rescued plasticity. Rapid ocular dominance shifts closely reflected Kv3.1 gene dosage that prevented prolonged spike discharge of their target pyramidal cells in vivo or the spike amplitude decrement of fast-spiking cells during bouts of high-frequency firing in vitro. Late postnatal expression of this unique channel in fast-spiking interneurons thus subtly regulates the speed of critical period plasticity with implications for mental illnesses.
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Neocórtex , Canales de Potasio Shaw , Animales , Período Crítico Psicológico , Interneuronas/metabolismo , Ratones , Neocórtex/metabolismo , Plasticidad Neuronal , Parvalbúminas/metabolismo , Canales de Potasio Shaw/genética , Canales de Potasio Shaw/metabolismoRESUMEN
Perceptual attunement to the native phonetic repertoire occurs over the first year of life: an infant's discrimination of non-native phonetic contrasts declines while their discrimination of native phonetic contrasts improves, with the timing of change consistent with sensitive periods. The statistics of speech sound distributions is one source of input used to collapse non-native phonetic category boundaries, while sharpening native ones. Distributional learning can be a domain-general mechanism, yet given the timing of perceptual attunement, we hypothesized that this learning mechanism may be maturationally delimited in the content domain of phonetic categories. Here, we assessed whether sensitivity to the distribution of speech sounds in the environment declines as the period of perceptual attunement closes. We used electroencephalography (EEG) to investigate whether neuronal responses to native 'ra' and 'la' phones are modulated differently in older vs young infants by exposure to either a bimodal or unimodal sound distribution spanning the [r] ~ [l] phoneme space. The native contrast, ra-la, is discriminable at all three ages, ensuring that we were testing the distributional learning mechanism, rather than confounding it with a decline in discrimination to a non-native distinction. English monolingual infants (n = 131) at 5-, 9- and 12-months-old were familiarized to either a unimodal or bimodal distribution of /ra/-/la/ speech sounds. Immediately following familiarization, an ERP oddball task was used to assess discrimination. Results showed that brief exposure to a bi- vs uni-modal distribution is sufficient to alter neuronal responses to subsequent /ra/ vs /la/ speech sounds at 5-months and 9-months, but not at 12-months. These results are the first to capture a progressive decline in sensitivity to distributional statistics in the environment. A potential mechanistic explanation based on critical period biology is discussed.
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Fonética , Percepción del Habla , Anciano , Humanos , Lactante , Lenguaje , Desarrollo del Lenguaje , AprendizajeRESUMEN
Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.
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Conmoción Encefálica/complicaciones , Encéfalo/fisiopatología , Ácido Glutámico/metabolismo , Interneuronas/fisiología , Estrés Oxidativo , Convulsiones/fisiopatología , Ácido gamma-Aminobutírico/metabolismo , Animales , Encéfalo/metabolismo , Ritmo Gamma , Masculino , Ratones Endogámicos C57BL , Parvalbúminas/análisis , Convulsiones/etiología , Convulsiones/metabolismoRESUMEN
Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.
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Encéfalo/fisiología , Plasticidad Neuronal , Animales , Encéfalo/crecimiento & desarrollo , Relojes Circadianos , Humanos , Neuronas/fisiología , Parvalbúminas/genética , Parvalbúminas/metabolismo , Factores de TiempoRESUMEN
Auditory experience drives neural circuit refinement during windows of heightened brain plasticity, but little is known about the genetic regulation of this developmental process. The primary auditory cortex (A1) of mice exhibits a critical period for thalamocortical connectivity between postnatal days P12 and P15, during which tone exposure alters the tonotopic topography of A1. We hypothesized that a coordinated, multicellular transcriptional program governs this window for patterning of the auditory cortex. To generate a robust multicellular map of gene expression, we performed droplet-based, single-nucleus RNA sequencing (snRNA-seq) of A1 across three developmental time points (P10, P15, and P20) spanning the tonotopic critical period. We also tone-reared mice (7 kHz pips) during the 3-d critical period and collected A1 at P15 and P20. We identified and profiled both neuronal (glutamatergic and GABAergic) and nonneuronal (oligodendrocytes, microglia, astrocytes, and endothelial) cell types. By comparing normal- and tone-reared mice, we found hundreds of genes across cell types showing altered expression as a result of sensory manipulation during the critical period. Functional voltage-sensitive dye imaging confirmed GABA circuit function determines critical period onset, while Nogo receptor signaling is required for its closure. We further uncovered previously unknown effects of developmental tone exposure on trajectories of gene expression in interneurons, as well as candidate genes that might execute tonotopic plasticity. Our single-nucleus transcriptomic resource of developing auditory cortex is thus a powerful discovery platform with which to identify mediators of tonotopic plasticity.
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Corteza Auditiva , Núcleo Celular/metabolismo , ARN , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Animales , Corteza Auditiva/crecimiento & desarrollo , Corteza Auditiva/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Ratones , Receptores Nogo/genética , Receptores Nogo/metabolismo , ARN/análisis , ARN/genética , ARN/metabolismo , Análisis de Secuencia de ARN/métodosRESUMEN
Dravet syndrome is a severe infantile-onset epileptic encephalopathy which begins with febrile seizures and is caused by heterozygous loss-of-function mutations of the voltage-gated sodium channel gene SCN1A. We designed a CRISPR-based gene therapy for Scn1a-haplodeficient mice using multiple guide RNAs (gRNAs) in the promoter regions together with the nuclease-deficient Cas9 fused to transcription activators (dCas9-VPR) to trigger the transcription of SCN1A or Scn1a in vitro. We tested the effect of this strategy in vivo using an adeno-associated virus (AAV) mediated system targeting inhibitory neurons and investigating febrile seizures and behavioral parameters. In both the human and mouse genes multiple guide RNAs (gRNAs) in the upstream, rather than downstream, promoter region showed high and synergistic activities to increase the transcription of SCN1A or Scn1a in cultured cells. Intravenous injections of AAV particles containing the optimal combination of 4 gRNAs into transgenic mice with Scn1a-haplodeficiency and inhibitory neuron-specific expression of dCas9-VPR at four weeks of age increased Nav1.1 expression in parvalbumin-positive GABAergic neurons, ameliorated their febrile seizures and improved their behavioral impairments. Although the usage of transgenic mice and rather modest improvements in seizures and abnormal behaviors hamper direct clinical application, our results indicate that the upregulation of Scn1a expression in the inhibitory neurons can significantly improve the phenotypes, even when applied after the juvenile stages. Our findings also suggest that the decrease in Nav1.1 is directly involved in the symptoms seen in adults with Dravet syndrome and open a way to improve this condition.
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Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Epilepsia/genética , Epilepsia/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.1/genética , Canal de Sodio Activado por Voltaje NAV1.1/fisiología , Neuronas/fisiología , Animales , Conducta Animal , Sistemas CRISPR-Cas , Modelos Animales de Enfermedad , Epilepsias Mioclónicas/prevención & control , Epilepsia/prevención & control , Femenino , Neuronas GABAérgicas/fisiología , Terapia Genética/métodos , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , FenotipoRESUMEN
Synesthesia is a neurologic trait in which specific inducers, such as sounds, automatically elicit additional idiosyncratic percepts, such as color (thus "colored hearing"). One explanation for this trait-and the one tested here-is that synesthesia results from unusually weak pruning of cortical synaptic hyperconnectivity during early perceptual development. We tested the prediction from this hypothesis that synesthetes would be superior at making discriminations from nonnative categories that are normally weakened by experience-dependent pruning during a critical period early in development-namely, discrimination among nonnative phonemes (Hindi retroflex /d̪a/ and dental /Éa/), among chimpanzee faces, and among inverted human faces. Like the superiority of 6-mo-old infants over older infants, the synesthetic groups were significantly better than control groups at making all the nonnative discriminations across five samples and three testing sites. The consistent superiority of the synesthetic groups in making discriminations that are normally eliminated during infancy suggests that residual cortical connectivity in synesthesia supports changes in perception that extend beyond the specific synesthetic percepts, consistent with the incomplete pruning hypothesis.
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Cognición/fisiología , Neuroimagen , Reconocimiento Visual de Modelos/fisiología , Sinestesia/diagnóstico por imagen , Adulto , Cara/diagnóstico por imagen , Cara/fisiología , Femenino , Humanos , Masculino , Estimulación Luminosa , Sinestesia/fisiopatologíaRESUMEN
Neurodevelopmental spectrum disorders like autism (ASD) are diagnosed, on average, beyond age 4 y, after multiple critical periods of brain development close and behavioral intervention becomes less effective. This raises the urgent need for quantitative, noninvasive, and translational biomarkers for their early detection and tracking. We found that both idiopathic (BTBR) and genetic (CDKL5- and MeCP2-deficient) mouse models of ASD display an early, impaired cholinergic neuromodulation as reflected in altered spontaneous pupil fluctuations. Abnormalities were already present before the onset of symptoms and were rescued by the selective expression of MeCP2 in cholinergic circuits. Hence, we trained a neural network (ConvNetACh) to recognize, with 97% accuracy, patterns of these arousal fluctuations in mice with enhanced cholinergic sensitivity (LYNX1-deficient). ConvNetACh then successfully detected impairments in all ASD mouse models tested except in MeCP2-rescued mice. By retraining only the last layers of ConvNetACh with heart rate variation data (a similar proxy of arousal) directly from Rett syndrome patients, we generated ConvNetPatients, a neural network capable of distinguishing them from typically developing subjects. Even with small cohorts of rare patients, our approach exhibited significant accuracy before (80% in the first and second year of life) and into regression (88% in stage III patients). Thus, transfer learning across species and modalities establishes spontaneous arousal fluctuations combined with deep learning as a robust noninvasive, quantitative, and sensitive translational biomarker for the rapid and early detection of neurodevelopmental disorders before major symptom onset.
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Acetilcolina/metabolismo , Nivel de Alerta , Trastorno Autístico/psicología , Aprendizaje Profundo , Animales , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/fisiopatología , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Pupila/fisiología , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatología , Síndrome de Rett/psicologíaRESUMEN
Adequate perinatal levels of thyroid hormones (THs) are required for normal brain function and development. Studies in non-mammalian species suggest that TH might be involved in the regulation of critical periods (CPs) of heightened plasticity. Yet, it is largely unknown what mechanisms controlling such CPs might be under TH regulation. Here, we briefly review the influence of TH in early life across evolution. We discuss possible links between TH and known circuit and/or molecular mechanisms determining the timing of CPs of heightened brain plasticity. We focus on the role of parvalbumin-positive (PV) interneurons since their maturation defines CP onset and closure. Specifically, abnormal PV circuits are associated with low perinatal levels of TH, possibly because thyroid hypofunction may increase oxidative stress and/or dysregulate Otx2-mediated maturation of neuroprotective perineuronal nets. In addition, the level of cholinergic transmission is important for CP plasticity. Potentially, TH levels could affect gain changes in cholinergic transmission that can alter brain development. We believe that understanding how TH impacts CPs of circuit refinement will shed light onto the principles underlying normal developmental trajectories. Given that the thyroid gland expresses estrogen and androgen receptors, its activity can potentially be regulated differently between the sexes, contributing to sexually dimorphic behaviors.