Influence Brain Development Research Articles

The Neurodevelopmental Perspective of Surgical Necrotizing Enterocolitis: The Role of the Gut-Brain Axis.

This state-of-the-art review article aims to highlight the most recent evidence about the therapeutic options of surgical necrotizing enterocolitis, focusing on the molecular basis of the gut-brain axis in relevance to the neurodevelopmental outcomes of primary peritoneal drainage and primary laparotomy. Current evidence favors primary laparotomy over primary peritoneal drainage as regards neurodevelopment in the surgical treatment of necrotizing enterocolitis. The added exposure to inhalational anesthesia in infants undergoing primary laparotomy is an additional confounding variable but requires further study. The concept of the gut-brain axis suggests that bowel injury initiates systemic inflammation potentially affecting the developing central nervous system. Signals about microbes in the gut are transduced to the brain and the limbic system via the enteric nervous system, autonomic nervous system, and hypothalamic-pituitary axis. Preterm infants with necrotizing enterocolitis have significant differences in the diversity of the microbiome compared with preterm controls. The gut bacterial flora changes remarkably prior to the onset of necrotizing enterocolitis with a predominance of pathogenic organisms. The type of initial surgical approach correlates with the length of functional gut and microbiome equilibrium influencing brain development and function through the gut-brain axis. Existing data favor patients who were treated with primary laparotomy over those who underwent primary peritoneal drainage in terms of neurodevelopmental outcomes. We propose that this is due to the sustained injurious effect of the remaining diseased and necrotic bowel on the developing newborn brain, in patients treated with primary peritoneal drainage, through the gut-brain axis and probably not due to the procedure itself.

Early Childhood Adverse Experiences, Inferior Frontal Gyrus Connectivity, and the Trajectory of Externalizing Psychopathology

Early adverse childhood experiences (ACEs) have been linked to the development of both internalizing and externalizing psychopathology. In our prior work, we found that ACEs predicted reductions in the volume of the inferior frontal gyrus (IFG), a brain region important for impulse control and emotion regulation. Here we tested the hypothesis that ACEs might influence child behavioral outcomes through an impact on IFG functional connectivity, which may influence impulsive or risk-taking behavior. We examined the effects of prospectively assessed ACEs on IFG connectivity in childhood, and their relationship to the trajectory of subsequent psychopathology from late school age and early adolescence, using data from an 11-year longitudinal study of children starting in preschool that included 3 waves of resting state functional connectivity across childhood and early adolescence. ACEs predicted functional connectivity of both left and right IFG. Multi-level modeling of symptoms across 3 waves of assessments indicated that more ACEs predicted both internalizing and externalizing symptoms. However, altered IFG connectivity specifically predicted greater externalizing symptoms over time in middle childhood and early adolescence, as compared to internalizing symptoms. Longitudinal modeling indicating that the relationships between externalizing and functional connectivity were maintained across 3 waves of functional connectivity assessment. These findings underscore the relationship of ACEs to later psychopathology, and suggest that connectivity of the IFG, a region known to play an important role in impulse control and emotion regulation, may play a key role in the risk trajectory of ACEs to externalizing problems. However, further work is needed to understand whether these relationships reflect a direct effect of ACEs or whether ACEs are a marker for other environmental or genetic factors that may also influence brain development and behavior.

Involvement of Amylin and Leptin in the Development of Projections from the Area Postrema to the Nucleus of the Solitary Tract.

The area postrema (AP) and the nucleus of the solitary tract (NTS) are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the inhibitory effect on gastric emptying induced by the pancreatic hormone amylin. Amylin’s target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte-derived hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance. Amylin appears to promote neurogenesis in the AP in adult rats. Here, we examined whether amylin and leptin are required for the development of projections from the AP to the NTS in postnatal and adult mice by conducting neuronal tracing studies with DiI in amylin- (IAPP−/−) and leptin-deficient (ob/ob) mice. Compared to wild-type littermates, postnatal (P10) and adult (P60) IAPP−/− mice showed a significantly reduced density of AP-NTS projections. While AP projections were also reduced in postnatal (P14) ob/ob mice, AP-NTS fiber density did not differ between adult ob/ob and wild-type animals. Our findings suggest a crucial function of amylin for the maturation of neuronal brainstem pathways controlling energy balance and gastrointestinal function. The impaired postnatal development of neuronal AP-NTS projections in ob/ob mice appears to be compensated in this experimental model during later brain maturation. It remains to be elucidated whether an amylin- and leptin-dependent modulation in neuronal development translates into altered AP/NTS-mediated functions.

Cortical morphometry and cognition in very preterm and term-born children at early school age

Very preterm birth influences brain development and may result in alterations of cortical morphometry. These structural alterations may interact with cognitive development. The aim of the present study was to investigate the structure-function relationship in school-aged very preterm and term-born control children. A comprehensive neuropsychological test battery was administered to 41 very preterm (<32 weeks of gestation) and 30 term-born control children aged seven to twelve years. The automated method FreeSurfer was used to obtain cortical thickness and cortical surface area measures from T1-weighted MRI images. Regional cortical thickness differed between groups but differences disappeared when controlling for age. Global cortical thickness differed between groups in the right hemisphere (very preterm children>controls). No group differences occurred for cortical surface area. The relationship between cortical morphometry and cognition differed between very preterm and control children. In very preterm children, some cognitive domains correlated positively and others negatively with regional cortical thickness and cortical surface area. Our findings contribute to the understanding of the structure-function relationship in very preterm children and their term-born peers. They add to the notion that this relationship varies depending on the brain region and the cognitive function in question and suggest developmental differences between very preterm and term-born children.

Brain structural connectivity during adrenarche: Associations between hormone levels and white matter microstructure

Levels of the adrenal hormones dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and testosterone, have all been linked to behavior and mental health during adrenarche, and preclinical studies suggest that these hormones influence brain development. However, little is known about how variation in these hormones is associated with white matter structure during this period of life. The current study aimed to examine associations between DHEA, DHEAS, and testosterone, and white matter microstructure during adrenarche. To avoid the confounding effect of age on hormone levels, we tested these associations in 87 children within a narrow age range (mean age 9.56 years, SD=0.34) but varying in hormone levels. All children provided saliva samples directly after waking and completed a diffusion-weighted MRI scan. Higher levels of DHEA were associated with higher mean diffusivity (MD) in a widespread cluster of white matter tracts, which was partially explained by higher radial diffusivity (RD) and partially by higher axial diffusivity (AD). In addition, there was an interaction between DHEA and testosterone, with higher levels of testosterone being associated with higher fractional anisotropy (FA) and lower MD and RD when DHEA levels were relatively high, but with lower FA and higher MD and RD when DHEA levels were low. These findings suggest that relatively early exposure to DHEA, as well as an imbalance between the adrenal hormones, may be associated with alterations in white matter microstructure. These findings highlight the potential relevance of adrenarcheal hormones for structural brain development.

Perinatal maternal depressive symptoms alter amygdala functional connectivity in girls.

Perinatal maternal depressive symptoms influence brain development of offspring. Such effects are particularly notable in the amygdala, a key structure involved in emotional processes. This study investigated whether the functional organization of the amygdala varies as a function of pre- and postnatal maternal depressive symptoms. The amygdala functional network was assessed using resting-state functional magnetic resonance imaging (rs-fMRI) in 128 children at age of 4.4 to 4.8 years. Maternal depressive symptoms were obtained at 26 weeks of gestation, 3 months, 1, 2, 3, and 4.5 years after delivery. Linear regression was used to examine associations between maternal depressive symptoms and the amygdala functional network. Prenatal maternal depressive symptoms were significantly associated with the functional connectivity between the amygdala and the cortico-striatal circuitry, especially the orbitofrontal cortex (OFC), insula, subgenual anterior cingulate (ACC), temporal pole, and striatum. Interestingly, greater pre- than post-natal depressive symptoms were associated with lower functional connectivity of the left amygdala with the bilateral subgenual ACC and left caudate and with lower functional connectivity of the right amygdala with the left OFC, insula, and temporal pole. These findings were only observed in girls but not in boys. Early exposure to maternal depressive symptoms influenced the functional organization of the cortico-striato-amygdala circuitry, which is intrinsic to emotional perception and regulation in girls. This suggests its roles in the transgenerational transmission of vulnerability for socio-emotional problems and depression. Moreover, this study underscored the importance of gender-dependent developmental pathways in defining the neural circuitry that underlies the risk for depression.

Post-weaning social isolation of rats leads to long-term disruption of the gut microbiota-immune-brain axis

Early-life stress is an established risk for the development of psychiatric disorders. Post-weaning isolation rearing of rats produces lasting developmental changes in behavior and brain function that may have translational pathophysiological relevance to alterations seen in schizophrenia, but the underlying mechanisms are unclear. Accumulating evidence supports the premise that gut microbiota influence brain development and function by affecting inflammatory mediators, the hypothalamic–pituitaryadrenal axis and neurotransmission, but there is little knowledge of whether the microbiota-gut-brain axis might contribute to the development of schizophrenia-related behaviors. To this end the effects of social isolation (SI; a well-validated animal model for schizophrenia)-induced changes in rat behavior were correlated with alterations in gut microbiota, hippocampal neurogenesis and brain cytokine levels. Twenty-four male Lister hooded rats were housed in social groups (group-housed, GH, 3 littermates per cage) or alone (SI) from weaning (post-natal day 24) for four weeks before recording open field exploration, locomotor activity/novel object discrimination (NOD), elevated plus maze, conditioned freezing response (CFR) and restraint stress at one week intervals. Post-mortem caecal microbiota composition, cortical and hippocampal cytokines and neurogenesis were correlated to indices of behavioral changes. SI rats were hyperactive in the open field and locomotor activity chambers traveling further than GH controls in the less aversive peripheral zone. While SI rats showed few alterations in plus maze or NOD they froze for significantly less time than GH following conditioning in the CFR paradigm, consistent with impaired associative learning and memory. SI rats had significantly fewer BrdU/NeuN positive cells in the dentate gyrus than GH controls. SI rats had altered microbiota composition with increases in Actinobacteria and decreases in the class Clostridia compared to GH controls. Differences were also noted at genus level. Positive correlations were seen between microbiota, hippocampal IL-6 and IL-10, conditioned freezing and open field exploration. Adverse early-life stress resulting from continuous SI increased several indices of ‘anxiety-like’ behavior and impaired associative learning and memory accompanied by changes to gut microbiota, reduced hippocampal IL-6, IL-10 and neurogenesis. This study suggests that early-life stress may produce long-lasting changes in gut microbiota contributing to development of abnormal neuronal and endocrine function and behavior which could play a pivotal role in the aetiology of psychiatric illness.

Earlier Alcohol Use Onset Predicts Poorer Neuropsychological Functioning in Young Adults.

Neurodevelopment may be shaped by environmental factors such as alcohol intake. Over 20% of U.S. high school students begin drinking before age 14, and those who initiated drinking before age 14 are 4 times more likely to develop psychosocial, psychiatric, and substance use difficulties than those who began drinking after turning 20. Little is known, however, about how the age of alcohol use onset influences brain development. This study prospectively examined the effects of alcohol use onset age on neurocognitive functioning in healthy adolescent drinkers (N=215). Youth were administered a neuropsychological battery before substance use initiation (M=13.6years, SD = 0.8) and on average 6.8years later (M=20.2years, SD = 1.5). Hierarchical linear regressions examined if earlier ages of onset for first and regular (i.e., weekly) alcohol use adversely influenced neurocognition, above and beyond baseline neurocognition, substance use severity, and familial and social environment factors. As hypothesized, an earlier age of first drinking onset (AFDO) predicted poorer performance in the domains of psychomotor speed and visual attention (ps<0.05, N=215) and an earlier age of weekly drinking onset (AWDO) predicted poorer performances on tests of cognitive inhibition and working memory, controlling for baseline neuropsychological performance, drinking duration, and past-year marijuana use (ps<0.05, N=127). No relationship between AFDO and AWDO was found with verbal learning and memory and visuospatial ability. This is the first study to assess the association between age of adolescent drinking onset and neurocognitive performance using a comprehensive test battery. This study suggests that early onset of drinking increases risk for alcohol-related neurocognitive vulnerabilities and that initiation of any or weekly alcohol use at younger ages appears to be a risk factor for poorer subsequent neuropsychological functioning. Findings have important implications for public policies related to the legal drinking age and prevention programming. Further studies are needed to replicate these preliminary findings and better understand mediating processes and moderating conditions.

Normal Development of the Corpus Callosum and Evolution of Corpus Callosum Sexual Dimorphism in Infancy.

The aim of this study was to establish reference ranges for the corpus callosum in infancy and to clarify how sexual dimorphism evolves between the fetal stage and infancy. Normal sonograms from cerebral ultrasonographic examinations of 1- to 6-month-old healthy full-term infants were selected. The length and thickness of the corpus callosum were determined, and the effect of sex on these values was analyzed. Studies on corpus callosum sexual dimorphism were reviewed. In total, sonograms from 236 1- to 6-month-old infants (120 male and 116 female) were collected, and the typical values (5th-95th percentiles) of the corpus callosum were determined for each group. During the first 2 months, with and without brain size adjustment, the corpus callosum in female infants was significantly thicker than that in male infants (mean thickness ± SD: 1 month, male infant, 1.8 ± 0.3 mm; female infant, 2.1 ± 0.3 mm; P = .005; 2 months, male infant, 1.8 ± 0.2 mm; female infant, 2.0 ± 0.3 mm; P = .002). The corpus callosum thickness of male and female infants had no significant differences after 2 months of age. Sexual dimorphism was not detected in corpus callosum length. Our study provides reference data on typical corpus callosum development in infants. In the fetal period and early infancy, the corpus callosum in female infants is thicker than that in male infants. From 3 months onward, the corpus callosum sexual dimorphism becomes insignificant throughout childhood. The evolvement of corpus callosum sexual dimorphism suggests that maternal factors may influence brain development.

Cross Talk: The Microbiota and Neurodevelopmental Disorders.

Humans evolved within a microbial ecosystem resulting in an interlinked physiology. The gut microbiota can signal to the brain via the immune system, the vagus nerve or other host-microbe interactions facilitated by gut hormones, regulation of tryptophan metabolism and microbial metabolites such as short chain fatty acids (SCFA), to influence brain development, function and behavior. Emerging evidence suggests that the gut microbiota may play a role in shaping cognitive networks encompassing emotional and social domains in neurodevelopmental disorders. Drawing upon pre-clinical and clinical evidence, we review the potential role of the gut microbiota in the origins and development of social and emotional domains related to Autism spectrum disorders (ASD) and schizophrenia. Small preliminary clinical studies have demonstrated gut microbiota alterations in both ASD and schizophrenia compared to healthy controls. However, we await the further development of mechanistic insights, together with large scale longitudinal clinical trials, that encompass a systems level dimensional approach, to investigate whether promising pre-clinical and initial clinical findings lead to clinical relevance.

Developmental alcohol exposure impairs synaptic plasticity without overtly altering microglial function in mouse visual cortex

Fetal alcohol spectrum disorder (FASD), caused by gestational ethanol (EtOH) exposure, is one of the most common causes of non-heritable and life-long mental disability worldwide, with no standard treatment or therapy available. While EtOH exposure can alter the function of both neurons and glia, it is still unclear how EtOH influences brain development to cause deficits in sensory and cognitive processing later in life. Microglia play an important role in shaping synaptic function and plasticity during neural circuit development and have been shown to mount an acute immunological response to EtOH exposure in certain brain regions. Therefore, we hypothesized that microglial roles in the healthy brain could be permanently altered by early EtOH exposure leading to deficits in experience-dependent plasticity. We used a mouse model of human third trimester high binge EtOH exposure, administering EtOH twice daily by subcutaneous injections from postnatal day 4 through postnatal day 9 (P4-:P9). Using a monocular deprivation model to assess ocular dominance plasticity, we found an EtOH-induced deficit in this type of visually driven experience-dependent plasticity. However, using a combination of immunohistochemistry, confocal microscopy, and in vivo two-photon microscopy to assay microglial morphology and dynamics, as well as fluorescence activated cell sorting (FACS) and RNA-seq to examine the microglial transcriptome, we found no evidence of microglial dysfunction in early adolescence. We also found no evidence of microglial activation in visual cortex acutely after early ethanol exposure, possibly because we also did not observe EtOH-induced neuronal cell death in this brain region. We conclude that early EtOH exposure caused a deficit in experience-dependent synaptic plasticity in the visual cortex that was independent of changes in microglial phenotype or function. This demonstrates that neural plasticity can remain impaired by developmental ethanol exposure even in a brain region where microglia do not acutely assume nor maintain an activated phenotype.

Principles of plasticity in the developing brain.

A discussion of the surprising range of factors influencing brain development Life experiences interact resulting in a phenomenon called metaplasticity.

Prenatal stress affects viability, activation, and chemokine signaling in astroglial cultures

CXCL12/SDF-1α and CX3CL1/fractalkine are constitutively expressed in the brain, which indicates their significant functions. Emerging evidence highlights the role of astrocytes and the immune system in the pathophysiology of stress-related disorders. The aim of this study was to assess whether prenatal stress affects chemokine signaling, cell viability/activation, and the iNOS pathway in astroglial cultures. Our results showed that prenatal stress lowered astrocyte viability and simultaneously increased GFAP expression. Furthermore, CX3CL1 production and the CXCL12/CXCR4-7 axis were also altered by prenatal stress. Taken together, malfunctions caused by prenatal stress may adversely influence brain development, leading to long-term effects on adult brain function and behavior.

The gene encoding the inwardly rectifying potassium channel Kir4.1 may be involved in sudden infant death syndrome.

Disturbances in brain function and development may play a role in sudden infant death syndrome (SIDS). This Norwegian study aimed to test the hypothesis that specific variants of genes involved in water transport and potassium homeostasis would be predisposing factors for SIDS. Genetic variation in the genes encoding aquaporin-4 (AQP4), Kir4.1 (KCNJ10) and α-syntrophin was analysed in 171 SIDS cases (62.6% male) with a median age of 15.5 (2-52) weeks and 398 adult controls (70.6% male) with a median age of 44 (11-91) years. All the subjects were Caucasians who were autopsied from 1988 to 2013. The CC genotype of rs72878794 in the AQP4 gene and a combination of the CC genotype in rs17375748, rs1130183, rs12133079 and rs1186688 in KCNJ10 (4xCC) were found to be associated with SIDS. The SIDS cases with the 4xCC SNP combination were younger than the SIDS cases with other genotype combinations (p = 0.006). This study indicates that genetic variations in KCNJ10 and AQP4 may be predisposing factors for SIDS. Alterations in the expression of the AQP4/Kir4.1 complex can disrupt water and ion homeostasis, which may influence brain development and facilitate brain oedema formation This may be especially unfavourable during the first weeks of life.

Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls.

The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.

The Gut Microbiota and Autism Spectrum Disorders.

Gastrointestinal (GI) symptoms are a common comorbidity in patients with autism spectrum disorder (ASD), but the underlying mechanisms are unknown. Many studies have shown alterations in the composition of the fecal flora and metabolic products of the gut microbiome in patients with ASD. The gut microbiota influences brain development and behaviors through the neuroendocrine, neuroimmune and autonomic nervous systems. In addition, an abnormal gut microbiota is associated with several diseases, such as inflammatory bowel disease (IBD), ASD and mood disorders. Here, we review the bidirectional interactions between the central nervous system and the gastrointestinal tract (brain-gut axis) and the role of the gut microbiota in the central nervous system (CNS) and ASD. Microbiome-mediated therapies might be a safe and effective treatment for ASD.

Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex.

The exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, especially in the prefrontal cortex and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fluorescent excitatory and inhibitory neurons, received a single injection of MK801 (NMDAR antagonist) or vehicle solution at postnatal day 7 and/or were socially isolated from the age of weaning until adulthood (3 months old). We found that anxiety-related behavior, brain volume, neuronal structure, and the expression of molecules related to plasticity and E/I neurotransmission in adult mice were importantly affected by early-life stress. Interestingly, many of these effects were potentiated when the stress paradigm was applied to mice perinatally injected with MK801 ("double-hit" model). These results clearly show the impact of early-life stress on the adult brain, especially on the structure and plasticity of inhibitory networks, and highlight the double-hit model as a valuable tool to study the contribution of early-life stress in the emergence of neurodevelopmental psychiatric disorders, such as schizophrenia.

Lower total and regional grey matter brain volumes in youth with perinatally-acquired HIV infection: Associations with HIV disease severity, substance use, and cognition

Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1years). PHIV youth had smaller (2.8–5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0–13.4%; marijuana use: 10.1–16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume.

Changes in stress-stimulated allopregnanolone levels induced by neonatal estradiol treatment are associated with enhanced dopamine release in adult female rats: reversal by progesterone administration.

Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood. Female rats were treated with 10μg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC). Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors. The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders.

A Glo1-Methylglyoxal Pathway that Is Perturbed in Maternal Diabetes Regulates Embryonic and Adult Neural Stem Cell Pools in Murine Offspring

Maternal diabetes is known to adversely influence brain development in offspring. Here, we provide evidence that this involves the circulating metabolite methylglyoxal, which is increased in diabetes, and its detoxifying enzyme, glyoxalase 1 (Glo1), which when mutated is associated with neurodevelopmental disorders. Specifically, when Glo1 levels were decreased in embryonic mouse cortical neural precursor cells (NPCs), this led to premature neurogenesis and NPC depletion embryonically and long-term alterations in cortical neurons postnatally. Increased circulating maternal methylglyoxal caused similar changes in embryonic cortical precursors andneurons and long-lasting changes in cortical neurons and NPCs in adult offspring. Depletion of embryonic and adult NPCs was also observed in murine offspring exposed to a maternal diabetic environment. Thus, the Glo1-methylglyoxal pathway integrates maternal and NPC metabolism to regulateneural development, and perturbations in this pathway lead to long-lasting alterations in adult neurons and NPC pools.