Correlation of telomere length in brain tissue with peripheral tissues in living human subjects.

Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.

Developmental Disruptions of the Dorsal Striatum in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental condition characterized by social and communication deficits as well as patterns of restricted, repetitive behavior. Abnormal brain development has long been postulated to underlie ASD, but longitudinal studies aimed at understanding the developmental course of the disorder have been limited. More recently, abnormal development of the striatum in ASD has become an area of interest in research, partially due to overlap of striatal functions and deficit areas in ASD, as well as the critical role of the striatum in early development, when ASD is first detected. Focusing on the dorsal striatum and the associated symptom domain of restricted, repetitive behavior, we review the current literature on dorsal striatal abnormalities in ASD, including studies on functional connectivity, morphometry, and cellular and molecular substrates. We highlight that observed striatal abnormalities in ASD are often dynamic across development, displaying disrupted developmental trajectories. Important findings include an abnormal trajectory of increasing corticostriatal functional connectivity with age and increased striatal growth during childhood in ASD. We end by discussing striatal findings from animal models of ASD. In sum, the studies reviewed here demonstrate a key role for developmental disruptions of the dorsal striatum in the pathogenesis of ASD. Directing attention toward these findings will improve our understanding of ASD and of how associated deficits may be better addressed.

Use of a polymeric implant system to assess the neurotoxicity of subacute exposure to 2,2',5,5'-tetrachlorobiphenyl-4-ol, a human metabolite of PCB 52, in male adolescent rats.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that ubiquitously exist in the environment. PCB exposure has been linked to cancer and multi-system toxicity, including endocrine disruption, immune inhibition, and reproductive and neurotoxicity. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) is one of the most frequently detected congeners in the environment and human blood. The hydroxylated metabolites of PCB 52 may also be neurotoxic, especially for children whose brains are still developing. However, it is challenging to discern the contribution of these metabolites to PCB neurotoxicity because the metabolism of PCB is species-dependent. In this study, we evaluated the subacute neurotoxicity of a human-relevant metabolite, 2,2',5,5'-tetrachlorobiphenyl-4-ol (4-52), on male adolescent Sprague Dawley rats, via a novel polymeric implant drug delivery system grafted subcutaneously, at total loading concentrations ranging from 0%, 1%, 5%, and 10% of the implant (w/w) for 28 days. Y-maze, hole board test, open field test, and elevated plus maze were performed on exposure days 24-28 to assess their locomotor activity, and exploratory and anxiety-like behavior. 4-52 and other possible hydroxylated metabolites in serum and vital tissues were quantified using gas chromatography with tandem mass spectrometry (GC-MS/MS). Our results demonstrate the sustained release of 4-52 from the polymeric implants into the systemic circulation in serum and tissues. Dihydroxylated and dechlorinated metabolites were detected in serum and tissues, depending on the dose and tissue type. No statistically significant changes were observed in the neurobehavioral tasks across all exposure groups. The results demonstrate that subcutaneous polymeric implants provide a straightforward method to expose rats to phenolic PCB metabolites to study neurotoxic outcomes, e.g., in memory, anxiety, and exploratory behaviors.

Common Issues for General Practitioners in the Medical Management of Child and Adolescent Psychiatric Care.

With a limited number of child and adolescent psychiatrists available to see youth patients, many common psychiatric problems in youth are managed by other providers. Clinical pearls from experts in child and adolescent psychiatry can help general practitioners with this management. Some common issues are discussed here for which practical guidance is offered, ranging from approaches to assessment and how to start and titrate medications for the treatment of attention deficit hyperactivity disorder, depression, and sleep problems.

Mouse In Vivo Placental Targeted CRISPR Manipulation.

The placenta is an essential organ that regulates and maintains mammalian development in utero. The placenta is responsible for the transfer of nutrients and waste between the mother and fetus and the production and delivery of growth factors and hormones. Placental genetic manipulations in mice are critical for understanding the placenta's specific role in prenatal development. Placental-specific Cre-expressing transgenic mice have varying effectiveness, and other methods for placental gene manipulation can be useful alternatives. This paper describes a technique to directly alter placental gene expression using CRISPR gene manipulation, which can be used to modify the expression of targeted genes. Using a relatively advanced surgical approach, pregnant dams undergo a laparotomy on embryonic day 12.5 (E12.5), and a CRISPR plasmid is delivered by a glass micropipette into the individual placentas. The plasmid is immediately electroporated after each injection. After dam recovery, the placentas and embryos can continue development until assessment at a later time point. The evaluation of the placenta and offspring after the use of this technique can determine the role of time-specific placental function in development. This type of manipulation will allow for a better understanding of how placental genetics and function impact fetal growth and development in multiple disease contexts.

Neonatal loss of FGFR2 in astroglial cells affects locomotion, sociability, working memory, and glia-neuron interactions in mice.

Fibroblast growth factor receptor 2 (FGFR2) is almost exclusively expressed in glial cells in postnatal mouse brain, but its impact in glia for brain behavioral functioning is poorly understood. We compared behavioral effects from FGFR2 loss in both neurons and astroglial cells and from FGFR2 loss in astroglial cells by using either the pluripotent progenitor-driven hGFAP-cre or the tamoxifen-inducible astrocyte-driven GFAP-creERT2 in Fgfr2 floxed mice. When FGFR2 was eliminated in embryonic pluripotent precursors or in early postnatal astroglia, mice were hyperactive, and had small changes in working memory, sociability, and anxiety-like behavior. In contrast, FGFR2 loss in astrocytes starting at 8 weeks of age resulted only in reduced anxiety-like behavior. Therefore, early postnatal loss of FGFR2 in astroglia is critical for broad behavioral dysregulation. Neurobiological assessments demonstrated that astrocyte-neuron membrane contact was reduced and glial glutamine synthetase expression increased only by early postnatal FGFR2 loss. We conclude that altered astroglial cell function dependent on FGFR2 in the early postnatal period may result in impaired synaptic development and behavioral regulation, modeling childhood behavioral deficits like attention deficit hyperactivity disorder (ADHD).

A narrative review of converging evidence addressing developmental toxicity of pyrethroid insecticides.

Pyrethroid insecticides are broadly used in agriculture and household products throughout the world. Exposure to this class of insecticides is widespread, and while generally believed to be safe for use, there is increasing concern regarding their effects on neurodevelopment. Due to the critical roles that molecular targets of pyrethroids play in the regulation of neurodevelopment, particular focus has been placed on evaluating the effects of in utero and childhood pyrethroid exposure on child cognition and behavior. As such, this narrative review synthesizes an assessment of converging study types; we review reports of neonatal pyrethroid levels together with current epidemiological literature that convergently address the risk for developmental toxicity linked to exposure to pyrethroid insecticides. We first address studies that assess the degree of direct fetal exposure to pyrethroids in utero through measurements in cord blood, meconium, and amniotic fluid. We then focus on the links between prenatal exposure to these insecticides and child neurodevelopment, fetal growth, and other adverse birth outcomes. Furthermore, we assess the effects of postnatal exposure on child neurodevelopment through a review of the data on pediatric exposures and child cognitive and behavioral outcomes. Study quality was evaluated individually, and the weight of evidence was assessed broadly to characterize these effects. Overall, while definitive conclusions cannot be reached from the currently available literature, the available data suggest that the potential links between pyrethroid exposure and child neurodevelopmental effects deserve further investigation.

Maternal and fetal tissue distribution of α-cypermethrin and permethrin in pregnant CD-1 mice.

Pyrethroid insecticides are widely used throughout agriculture and household products. Recent studies suggest that prenatal exposure to these insecticides may adversely affect fetal development; however, little is known about the distribution of these chemicals in pregnant animals. The present study aimed to address this gap in knowledge by investigating the distribution of two commonly used pyrethroid insecticides, permethrin and α-cypermethrin, in maternal and fetal tissues of pregnant CD-1 mice. Dams were dosed from gestational days 6 to 16 via oral gavage with permethrin (1.5, 15, and 50 mg/kg), α-cypermethrin (0.3, 3, and 10 mg/kg), or corn oil vehicle. Pyrethroid levels were determined in gestational day 16 tissues collected 90 min after the final dose was administered. Across maternal tissues, levels of both pyrethroids were the highest in maternal ovaries, followed by liver and brain, respectively. In addition, levels of both pyrethroids in maternal tissues and placenta were significantly higher than those in the fetal body and amniotic fluid, suggesting that these compounds may exhibit low transfer across the mouse placenta. While additional toxicokinetic studies are needed to verify the time course of pyrethroids in the fetal compartment, these findings support investigation into indirect modes of action relevant to the effects of pyrethroids on mammalian fetal development.

Dataset describing maternal prenatal restraint stress effects on immune factors in mice.

Maternal immune dysregulation, caused by gestational psychological stress, infection, and other perturbations, results in altered offspring neurodevelopment and increases risk for psychiatric disorders. Prior work has found that multiple cytokines play critical roles in shaping offspring neurodevelopment after gestational stress, though how maternal psychological stress impacts maternal, placental, and fetal cytokine levels more broadly remains unclear. The purpose of the present study was to assess changes to IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-17A, IFNγ, and TNFα in a widely-used mouse prenatal restraint stress model. After repetitive restraint stress on gestational days 12-14, stressed dams had increased serum levels of IL-1ß, IL-6, and IL-10. Embryonic day 14 IL-2 and IL-1ß levels were decreased in prenatally stressed male fetal forebrain, while placental IL-2 was decreased by stress regardless of offspring sex. Placental and fetal forebrain IL-2 levels were negatively correlated. These data provide important insights into the immune changes that occur with prenatal restraint stress.

The Impact of Maternal Antioxidants on Prenatal Stress Effects on Offspring Neurobiology and Behavior.

Prenatal stress is a neuropsychiatric risk factor, and effects may be mediated by prenatal oxidative stress. Cell types in the brain sensitive to oxidative stress-cortical microglia and cortical and hippocampal interneurons-may be altered by oxidative stress generated during prenatal stress and may be neurobiological substrates for altered behavior. Our objective was to determine the critical nature of oxidative stress in prenatal stress effects by manipulating prenatal antioxidants. CD1 mouse dams underwent restraint embryonic day 12 to 18 three times daily or no stress and received intraperitoneal injections before each stress period of vehicle, N-acetylcysteine (200 mg/kg daily), or astaxanthin (30 mg/kg before first daily stress, 10 mg/kg before second/third stresses). Adult male and female offspring behavior, microglia, and interneurons were assessed. Results supported the hypothesis that prenatal stress-induced oxidative stress affects microglia; microglia ramification increased after prenatal stress, and both antioxidants prevented these effects. In addition, N-acetylcysteine or astaxanthin was effective in preventing distinct male and female interneuron changes; decreased female medial frontal cortical parvalbumin interneurons was prevented by either antioxidant; increased male medial frontal cortical parvalbumin interneurons was prevented by N-acetylcysteine and decreased male hippocampal GAD67GFP+ cells prevented by astaxanthin. Prenatal stress-induced increased anxiety-like behavior and decreased sociability were not prevented by prenatal antioxidants. Sensorimotor gating deficits in males was partially prevented by prenatal astaxanthin. This study demonstrates the importance of oxidative stress for persistent impacts on offspring cortical microglia and interneurons, but did not link these changes with anxiety-like, social, and sensorimotor gating behaviors.

Psychiatry Match Rates Increase After Exposure to a Medical Student Mentorship Program: A Multisite Retrospective Cohort Analysis.

OBJECTIVE: Since 2002, the Klingenstein Third Generation Foundation (KTGF) has supported a network of medical student mentorship programs (MSMPs) across the USA with the explicit aim of enhancing interest in, and eventual recruitment into the field of child and adolescent psychiatry (CAP). The authors conducted a multisite, retrospective cohort analysis to examine the impact of the program on career selection, as reflected by graduation match rates into psychiatry or pediatrics. METHODS: The authors collected graduating match information (2008-2019) from fourteen participating medical schools (Exposed) and thirteen non-participating schools (Control). Control schools were selected based on region, comparable student body and faculty size, national standing, and rank in NIH funding. Match rates into psychiatry and pediatrics were compared between Exposed and Control groups. RESULTS: Exposed schools had significantly higher match rates into psychiatry as compared to unexposed schools (6.1% and 4.8%, respectively; OR [95%CI] = 1.29 [1.18, 1.40]; X2 = 32.036, p < 0.001). In contrast, during the same time period, exposed schools had significantly lower match rates into pediatrics than unexposed ones (11.6 and 10.5%, respectively; OR [95%CI] = 0.89 (0.83, 0.95); X2 = 12.127, p < 0.001). These findings persisted even after adjustment for secular trends in match rates. CONCLUSIONS: Seventeen years after its inception, the KTGF medical student mentorship program network has had a positive impact on match rates into general psychiatry. Future studies will address whether these results translate to trainees' eventual selection of careers in CAP.

Maternal treatment with P7C3-A20 protects from impaired maternal care after chronic gestational stress.

Chronic stress during pregnancy harms both the mother and developing child, and there is an urgent unmet need to understand this process in order to develop protective treatments. Here, we report that chronic gestational stress (CGS) causes aberrant maternal care behavior in the form of increased licking and grooming, decreased nursing, and increased time spent nest building. Treatment of CGS-exposed dams with the NAD+-stabilizing agent P7C3-A20 during pregnancy and postpartum, however, preserved normal maternal care behavior. CGS also caused abnormally low weight gain during gestation and postpartum, which was partially ameliorated by maternal treatment with P7C3-A20. Dams also displayed hyperactive locomotion after CGS, which was not affected by P7C3-A20. Although dams did not display a classic depressive-like phenotype after CGS, some changes in anxiety- and depressive-like behaviors were observed. Our results highlight the need for further characterization of the effects of chronic gestational stress on maternal care behavior and provide clues to possible protective mechanisms.

The Effects of Polychlorinated Biphenyl Exposure During Adolescence on the Nervous System: A Comprehensive Review.

Exposure to polychlorinated biphenyls (PCBs) is implicated in adverse neurotoxic outcomes. However, the impact of PCBs on the adolescent nervous system has received inadequate attention. We conducted a comprehensive review to identify studies of neurotoxic outcomes following PCB exposure during the adolescent period in rodents. Only four papers were found to meet all inclusion criteria. PCB exposure in adolescent rats caused disruptions in the main functions of the prefrontal cortex, resulting in cognitive deficits. This comprehensive review demonstrates that more research is needed to characterize how PCB exposure adversely affects the adolescent nervous system.

Editorial: Macaque At-Birth Adoption: Its Power and Promise.

A compelling piece of science in this month's issue is the work of Wood et al., which addresses a long-standing question about adoption in infancy-could the process of adoption affect the later characteristics of adopted children?1 This question arises from studies showing that children adopted at birth have higher rates of behavioral problems on average later in life.2 Potential confounds of such studies are that adopted children may enter the adoption with pre-existing vulnerabilities related to the reason for adoption, which in turn could lead to behavioral differences. Scientists trying to minimize this confound previously have capitalized on the benefits of animal model approaches-randomization, controlled genetic background, controlled environmental factors, faster development, opportunities for close observation3-showing that adoption at birth can affect rodent offspring long term.4 However, a nonhuman primate study comes closer to addressing this question specifically for our human, primate vulnerability.

A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment.

Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.

Maternal P7C3-A20 Treatment Protects Offspring from Neuropsychiatric Sequelae of Prenatal Stress.

Aims: Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Results: Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Innovation: Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. Conclusion: NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment. Antioxid. Redox Signal. 35, 511-530.

Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model.

Preeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate-putamen volume, increased caudate-putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate-putamen volume, while females had increased caudate-putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

Telomere Length and ADHD Symptoms in Young Adults.

Objective: Previous research examining telomeres in individuals with neuropsychiatric disorders shows that greater illness, symptoms, or cognitive impairment are linked with shorter telomeres. However, the relationships of telomere length and neuropsychological processes or psychiatric symptoms are not understood in individuals with Attention Deficit/Hyperactivity Disorder (ADHD). Method: 390 young adults with and without ADHD completed a multi-informant diagnostic assessment and neuropsychological testing battery. Participant DNA was isolated from saliva samples, and telomere length was determined using qPCR. Results: Linear regression models demonstrated the only significant association to survive correction for multiple testing was for childhood hyperactivity-impulsivity symptoms and longer telomere length. Conclusion: Contrary to expectations, longer telomere length in young adults was associated only with childhood ADHD symptoms, particularly hyperactivity-impulsivity, in this sample. These findings are an important demonstration that the neuropsychological deficits and symptoms experienced by individuals diagnosed with ADHD during adulthood may not be negatively associated with telomere length.