Sensitive Period Of Brain Development Research Articles

Listening Preference for Child-Directed Speech Versus Time-Reversed Speech in Moderate-Preterm Infants Compared to Full-Term Infants.

The purpose of the present study was to examine whether there is a listening preference for child-directed speech (CDS) over backward speech in moderate-preterm infants (MPIs). Eighteen MPIs of gestational age of 32.0 weeks (range: 32-34.06 weeks), chronological age of 8.09 months, and maturation age of 6.48 months served as the experimental group. The two control groups consisted of a total of 36 infants-20 full-term infants matched for chronological age and 16 full-term infants matched for maturation age. The infants were tested using the central fixation procedure and were presented with 16 trials of CDS and backward speech. A follow-up was conducted 5 years after the initial experiment using a developmental and a five-item parent questionnaire. MPIs did not demonstrate a preference for CDS over backward speech, whereas both control groups demonstrated a listening preference for CDS over backward speech. MPIs showed a delayed use of first words and word combinations and lower scores on the five-item questionnaire compared to term infants. Twelve MPIs (67%) did not demonstrate a preference for CDS over backward speech. Four of them (33%) were later diagnosed with neurodevelopmental disorders. The lack of preference for CDS over backward speech in the MPIs group suggests delayed developmental pattern of speech processing compared to full-term peers. Delays in neurological maturation as well as listening experience in an unregulated environment outside the uterus during a sensitive period of brain development may affect the recognition of phonological and prosodic patterns that support listening preference for speech over backward speech.

Central role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to anxiety in mice

Having experienced stress during sensitive periods of brain development strongly influences how individuals cope with later stress. Some are prone to develop anxiety or depression, while others appear resilient. The as-yet-unknown mechanisms underlying these differences may lie in how genes and environmental stress interact to shape the circuits that control emotions. Here, we investigated the role of the habenulo-interpeduncular system (HIPS), a critical node in reward circuits, in early stress-induced anxiety in mice. We found that habenular and IPN components characterized by the expression of Otx2 are synaptically connected and particularly sensitive to chronic stress (CS) during the peripubertal period. Stress-induced peripubertal activation of this HIPS subcircuit elicits both HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We also show that HIPS silencing through conditional Otx2 knockout counteracts these effects of stress. Together, these results demonstrate that a genetic factor, Otx2, and stress interact during the peripubertal period to shape the stress sensitivity of the HIPS, which is shown to be a key modulator of susceptibility or resilience to develop anxiety.

Fostering Resilience to Adverse Childhood Experiences Among Adolescents: Investing in Social Brain Development in the Age of the COVID-19 Pandemic

Social experiences are central to developing resilience to adverse childhood experiences (ACEs). Disruptions to social interactions during the COVID-19 pandemic may compromise resilience, or the ability to psychologically adapt to ACEs, by blunting social brain development. This is especially concerning for children with access to limited resources. Drawing from evolutionary psychology and resilience research, we understand that the development of the social brain —a complex network of brain regions involved in social behaviors—is shaped by life experiences throughout childhood. Adolescence is a sensitive period of brain development during which rapid and lasting attunement of the brain to the environment occurs.1 Therefore, to counter potential negative effects of the COVID-19 pandemic on resilience to ACEs among vulnerable adolescents, interventions should focus on promoting social brain development through positive social experiences. Critically, this effort will support youth who are economically marginalized, and/or racially and ethnically minoritized. Not only are these adolescents highly exposed to ACEs and to discrimination-based social rejection, they often lack access to resources that foster resilience.2 Individual, family, and community level interventions can promote trajectories toward resilience by facilitating supportive relationships, providing access to social resources, and promoting social cohesion by reducing experiences of social rejection.

4.1 Neurobiology of Attachment and Sensitive Periods of Brain Development

The interplay of nature and nurture are primary pieces to the formation of attachment, which sets the stage for all future development. The Circle of Security Parenting (COS-P) is a powerful model to use for translating this complicated neurobiology of attachment into a powerful tool for relationship change. Clinicians are essential in bridging this language gap to improve family care.

Differential auditory cortical development in left and right cochlear implanted children.

Unilateral aural stimulation has been shown to cause massive cortical reorganization in brain with congenital deafness, particularly during the sensitive period of brain development. However, it is unclear which side of stimulation provides most advantages for auditory development. The left hemisphere dominance of speech and linguistic processing in normal hearing adult brain has led to the assumption of functional and developmental advantages of right over left implantation, but existing evidence is controversial. To test this assumption and provide evidence for clinical choice, we examined 34 prelingually deaf children with unilateral cochlear implants using near-infrared spectroscopy. While controlling for age of implantation, residual hearing, and dominant hand, cortical processing of speech showed neither developmental progress nor influence of implantation side weeks to months after implant activation. In sharp contrast, for nonspeech (music signal vs. noise) processing, left implantation showed functional advantages over right implantation that were not yet discernable using clinical, questionnaire-based outcome measures. These findings support the notion that the right hemisphere develops earlier and is better preserved from adverse environmental influences than its left counterpart. This study thus provides, to our knowledge, the first evidence for differential influences of left and right auditory peripheral stimulation on early cortical development of the human brain.

Differences in Brain Structural Covariance Network Characteristics in Children and Adults With Autism Spectrum Disorder.

Systematically describing the structural topological configuration of human brain during development is an essential task. Autism spectrum disorder (ASD) represents a powerful challenge for psychiatry and neuroscience researchers. In this study, we investigated variations in the structural covariance network properties of 441 patients with ASD ranging in age from 7 to 45 years and in 426 age-matched healthy controls (HCs) using structural magnetic resonance neuroimaging from the ABIDE database. We applied a sliding window approach to study topological variation during development using comprehensive graph theoretical analysis. The main findings are as follows: (1) Cross-sectional trajectories of the network characteristics exhibited inverted U-shapes in both HCs and participants with ASD, with the latter exhibiting a 7-year delay in reaching the maximum value, (2) network resilience to targeted attacks peaked at 18' and 19' in the HCs and at 25' in the participants with ASD, and the weakest resilience occurred at age 7', (3) the HCs and participants with ASD exhibited normalized mean degree differences in the right amygdala, and (4) significant differences in the network characteristics were observed in the 18' age group at most of the densities analyzed. We used cross-sectional analysis to infer distinct neurodevelopmental trajectories in ASD in the brain structural connectome. Our findings are consistent with the notion that adolescence is a sensitive period of brain development with strong potential for brain plasticity, offering opportunities for environmental adaptation and social integration and for increasing vulnerability. ASD may be a product of susceptibility. LAY SUMMARY: We used cross-sectional analysis to preliminarily infer distinct neurodevelopmental trajectories in ASD in the brain structural connectome. The main findings are as follows: (1) Cross-sectional trajectories of the network characteristics exhibited inverted U-shapes in both HCs and participants with ASD, with the latter exhibiting a 7-year delay in reaching the maximum value, (2) Network resilience to targeted attacks peaked at 18' and 19' in the HCs and at 25' in the participants with ASD, and the weakest resilience occurred at age 7', (3) The HCs and participants with ASD exhibited normalized mean degree differences in the right amygdala, and (4) significant differences in the network characteristics were observed in the 18' age group at most of the densities analyzed.

Nutrition and Brain Development.

All nutrients are essential for brain development, but pre-clinical and clinical studies have revealed sensitive periods of brain development during which key nutrients are critical. An understanding of these nutrient-specific sensitive periods and the accompanying brain regions or processes that are developing can guide effective nutrition interventions as well as the choice of meaningful circuit-specific neurobehavioral tests to best determine outcome. For several nutrients including protein, iron, iodine, and choline, pre-clinical and clinical studies align to identify the same sensitive periods, while for other nutrients, such as long-chain polyunsaturated fatty acids, zinc, and vitamin D, pre-clinical models demonstrate benefit which is not consistently shown in clinical studies. This discordance of pre-clinical and clinical results is potentially due to key differences in the timing, dose, and/or duration of the nutritional intervention as well as the pre-existing nutritional status of the target population. In general, however, the optimal window of success for nutritional intervention to best support brain development is in late fetal and early postnatal life. Lack of essential nutrients during these times can lead to long-lasting dysfunction and significant loss of developmental potential.

Visual experience dependent plasticity in humans.

While sensitive periods in brain development have often been studied by investigating the recovery of visual functions after a congenital phase of visual deprivation in non-human animals, research in humans who had recovered sight after a transient phase of congenital blindness is still scarce. Here, we discuss the hypothesis put forward based on non-human primate work which states that the effects of experience increase downstream the visual processing hierarchy. Recent results from behavioral and neuroscience studies in sight recovery individuals are discussed in the context of research findings from permanently congenitally blind humans as well as from prospective studies in infants and children.

Early life stress and brain plasticity: from molecular alterations to aberrant memory and behavior.

Early life stress (ELS) is one of the most critical factors that could modify brain plasticity, memory and learning abilities, behavioral reactions, and emotional response in adulthood leading to development of different mental disorders. Prenatal and early postnatal periods appear to be the most sensitive periods of brain development in mammals, thereby action of various factors at these stages of brain development might result in neurodegeneration, memory impairment, and mood disorders at later periods of life. Deciphering the processes underlying aberrant neurogenesis, synaptogenesis, and cerebral angiogenesis as well as deeper understanding the effects of ELS on brain development will provide novel approaches to prevent or to cure psychiatric and neurological deficits caused by stressful conditions at the earliest stages of ontogenesis. Neuropeptide oxytocin serves as an amnesic, anti-stress, pro-angiogenic, and neurogenesis-controlling molecule contributing to dramatic changes in brain plasticity in ELS. In the current review, we summarize recent data on molecular mechanisms of ELS-driven changes in brain plasticity with the particular focus on oxytocin-mediated effects on neurogenesis and angiogenesis, memory establishment, and forgetting.

Treatment Considerations for Adolescents Who Exhibit Cognitive/Communication Problems: A Neuroscience Perspective

Purpose Adolescence is a period of substantial neurophysiological and behavioral growth, representing a second sensitive period of brain development. It is a psychological and social transition period between childhood and adulthood with many beneficial changes occurring, especially with respect to potential responsiveness to clinical intervention. However, adolescent behavioral complexities introduce clinical challenges as well. The purpose of this review article is to review the current neuroimaging research on neurophysiological changes observed during adolescence and the cognitive and social behavioral counterparts, with specific attention to the clinical implications. The review article will then summarize currently available intervention tools that can be utilized by speech-language pathologists working with this population. It will conclude with available evidence-based social-communication approaches that may be applicable as well as available evidence-based supplemental technological cognitive interventions that may be useful in working with adolescents who exhibit language and communication issues. Conclusion As a transition period between childhood and adulthood, adolescence represents a second sensitive period during which there is opportunity for clinically derived beneficial cognitive and communication growth.

Influence of the hypothalamus–pituitary–gonadal axis reactivation and pubertal hormones on gray matter volume in early pubertal girls

Objective Puberty is a sensitive period of brain development accompany with pubertal hormones fluctuation. However, the underlying mechanisms of the impact of hypothalamus–pituitary–gonadal (HPG) axis reactivation and associated elevated pubertal hormones on brain structure are still unclear. Here, we investigated the brain structure differences between girls with and without HPG axis reactivation and the influence of pubertal hormones on these brain regions. Methods 126 girls aged 8–9.5 years underwent a gonadotropin-releasing hormone (GnRH) stimulation test to identify the HPG axis status and categorized into HPG+ group (n = 80) and HPG- group (n = 46). T1-weighted gradient echo three dimensional MRI was performed using a 3.0-Tesla scanner to assess the difference in GMV between the two groups. Correlation analyses were conducted to explore the relations between the brain regions showing significant GMV differences and serum hormone concentrations. Result The HPG+ group showed significantly higher GMV in the bilateral lingual gyrus and lower GMV within the right orbital inferior frontal gyrus compare to the HPG − group. Furthermore, GMV in the right orbital inferior frontal gyrus was positively associated with plasma concentrations of follicle stimulating hormone (FSH) in HPG+ group. Conclusion The present study suggests that the reactivated HPG axis could affects regional structural brain changes in early pubertal girls. FSH production play an important role in bilateral lingual gyrus, which are involved in vision processing, semantic processing and emotional expression.

The neonatal period: A missed opportunity for the prevention of iron deficiency and its associated neurological consequences?

AbstractIron deficiency is the most common micronutrient deficiency worldwide. Iron is essential for the development of multiple organ systems, most especially the developing brain. Iron deficiency, particularly during sensitive periods of brain development, such as in early childhood, is associated with long‐lasting adverse consequences for cognition, motor function and behaviour. Little consideration has been given to iron deficiency in newborn infants and its potential health consequences. Fetal iron accretion is compromised by pregnancy complications such as pre‐term birth and gestational diabetes mellitus, and our work has identified an increased risk of low iron stores at birth from maternal lifestyle factors such as smoking and obesity. Early‐life events, including Caesarean section delivery, further add to the cumulative risk of neonatal iron deficiency, which can persist throughout infancy into early childhood. While investigations into the long‐term neurological consequences of neonatal iron deficiency are limited, there is evidence of poorer memory, motor function and language ability in children born iron deficient. Recently, we also identified significant behavioural consequences of neonatal deficiency persisting from 2 to 5 years of age, with effects particularly apparent in ‘high‐risk’ children born to obese or smoking mothers or delivered by Caesarean section. Interventions targeting the fetal/neonatal period could therefore represent a key opportunity for the prevention of iron deficiency and its associated long‐term health consequences. A dual approach is required, comprising public health strategies targeting prevention, to improve health in women of reproductive age, and the development of screening strategies for the early detection of iron deficiency in newborn infants.

Altered Functional Connectivity in Patients With Sloping Sensorineural Hearing Loss

BackgroundSensory deprivation, such as hearing loss, has been demonstrated to change the intrinsic functional connectivity (FC) of the brain, as measured with resting-state functional magnetic resonance imaging (rs-fMRI). Patients with sloping sensorineural hearing loss (SNHL) are a unique population among the hearing impaired, as they have all been exposed to some auditory input throughout their lifespan and all use spoken language.Materials and MethodsTwenty patients with SNHL and 21 control subjects participated in a rs-fMRI study. Whole-brain seed-driven FC maps were obtained, with audiological scores of patients, including hearing loss severity and speech performance, used as covariates.ResultsMost profound differences in FC were found between patients with prelingual (before language development, PRE) vs. postlingual onset (after language development, POST) of SNHL. An early onset was related to enhancement in long-range network connections, including the default-mode network, the dorsal-attention network and the fronto-parietal network, as well as in local sensory networks, the visual and the sensorimotor. A number of multisensory brain regions in frontal and parietal cortices, as well as the cerebellum, were also more internally connected. We interpret these effects as top-down mechanisms serving optimization of multisensory experience in SNHL with a prelingual onset. At the same time, POST patients showed enhanced FC between the salience network and multisensory parietal areas, as well as with the hippocampus, when they were compared to those with PRE hearing loss. Signal in several cortex regions subserving visual processing was also more intra-correlated in POST vs. PRE patients. This outcome might point to more attention resources directed to multisensory as well as memory experience. Finally, audiological scores correlated with FC in several sensory and high-order brain regions in all patients.ConclusionThe results show that a sloping hearing loss is related to altered resting-state brain organization. Effects were shown in attention and cognitive control networks, as well as visual and sensorimotor regions. Specifically, we found that even in a partial hearing deficit (affecting only some of the hearing frequency ranges), the age at the onset affects the brain function differently, pointing to the role of sensitive periods in brain development.

NeoDoppler: New ultrasound technology for continuous cerebral circulation monitoring in neonates

BackgroundThere is a strong need for continuous cerebral circulation monitoring in neonatal care, since suboptimal cerebral blood flow may lead to brain injuries in preterm infants and other critically ill neonates. NeoDoppler is a novel ultrasound system, which can be gently fixed to the anterior fontanel and measure cerebral blood flow velocity continuously in different depths of the brain simultaneously. We aimed to study the feasibility, accuracy, and potential clinical applications of NeoDoppler in preterm infants and sick neonates.MethodTwenty-five infants born at different gestational ages with a variety of diagnoses on admission were included. The probe was placed over the anterior fontanel, and blood flow velocity data were continuously recorded. To validate NeoDoppler, we compared the measurements with conventional ultrasound; agreement was assessed using Bland–Altman plots.ResultsNeoDoppler can provide accurate and continuous data on cerebral blood flow velocity in several depths simultaneously. Limits of agreement between the measurements obtained with the two methods were acceptable.ConclusionBy monitoring the cerebral circulation continuously, increased knowledge of cerebral hemodynamics in preterm infants and sick neonates may be acquired. Improved monitoring of these vulnerable brains during a very sensitive period of brain development may contribute toward preventing brain injuries.

Early Childhood Education in the Era of the Fourth Industrial Revolution: Based on Brain Development

본 연구는 4차 산업혁명시대에 즈음하여 유아교육의 방향이 어떻게 되어야 하는지를 뇌 발달에 근거하여 알아보았다. 뇌 발달 연구들이 말하는 유아교육에 대한 시사점을 정리하면 다음과 같다. 첫째, 뇌의 가소성으로 인해 뇌 기능과 발달은 활발해지며 둘째, 뇌는 모델의 모방을 통해 발달하고 셋째, 뇌 발달의 민감기는 영⋅유아기이며 넷째, 감각의 자극은 뇌 발달에 좋은 영향을 미친다. 그리고 다섯째, 정서적 안정과 편안함은 뇌 기능 증진에 좋은 영향을 미치며 여섯째, 뇌는 사회적 상호작용을 통해 발달하고 마지막으로 뇌는 각 부위가 독자적이지만 이들이 서로 통합하여 발달한다는 것을 알 수 있었다.This study explored the direction of early childhood education based on brain development in the era of the fourth industrial revolution. The summary of brain research in early childhood education has several implications. First, the brain plasticity makes the brain function and development active. Second the brain develops copying of model’s behaviors. Third, the sensitive period of brain development is the period of infant and early childhood. Fourth, the stimulation of the senses has a positive effect on brain function and development. Fifth, the emotional security and comfort affect brain development positively. Lastly, brain function and development depends on the integration of each part of the brain.

Evidence that inflammation promotes estradiol synthesis in human cerebellum during early childhood

Discovering and characterizing critical and sensitive periods in brain development is essential for unraveling the myriad variables that impact disease risk. In previous work, we identified a critical period in cerebellar development in the rat that depends upon an intrinsic gene expression program and links increased prostaglandin production to local estradiol synthesis by stimulating Cyp19a, the estradiol synthetic enzyme, aromatase. This intrinsic critical period is sensitive to disruption by either inflammation or administration of cyclooxygenase (COX) inhibitors, ultimately impacting Purkinje cell dendritic growth. In a first step towards determining if a similar sensitive period exists in humans, the same gene expression profile was characterized in post-mortem cerebellar tissue of 58 children aged 0 to 9 years. Subjects were categorized as experiencing inflammation or not at the time of death. In individuals experiencing inflammation and over 1 year of age, there was a significant increase in the messenger RNA (mRNA) of the COX-1 and COX-2 enzymes and this strongly correlated with mRNA levels of aromatase. A step-wise linear model accounted for 94% of the variance in aromatase mRNA levels by co-variance with the COX enzymes, prostaglandin E2 synthase and other inflammatory mediators (Toll-like receptor 4), and Purkinje cell markers (calbindin, estrogen receptor 2). The influence of inflammation on these measures was not seen in subjects younger than 1 year. These data suggest a sensitive period to inflammation in the human cerebellum begins at about 1 year of age and may provide insight into sources of vulnerability of very young children to either inflammation or drugs designed to treat it.

Adolescent exposure to Δ9-tetrahydrocannabinol delays acquisition of paired-associates learning in adulthood.

Adolescence is a sensitive period of brain development, during which there may be a heightened vulnerability to the effects of drug use. Despite this, the long-term effects of cannabis use during this developmental period on cognition are poorly understood. We exposed adolescent rats to escalating doses of Δ9-tetrahydrocannabinol (THC)-the primary psychoactive component of cannabis-or vehicle solution during postnatal days (PND) 35-45, a period of development that is analogous to human adolescence (THC doses: PND 35-37, 2.5mg/kg; PND 38-41, 5mg/kg; PND 42-45, 10mg/kg). After a period of abstinence, in adulthood, rats were tested on an automated touchscreen version of a paired-associates learning (PAL) task to assess their ability to learn and recall object-location associations. Prepulse inhibition (PPI) of the startle response was also measured at three time points (5days, 4months, and 6months after exposure) to assess sensorimotor gating, the ability to filter out insignificant sensory information from the environment. Compared to rats exposed to vehicle alone, rats exposed to THC during adolescence took longer to learn the PAL task when tested in adulthood, even when trials contained visually identical stimuli that differed only in location. Despite this, no differences were observed later in testing, when trials contained visually distinct stimuli in different locations. Rats exposed to THC also displayed impairments in sensorimotor gating, as measured by prepulse inhibition of the startle response, though this deficit did appear to decrease over time. Taken together, THC exposure during adolescence produces long-term deficits in associative learning and sensorimotor gating, though the impact of these deficits seems to diminish with time. Thus, adolescence may represent a period of neurocognitive development that is vulnerable to the harms of cannabis use, though the stability of such harms is uncertain.

Chapter 1 - Fetal neurology: Principles and practice with a life-course perspective

Clinical service, educational, and research components of a fetal/neonatal neurology program are anchored by the disciplines of developmental origins of health and disease and life-course science as programmatic principles. Prenatal participation provides perspectives on maternal, fetal, and placental contributions to health or disease for fetal and subsequent neonatal neurology consultations. This program also provides an early-life diagnostic perspective for neurologic specialties concerned with brain health and disease throughout childhood and adulthood. Animal models and birth cohort studies have demonstrated how the science of epigenetics helps to understand gene-environment interactions to better predict brain health or disease. Fetal neurology consultations provide important diagnostic contributions during critical or sensitive periods of brain development when future neurotherapeutic interventions will maximize adaptive neuroplasticity. Age-specific normative neuroinformatics databases that employ computer-based strategies to integrate clinical/demographic, neuroimaging, neurophysiologic, and genetic datasets will more accurately identify either symptomatic patients or those at risk for brain disorders who would benefit from preventive, rescue, or reparative treatment choices throughout the life span.

The biological embedding of neonatal stress exposure: A conceptual model describing the mechanisms of stress-induced neurodevelopmental impairment in preterm infants.

The biological embedding of early life stress exposure may result in life-long neurodevelopmental impairment in preterm infants. Infants hospitalized in the neonatal intensive care unit are exposed to significant experiential, environmental, and physiologic stressors over the course of their extended hospitalization. Stress exposure during the sensitive period of brain development may alter biological processes, including functioning of the immune system, the autonomic nervous system, and the hypothalamic-pituitary-adrenal axis as well as gene expression. These alterations may subsequently affect brain structure and function. Changes to these processes may mediate the relationship between neonatal stress exposure and neurodevelopment in preterm infants and represent potential therapeutic targets to improve long-term outcomes. The purpose of this paper is to introduce a conceptual model, based on published research, that describes the mechanisms mediating stress exposure and neurodevelopment impairment in preterm infants and to provide the theoretical foundation on which to base future descriptive research, intervention studies, and clinical care.

Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood-brain barrier's tight junction proteins.

For the past decade, there has been an increased concern about the health risks from arsenic (As) exposure, because of its neurotoxic effects on the developing brain. The exact mechanism underlying As-induced neurotoxicity during sensitive periods of brain development remains unclear, especially the role of blood-brain barrier's (BBB) tight junction (TJ) proteins during As-induced neurotoxicity. Here, we highlight the involvement of TJ proteins in As-induced autophagy in cerebral cortex and hippocampus during developmental periods [postnatal day (PND) 21, 28, 35 and 42]. Here, the administration of arsenic trioxide (As2O3) at doses of 0.15mg or 1.5mg or 15mg As2O3/L in drinking water from gestational to lactational and continued to the pups till PND42 resulted in a significant decrease in the mRNA expression levels of TJ proteins (Occludin, Claudin, ZO-1 and ZO-2) and Occludin protein expression level. In addition, As exposure significantly decreased PI3K, Akt, mTOR, and p62 with a concomitant increase in Beclin1, LC3I, LC3II, Atg5 and Atg12. Moreover, As exposure also significantly downregulated the protein expression levels of mTOR with a concomitant upregulation of Beclin 1, LC3 and Atg12 in all the developmental age points. However, no significant alterations were observed in low and medium dose-exposed groups of PND42. Histopathological analysis in As-exposed mice revealed decreased number of pyramidal neurons in hippocampus; and neurons with degenerating axons, shrinkage of cells, remarkable vacuolar degeneration in cytoplasm, karyolysis and pyknosis in cerebral cortex. Ultrastructural analysis by transmission electron microscopy revealed the occurrence of autophagosomes and vacuolated axons in the cerebral cortex and hippocampus of the mice exposed to high dose As at PND21 and 42. The severities of changes were found to more persist in the cerebral cortex than in the hippocampus of As-exposed mice. Finally, we conclude that the leaky BBB in cerebral cortex and hippocampus may facilitate the transfer of As and induces autophagy by inhibiting PI3K/Akt/mTOR signaling pathway in an age-dependent manner, i.e., among the four different developmental age points, PND21 animals were found to be more vulnerable to the As-induced neurotoxicity than the other three age points.