Opioid replacement therapy with methadone or buprenorphine has been recommended for managing opioid dependence during pregnancy. Although opioid replacement therapy decreases harmful consequences from maternal illicit drug seeking behaviors, the effects of methadone and buprenorphine on neurogenesis and myelination in the developing fetus have not been thoroughly reviewed. Methadone and buprenorphine may alter newborn neurobehavioral functions by impairing neurogenesis and changing the developmental pattern of myelination. This review found that therapeutic doses of methadone and buprenorphine disturb both neurogenesis and myelination in rodents. Methadone and buprenorphine may alter newborn neurobehavioral functions by impairing neurogenesis and changing the developmental pattern of myelination. However, further studies are required to bridge the gap in the understanding between changes in neural development and abnormalities in neurobehavioral functions in the newborn.

BACKGROUND: While manganese (Mn) is essential for growth and development, evidence for Mn as a developmental neurotoxicant is mounting. However, inconsistencies in exposure metrics, susceptibility factors and neurobehavioral outcomes muddle the understanding of Mn effects on the developing nervous system. OBJECTIVE: To estimate Mn-neurobehavioral associations in varied neurobehavioral tasks and evaluate susceptibility factors (sex differences, co-exposures, exposure timing). METHODS: Research aims were conducted using the Public Health Impact of Mixed element Exposure (PHIME) study, including 720 Italian adolescents living near ferro-manganese industry. Blood, hair, nails, urine and saliva were collected in adolescence and metals [Mn, lead (Pb), copper (Cu), chromium (Cr)] were measured using ICP-MS. Mn was measured in deciduous teeth in a subset of participants (n=195) using LA ICP-MS to represent prenatal, postnatal and childhood exposure periods. Trained neuropsychologists administered a neurobehavioral battery to adolescents. In the first aim, we estimated associations of early-life Mn levels measured in deciduous teeth with visuospatial learning and memory, assessed using the Virtual Radial Arm Maze (VRAM), a novel animal-human translational neurobehavioral task. The second aim estimated associations of prenatal, early postnatal (0-1 year) and childhood (1~6 years) Mn measured in deciduous teeth with IQ scores and subtests measured by the Wechsler Intelligence Scale for Children (WISC-III). The third aim evaluated the association of a mixture of metals (Mn, Pb, Cu, Cr) measured in multiple biomarkers (hair, blood, urine, nails, saliva) and IQ. Data analysis included generalized additive models, linear regression, zero-inflated Poisson regression (for VRAM count outcomes), and Bayesian kernel machine regression (BKMR). RESULTS: In the first aim we observed U-shaped associations between prenatal Mn and VRAM outcomes among girls only, suggesting that low and high prenatal Mn levels may be harmful to visuospatial learning and memory. In the second aim, several associations were found with specific subtests that assess visuospatial ability, working memory, problem solving and attention, wherein estimates from the prenatal period suggested beneficial Mn associations, unlike the early postnatal and childhood periods. For the third aim we found inverse associations of adolescent Mn, measured either in hair or saliva, with verbal IQ (VIQ) scores, and an inverted U-shaped association for hair Cu. Strongest associations for the overall metals mixture were estimated with VIQ, where the joint increase in metals concentrations was associated with lower VIQ scores. / 2022-09-25T00:00:00Z

Opiate addiction is now a major public health problem. Pregnant women continue to use opiates during gestation; up to 5.4% of pregnant women report using illicit drugs during pregnancy. Previous studies have shown that perinatal insults and exposure to opiates such as morphine in utero can affect the development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring and are associated with higher risk of developing neurobehavioral problems. Oxycodone, a semisynthetic putative kappa opioid receptor and partial mu opioid receptor agonist is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters the development and functions of the HPA-axis, the related stress axis and neurobehavioral outcomes of the offspring. Data from these experiments have provided novel evidence that POE indeed is associated with sex-specific changes in the HPA-axis in response to stress that persist beyond the neonatal period. 1) POE is associated with an increased adrenocorticotropic hormone (ACTH) response to corticotropin-releasing hormone (CRH), but not the corticosterone (CORT) response to CRH stimulation in late adolescent male offspring. 2) POE is associated with increased CORT, but not ACTH response to restraint stress test in adult female offspring. These changes in the HPA-axis response to stress may be partially explained by 1) an increase in the subpopulation of CRH neurons that also contain estrogen receptor-beta immunoreactivity following POE which then can exaggerate the stimulation of the HPA-axis, and 2) a decrease in mineralocorticoid receptor-mRNA expression in the hippocampus which may be associated with impaired negative feedback control of the HPA-axis by the limbic system. POE is also associated with cardiovascular changes in response to stress during a classical conditioning paradigm; adolescent male POE rats have a larger blood pressure increase than the control group. Although POE male rats can properly discriminate the stress versus non-stress cues in the conditioning paradigm, they do not retain this memory when retested during adulthood. When tested for learning and memory in a water maze, however, we did not find any differences between control rats and rats exposed to high dose oxycodone in utero. In addition, we demonstrated that exposure to the lower dose of oxycodone in utero is associated with hyperactivity in adult rats when tested in an open field. Our results make a significant contribution to the literature because they extend our knowledge about the effects of oxycodone on the developing brain and the resulting outcomes in animal models that are actually relevant to a current major public health problem in humans and will provide a platform for us to further study the underlying mechanisms and interventions that may mitigate these effects.

Neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder, are a heterogeneous set of developmental disorders affecting the central nervous system. Studies into their etiology remain challenging, as neurodevelopmental disorders frequently present with a wide range of biological, behavioral, and comorbid symptomologies. Increasing epidemiological reports of antibiotic use during pregnancy as a significant correlate of subsequent mental disorder diagnosis in children suggest a mechanism of influence via the maternal gut-fetal brain axis. Importantly, antibiotics cause dysbiosis of the gut microbiome and disrupt the delicate composition of the microbial inoculum transferred from mother to child, which is critical for development of the immune system and holds implications for long-term health outcomes. The research objective of this dissertation is to reveal a causal mechanism of maternal microbial influence on neurodevelopment by examining the brain's resident immune cells, microglia, and corresponding behavioral outcomes in a mouse model of antibiotics-driven maternal microbiome dysbiosis (MMD). We identify early gross motor deficits and social behavior impairments in offspring born to MMD dams, which paralleled hyperactivated microglia in brain regions specific to cognition and social reward. The MMD microglia also exhibited altered transcriptomic signatures reflective of premature cellular senescence that support evidence of impaired synaptic modeling found in MMD brains. We report that these deficits are rescued in the absence of Cx3cr1, a chemokine receptor expressed ubiquitously on microglia, to highlight a pathway in which maternal microbiota may signal to neonatal microglia to undergo appropriate neurodevelopmental actions. Finally, we characterize Lactobacillus murinus HU-1, a novel strain of an important gut bacterium found in native rodent microbiota, and demonstrate its use as a probiotic to restore microglial and behavioral dysfunction in MMD offspring. / Ph. D. / Population studies on neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder, highlight antibiotic use during pregnancy as a major correlate of subsequent diagnoses in children. These findings support a growing body of evidence from animal and human studies that the microbial ecosystems (“microbiome”) found in and on our bodies play significant roles in mental health, including mood, cognition, and brain function. Importantly, antibiotics during pregnancy create an imbalance of the gut microbiome (“dysbiosis”) and disrupt the microbial inoculum transferred from mother to child, which is critical for maturation of the infant immune system and holds implications for long-term health outcomes. Thus, the research objective of this dissertation is to identify a mechanism of influence from the mother’s gut to the neonate’s brain by examining the brain’s resident immune cells (“microglia”) in a mouse model of antibiotics-driven maternal microbiome dysbiosis (MMD). We uncover autism-like behavioral deficits and dysfunctional microglia in MMD offspring, and characterize signaling cues specific to microglia by which improper neurodevelopment may be taking place. We also reveal that the detrimental effects of MMD are reversed in mice born to mothers pretreated with a probiotic candidate, Lactobacillus murinus HU-1, to suggest maternally-derived Lactobacillus may help to mediate proper neurodevelopment.

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Prenatal opioid exposure has been studied in relation to infants' medical outcomes. However, large gaps exist in the literature supporting early identification of atypical neurobehavior and motor development of infants with prenatal opioid exposure. The purpose of the study was to investigate whether prenatal opioid exposure has a negative influence on a newborn infant’s neurobehavior and motor development to aid in the early identification of potential delays. Using a prospective quasi experimental design, infants motor development using the Test of Infant Motor Performance (TIMP) and neurobehavior using the NICU Neonatal Network Scale (NNNS) was assessed on 58 infants in a hospital setting. Even after statistically controlling for covariates both the TIMP and the six out of twelve subscales of the NNNS: attention, handling, self-regulation, arousal, excitability, and stress were significantly different between the two groups of infants. Infants’ TIMP z-scores were significantly correlated with the NNNS subscales of attention, handing, self-regulation, arousal, excitability, hypertonicity, non-optimal reflexes, and stress. The findings highlight the similarities between the two groups and the outcome measures used for early identification of infants at-risk for delays following prenatal opioid exposure. The neonatal outcomes described here, including growth deficits, motor delays and altered neurobehavior are critical given their association with longer-term health and developmental impacts.