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Thermal videos provide a privacy-preserving yet information-rich data source for remote health monitoring, especially for respiration rate (RR) estimation. This paper introduces an end-to-end deep learning approach to RR measurement using thermal video data. A detection transformer (DeTr) first finds the subject's facial region of interest in each thermal frame. A respiratory signal is estimated from a dynamically cropped thermal video using 3D convolutional neural networks and bi-directional long short-term memory stages. To account for the expected phase shift between the respiration measured using a respiratory effort belt vs. a facial video, a novel loss function based on negative maximum cross-correlation and absolute frequency peak difference was introduced. Thermal recordings from 22 subjects, with simultaneous gold standard respiratory effort measurements, were studied while sitting or standing, both with and without a face mask. The RR estimation results showed that our proposed method outperformed existing models, achieving an error of only 1.6 breaths per minute across the four conditions. The proposed method sets a new State-of-the-Art for RR estimation accuracy, while still permitting real-time RR estimation.

Objective: Small for gestational age (SGA) infants are at increased risk for neonatal morbidity and developmental problems in childhood. No current interventions during human pregnancy address this problem. This study investigated the possible relationship between maternal choline concentration during pregnancy and SGA infants., Study Design: Maternal plasma choline concentrations were sampled at 16 and 28 weeks' gestation from women in a public prenatal clinic. Additional factors assessed were maternal age, body mass index, infection, C-reactive protein, hair cortisol, and compliance with prenatal vitamins and folate. Infants below the 10th percentile for gestational age were classified as SGA. Binary logistic regression was used to identify significant associated factors in pregnancies resulting in SGA infants compared with pregnancies resulting in non-SGA infants., Results: Thirteen (8%) of 159 women had SGA infants. Maternal plasma choline concentrations were low for pregnant participants whose infants were SGA, with the 28-week concentration significantly lower compared with other participants. Plasma choline concentrations ≥7 μM at 28 weeks, consistent with a minimally adequate dietary intake of choline-containing foods, were achieved by only 2 (15%) of mothers with SGA infants, compared with 51% of mothers whose infants were not SGA. Choline concentrations <7 μM at 28 weeks' gestation were associated with an odds ratio for SGA of 16.6 (95% confidence interval: 1.5-189.2, p  = 0.023). Other significant factors were female sex and maternal C-reactive protein plasma concentration during gestation., Conclusion: This observational study suggests that higher maternal choline levels may influence the risk for SGA. Maternal plasma choline concentrations are not routinely available in clinical laboratories. However, plasma choline levels can be increased by the mothers' intake of choline or phosphatidylcholine supplements. No nutritional intervention is currently recommended to prevent SGA, but the evidence from this study suggests that further consideration of the role of maternal choline may be warranted., Key Points: · More females are small for gestational age.. · Low maternal choline is related to small infants.. · Maternal choline ≥7 μM at 28 weeks appears optimal.., Competing Interests: A.D. disclosed that he is a founder and Chief Scientific Officer of Omix Technologies, Inc. and Altis Biosciences, and Scientific Advisory Board member of Hemanext Inc. The other authors report no conflict of interest., (Thieme. All rights reserved.)

The vehicle emissions testing programme was conducted by the UK Department of Transport in 2016 in response to emissions tampering exposed in the Volkswagen (VW) emissions scandal. The programme identified large emissions discrepancies between real-world and in-lab testing across a range of Euro 5 and Euro 6 diesel passenger vehicles. The large vehicle test fleet reflects the current challenges faced in controlling vehicle emissions. This paper presents the following findings: NO x emissions are altered due to exhaust gas recirculation mismanagement. A new Real-Life Emissions methodology is introduced to improve upon the current Real Driving Emissions standard. A large and concerning emissions divergence was discovered between the achieved NO x improvement and deterioration of CO 2 . The findings act as catalysts to improve vehicle emissions testing beyond standards established since the VW scandal, aiding in the development of better climate change mitigation strategies and bring tangible air quality improvements to the environment., (© 2023. Crown.)

For military rotary-wing aircrew, little is known about the interactive effects of vibration exposure and the addition of head supported mass (HSM) on target acquisition performance, head kinematics, and muscular demand. Sixteen healthy male participants wore an aviator helmet with replica night vision goggles and completed rapid aiming head movements to acquire visual targets in axial and off-axis movement trajectories while secured in a Bell-412 helicopter seat mounted to a human-rated shaker platform. HSM configuration (with or without a counterweight (CW)) and vertical whole-body vibration (WBV) conditions (vibration or no vibration exposure) were manipulated as independent variables. WBV exposure degraded target acquisition performance and lengthened time to peak velocity of head movements. For yaw peak velocity in the axial movement trajectory, peak velocity was 9.9%, 11.6%, and 8.4% higher in the noCW + WBV condition compared to the CW + WBV, CW + noWBV, and noCW + noWBV conditions, respectively. Practitioner summary: The majority of military helicopter aircrew use a counterweight to counteract the anteriorly displaced load of night vision googles. This study was undertaken to better understand how helicopter vibration and counterweight use interactively affect performance and health-related measures during rapid scanning head movements.

Background: Prenatal choline is a key nutrient, like folic acid and vitamin D, for fetal brain development and subsequent mental function. We sought to determine whether effects of higher maternal plasma choline concentrations on childhood attention and social problems, found in an initial clinical trial of choline supplementation, are observed in a second cohort., Methods: Of 183 mothers enrolled from an urban safety net hospital clinic, 162 complied with gestational assessments and brought their newborns for study at 1 month of age; 83 continued assessments through 4 years of age. Effects of maternal 16 weeks of gestation plasma choline concentrations ⩾7.07 μM, 1 s.d. below the mean level obtained with supplementation in the previous trial, were compared to lower levels. The Attention Problems and Withdrawn Syndrome scales on Child Behavior Checklist 1½-5 were the principal outcomes., Results: Higher maternal plasma choline was associated with lower mean Attention Problems percentiles in children, and for male children, with lower Withdrawn percentiles. Higher plasma choline concentrations also reduced Attention Problems percentiles for children of mothers who used cannabis during gestation as well as children of mothers who had gestational infection., Conclusions: Prenatal choline's positive associations with early childhood behaviors are found in a second, more diverse cohort. Increases in attention problems and social withdrawal in early childhood are associated with later mental illnesses including attention deficit disorder and schizophrenia. Choline concentrations in the pregnant women in this study replicate other research findings suggesting that most pregnant women do not have adequate choline in their diets.

Choline, folic acid, and Vitamin D are essential for fetal brain development that may be the first steps in the pathogenesis of the psychotic spectrum. Micronutrient deficiencies have been associated with changes in fetal brain development, manifest as early problems in childhood behavior, and cognition, and later as increased incidence of psychotic and autism spectrum disorders. Micronutrient supplements may not only prevent deficiency, but they may also positively affect brain development in the context of other maternal risk factors, including maternal infection, stress, inflammation, and substance abuse. Many genes associated with later psychotic illness are highly expressed in the fetal brain, where they are responsible for various neurodevelopmental mechanisms. Interaction of micronutrient vitamins with these genetically programmed mechanisms to prevent pathological brain development associated with later psychosis is under active investigation. In addition to their effects on brain development, micronutrient vitamins have effects on other aspects of gestation and fetal development, including the prevention of premature delivery and other developmental abnormalities. Supplemental micronutrient vitamins should be part of good prenatal care, as has already happened for folic acid and Vitamin D and is now advocated by the American Medical Association for choline. The benefits of these micronutrient supplements include protection of brain development and the possibility of decreased risk for future psychotic disorders in those children who are either genetically or environmentally vulnerable. The purpose of this review is to present the current evidence supporting the safety and effectiveness of micronutrients in gestation and to suggest areas for future research., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Maternal depression during gestation is an adverse factor in fetal brain development that manifests in later childhood behavioral problems. Fetal heart rate variability (FHRV) mediated by parasympathetic input is a marker of gestational nervous system development. Biological mediators of adverse effects of maternal depression may involve the mother's corticosteroids; however, links between depression, corticosteroids, and early nervous system development remain inconclusive., Methods: Heart rate was recorded in 23 fetuses by transabdominal Doppler at 28-33 weeks gestation. The SD of interbeat intervals over 20 min assessed FHRV. Maternal depression ratings and hair concentrations of cortisol and cortisone were assayed. An auditory sensory gating paradigm assessed newborn development of cerebral inhibition. Parents rated their infant's temperament characteristics on the Infant Behavior Questionnaire-Revised Short Form (IBQ-R)., Results: Maternal depression was associated with lower FHRV, especially for male fetuses, β = -0.633, P = 0.045. Maternal depression was associated with lower cortisol to total corticosteroids ratios, β = -0.519, P = 0.033. Lower cortisol ratios were associated with decreased FHRV, β = 0.485, P = 0.019. Decreased FHRV was associated with increased newborn sensory gating deficits, β = -0.992, P = 0.035, indicating poorer development of cerebral inhibition. Higher FHRV was related to increased infant IBQ-R self-regulatory behaviors, r = 0.454, P = 0.029., Conclusion: Maternal depression is associated via corticosteroids with decreased development of nervous system control of fetal heart rate. Decreased FHRV indicates developmental alterations in gestation that correlate with altered brain function and subsequent regulatory challenges in early infancy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Maternal gestational inflammation from infection, obesity, depression, and adverse childhood experiences negatively affects offspring cognitive development. Choline is a key nutrient in fetal brain development. We investigated whether higher maternal plasma choline concentrations have a positive association with offspring cognition, specifically processing speed, in the presence of inflammation. Forty-eight children were evaluated at 4 years of age. Processing Speed Composite Score on the Wechsler Preschool & Primary Scales of Intelligence was the principal outcome. Maternal C-reactive protein (CRP), a marker of inflammation, and choline plasma concentration had been measured at 16 weeks' gestation. Choline concentrations >7.07μM were compared to lower levels. Mothers with lower choline levels reported more depression and stress. Head circumference was larger for neonates of mothers with higher choline levels. In analyses with maternal CRP, higher maternal choline was associated with higher offspring Processing Speed Composite Scores for both sexes. For males, higher maternal choline competed with the negative association of maternal CRP on Processing Speed. Higher Processing Speed was related to the child's behavioral ratings, with fewer Withdrawn Problems on the Child Behavior Checklist 1 ½-5 years at 4 years and higher Infant Behavior Questionnaire Orienting/Regulation at 3 months of age, consistent with persistent developmental effects. Higher processing speed and decreased problems in social withdrawal are positively associated with prenatal maternal choline. Both lower processing speed and social withdrawal problems are precursors to later mental difficulties. Choline supplementation in pregnancy may mitigate effects of maternal inflammation that contribute to problems in offspring's' cognition and behavior., (Copyright © 2021. Published by Elsevier Ltd.)

Black Americans have increased risk for schizophrenia and other mental illnesses with prenatal origins. Prenatal choline promotes infant brain development and behavioral outcomes, but choline has not been specifically assessed in Black Americans. Pregnant women (N = 183, N = 25 Black Americans) enrolled in a study of prenatal stressors and interactions with prenatal choline. Black American women had lower 16-week gestation plasma choline than Whites. Lower choline was not related to obesity, income, or metabolic genotypes. Pregnant women in rural Uganda have higher choline levels than Black American women. Black Americans' lower choline was associated with higher hair cortisol, indicative of higher stress. Lower maternal choline was associated with offsprings' lower gestational age at birth and with decreased auditory P50 inhibition, a marker of inhibitory neuron development. Behavioral development was assessed on the Infant Behavior Questionnaire-R-SF (IBQ-R) at 3 months. Lower Black American maternal gestational choline was associated with lower infant IBQ-R Orienting/Regulation, indicating decreased attention and relation to caregivers. Additional evidence for developmental effects of choline in Black Americans comes from a randomized clinical trial of gestational phosphatidylcholine supplementation versus placebo that included 15 Black Americans. Phosphatidylcholine increased gestational age at birth and newborn P50 inhibition and decreased Social Withdrawn and Attention problems at 40 months of age in Black Americans' offspring compared to placebo. Inhibitory and behavioral deficits associated with lower prenatal choline in offspring of Black American women indicate potential developmental predispositions to later mental illnesses that might be ameliorated by prenatal choline or phosphatidylcholine supplementation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

These initial data suggest that with prenatal vitamins and choline supplements, we might decrease one risk factor associated with poorer health outcomes disproportionally affecting Black families, ie, preterm birth. Dissemination of this research fulfills the principle of Justice in the Belmont Report, to ensure that participants from different racial, ethnic and socioeconomic groups receive benefits from research directed to their specific problems., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Maternal gestational infection is a well-characterized risk factor for offsprings' development of mental disorders including schizophrenia, autism, and attention deficit disorder. The inflammatory response elicited by the infection is partly directed against the placenta and fetus and is the putative pathogenic mechanism for fetal brain developmental abnormalities. Fetal brain abnormalities are generally irreversible after birth and increase risk for later mental disorders. Maternal immune activation in animals models this pathophysiology. SARS-CoV-2 produces maternal inflammatory responses during pregnancy similar to previously studied common respiratory viruses., Method: Choline, folic acid, Vitamin D, and n-3 polyunsaturated fatty acids are among the nutrients that have been studied as possible mitigating factors for effects of maternal infection and inflammation on fetal development. Clinical and animal studies relevant to their use in pregnant women who have been infected are reviewed., Results: Higher maternal choline levels have positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy. No other nutrient has been studied in the context of viral inflammation. Vitamin D reduces pro-inflammatory cytokines in some, but not all, studies. Active folic acid metabolites decrease anti-inflammatory cytokines. N-3 polyunsaturated fatty acids have no effect., Conclusions: Vitamin D and folic acid are already supplemented in food additives and in prenatal vitamins. Despite recommendations by several public health agencies and medical societies, choline intake is often inadequate in early gestation when the brain is forming. A public health initiative for choline supplements during the pandemic could be helpful for women planning or already pregnant who also become exposed or infected with SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Prenatal depression has lasting effects on development in offspring, including later mental illness risk. Maternal responses to depression include inflammation and hypothalamic-pituitary-adrenal axis stimulation. Effects on development of cerebral inhibitory neurocircuits may differ for female and male fetuses., Methods: Mothers (N = 181) were assessed periodically, beginning at 16 weeks' gestation, using the Center for Epidemiologic Studies-Depression Scale. Maternal prenatal C-reactive protein and hair cortisol and cortisone levels were determined. Cortisone was determined in neonatal hair. Development of cerebral inhibitory neurocircuits was assessed in 162 1-month-old newborns by inhibition of P50 electrophysiological responses to repeated sounds., Results: Maternal depression was associated with decreased newborn P50 inhibition in both sexes. Maternal C-reactive protein levels were significantly associated with depression only in pregnancies with male fetuses and with decreased newborn P50 inhibition only in male newborns. Maternal cortisol levels were significantly associated with depression only in pregnancies with female fetuses and with decreased newborn P50 inhibition only in female newborns. In pregnancies with male fetuses compared with pregnancies with female fetuses, cortisol was more robustly metabolized to cortisone, which does not activate cortisol receptors., Conclusions: This study finds sex-specific associations of C-reactive protein and cortisol levels with prenatal depression in women and with decreased development of newborn P50 inhibition. Sex-based differences in maternal response to depression with inflammation or cortisol and their developmental effects may reflect evolutionary influences to promote survival in adversity. Decreased newborn P50 inhibition is associated with later childhood behavioral problems, and decreased P50 inhibition is a pathophysiological feature of several mental illnesses., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The serine/threonine protein kinase v-AKT homologs (AKTs), are implicated in typical and atypical neurodevelopment. Akt isoforms Akt1, Akt2, and Akt3 have been extensively studied outside the brain where their actions have been found to be complementary, non-overlapping and often divergent. While the neurological functions of Akt1 and Akt3 isoforms have been investigated, the role for Akt2 remains underinvestigated. Neurobehavioral, electrophysiological, morphological and biochemical assessment of Akt2 heterozygous and knockout genetic deletion in mouse, reveals a novel role for Akt2 in axonal development, dendritic patterning and cell-intrinsic and neural circuit physiology of the hippocampus and prefrontal cortex. Akt2 loss-of-function increased anxiety-like phenotypes, impaired fear conditioned learning, social behaviors and discrimination memory. Reduced sensitivity to amphetamine was observed, supporting a role for Akt2 in regulating dopaminergic tone. Biochemical analyses revealed dysregulated brain mTOR and GSK3β signaling, consistent with observed learning and memory impairments. Rescue of cognitive impairments was achieved through pharmacological enhancement of PI3K/AKT signaling and PIK3CD inhibition. Together these data highlight a novel role for Akt2 in neurodevelopment, learning and memory and show that Akt2 is a critical and non-redundant regulator of mTOR activity in brain.

Background: Maternal inflammation in early pregnancy has been identified epidemiologically as a prenatal pathogenic factor for the offspring's later mental illness. Early newborn manifestations of the effects of maternal inflammation on human fetal brain development are largely unknown., Methods: Maternal infection, depression, obesity, and other factors associated with inflammation were assessed at 16 weeks gestation, along with maternal C-reactive protein (CRP), cytokines, and serum choline. Cerebral inhibition was assessed by inhibitory P50 sensory gating at 1 month of age, and infant behavior was assessed by maternal ratings at 3 months of age., Results: Maternal CRP diminished the development of cerebral inhibition in newborn males but paradoxically increased inhibition in females. Similar sex-dependent effects were seen in mothers' assessment of their infant's self-regulatory behaviors at 3 months of age. Higher maternal choline levels partly mitigated the effect of CRP in male offspring., Conclusions: The male fetal-placental unit appears to be more sensitive to maternal inflammation than females. Effects are particularly marked on cerebral inhibition. Deficits in cerebral inhibition 1 month after birth, similar to those observed in several mental illnesses, including schizophrenia, indicate fetal developmental pathways that may lead to later mental illness. Deficits in early infant behavior follow. Early intervention before birth, including prenatal vitamins, folate, and choline supplements, may help prevent fetal development of pathophysiological deficits that can have life-long consequences for mental health.

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6-16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants' level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ≥7.5 μM, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neuregulin-ErbB signaling is essential for numerous functions in the developing, adult, and aging brain, particularly in the prefrontal cortex (PFC). Mouse models with disrupted Nrg and/or ErbB genes are relevant to psychiatric, developmental, and age-related disorders, displaying a range of abnormalities stemming from cortical circuitry impairment. Many of these models display nonoverlapping phenotypes dependent upon the gene target and timing of perturbation, suggesting that cortical expression of the Nrg-ErbB network undergoes temporal regulation across the lifespan. Here, we report a comprehensive temporal expression mapping study of the Nrg-ErbB signaling network in the mouse PFC across postnatal development through aging. We find that Nrg and ErbB genes display distinct expression profiles; moreover, splice isoforms of these genes are differentially expressed across the murine lifespan. We additionally find a developmental switch in ErbB4 splice isoform expression potentially mediated through coregulation of the lncRNA Miat expression. Our results are the first to comprehensively and quantitatively map the expression patterns of the Nrg-ErbB network in the mouse PFC across the postnatal lifespan and may help disentangle the pathway's involvement in normal cortical sequences of events across the lifespan, as well as shedding light on the pathophysiological mechanisms of abnormal Nrg-ErbB signaling in neurological disease., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Normative brain development is contingent on the complex interplay between genes and environment. Schizophrenia (SCZ) is considered a highly polygenic, neurodevelopmental disorder associated with impaired neural circuit development, neurocognitive function and variations in neurotransmitter signaling systems, including dopamine. Significant evidence, accumulated over the last 30 years indicates a role for the in utero environment in SCZ pathophysiology. Emerging data suggests that changes in placental programming and function may mediate the link between genetic risk, early life complications (ELC) and adverse neurodevelopmental outcomes, with risk highlighted in key developmental drivers that converge on AKT/mTOR signaling. In this article we overview select risk genes identified through recent genome-wide association studies of SCZ including AKT3, miR-137, DRD2, and AKT1 itself. We propose that through convergence on AKT/mTOR signaling, these genes are critical factors directing both placentation and neurodevelopment, influencing risk for SCZ through dysregulation of placental function, metabolism and early brain development. We discuss association of risk genes in the context of their known roles in neurodevelopment, placental expression and their possible mechanistic links to SCZ in the broad context of the 'developmental origins of adult disease' construct. Understanding how common genetic variation impacts early fetal programming may advance our knowledge of disease etiology and identify early critical developmental windows for prevention and intervention., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. This work was supported by the National Institute of Mental Health under Award Number R01MH103716 (AJL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Activity and expression of the phosphoinositide 3-kinase (PI3K) catalytic isoform, PIK3CD/p110δ, is increased in schizophrenia, autism, and intellectual delay and pro-cognitive preclinical efficacy of p110δ-inhibition has been demonstrated in pharmacological, genetic, and developmental rodent models of psychiatric disorders. Although PI3K signaling has been implicated in the development and function of neurons and glia; isoform-specific roles of the individual PI3Ks are less clear and the biological effects of increased p110δ on neuronal development are unknown. Since the pathobiological direction of p110δ changes in neurodevelopmental disorders are increased expression and activity, we hypothesized that overexpression of p110δ would impact measures of neuronal development and maturation relevant to connectivity and synaptic transmission. p110δ overexpression in primary rat hippocampal cultures significantly reduced dendritic morphogenesis and arborization and increased immature and mature dendritic spine densities, without impacting cell viability, soma size, or axon length. Together, our novel findings demonstrate the importance of homeostatic regulation of the p110δ isoform for normative neuronal development and highlight a potential pathophysiological mechanism of association to disorders of neurodevelopment., (Copyright © 2020 Hood, Paterson and Law.)

PIK3CD encodes the phosphoinositide 3-kinase (PI3K) catalytic subunit, p110δ, a lipid kinase linked to neurodevelopmental disorders, including schizophrenia (SZ). PIK3CD is regulated at the transcript level through alternate use of 5' untranslated exons (UTRs), promoters, and proinflammatory cytokines. Increases in global PIK3CD expression and downregulation by neuroleptics are observed in SZ, and preclinical efficacy of a p110δ-selective inhibitor is seen in rodent models of risk. Here, we cloned PIK3CD alternative transcripts in human brain and evaluated temporal- and tissue-specific expression. We quantified PIK3CD transcripts in B-lymphoblastoid cells from patients with SZ and examined 5' UTR transcriptional regulation by tumor necrosis factor α (TNFα) and interleukin-1β (IL1β) in patient-derived fibroblasts. We report that PIK3CD transcripts are differentially expressed in human brain in a developmental-specific manner. Transcripts encoding 5' UTRs -2A and alternative exon -1 (Alt1), P37 and AS1 and AS2 were increased in SZ. Alt1, P37, and AS2 were also preferentially expressed in fetal brain, and all transcripts were regulated by TNFα and IL1β. Our findings provide novel insight into the complexity of PIK3CD regulation in human brain, implicate PIK3CD in human neurodevelopment, and identify isoform-specific disruption in SZ., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The MIR137HG gene encoding microRNA-137 (miR-137) is genome-wide associated with schizophrenia (SZ), however, the underlying molecular mechanisms remain unknown. Through cloning and sequencing of individual transcripts from fetal and adult human brain tissues we describe novel pri-miR-137 splice variants which exclude the mature miR-137 sequence termed 'del-miR-137' that would function to down-regulate miR-137 expression. Sequencing results demonstrate a significant positive association between del-miR-137 transcripts and the length of a proximal variable number tandem repeat (VNTR) element. Additionally, a significantly higher proportion of sequenced transcripts from fetal brain were del-miR-137 transcripts indicating neurodevelopmental splicing regulation. In-silico results predict an independent regulatory function for del-miR-137 transcripts through competitive endogenous RNA function. A case-control haplotype analysis (n = 998) in SZ implicates short VNTR length in risk, with longer lengths imparting a protective effect. Rare high risk haplotypes were also observed indicating multiple risk variants within the region. A second haplotype analysis was performed to evaluate recombination effects excluding the VNTR and results indicate that recombination of the region was found to independently contribute to risk. Evaluation of the evolutionary conservation of the VNTR reveals a human lineage specific expansion. These findings shed further light on the risk architecture of the miR-137 region and provide a novel regulatory mechanism through VNTR length and alternative MIR137HG transcripts which contribute to risk for SZ.

Objective: To assess whether maternal choline decreases effects of mothers' infections on fetal brain circuit development and on expression of infant behavior at 1 year of age., Study Design: A cross-sectional study was conducted in a public hospital obstetrics and midwifery service, with prenatal assessments of maternal infection, C-reactive protein, and choline level and postnatal assessments of cerebral neuronal inhibition in 162 newborns. At 1 year, 136 parents completed reports of their child's behavior., Results: Maternal infection at 16 weeks of gestation, experienced by 41% of mothers, raised mean maternal C-reactive protein (d' = 0.47, P = .002) and decreased the development of cerebral inhibition of auditory response at 1 month of age (d' = 0.39, P < .001). Decreased newborn cerebral inhibition manifested as decreased behavioral self-regulation at 1 year. Greater choline levels in mothers with infections were associated with improved newborn inhibition of auditory cerebral response, mitigating the effect of infection (β = -0.34 [95% CI, -5.35 to -0.14], P = .002). At 1 year of age, children of mothers with infection and greater gestational choline levels had improved development of self-regulation, approaching the level of children of mothers without infection (β = 0.29 [95% CI 0.05-0.54], P = .03)., Conclusions: Greater maternal choline, recommended by the American Medical Association as a prenatal supplement, is associated with greater self-regulation among infants who experienced common maternal infections during gestation. Behavioral problems with diminished self-regulation often lead to referrals to pediatricians and might lead to later mental illness., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Transgenic mice overexpressing the type I isoform of neuregulin 1 (Nrg1; NRG1) have alterations in hippocampal gamma oscillations and an age-emergent deficit in hippocampus-dependent spatial working memory. Here, we examined the molecular and morphological correlates of these findings. Microarrays showed over 100 hippocampal transcripts differentially expressed in Nrg1 tg-type I mice, with enrichment of genes related to neuromodulation and, in older mice, of genes involved in inflammation and immunity. Nrg1 tg-type I mice had an enlarged hippocampus with a widened dentate gyrus. The results show that Nrg1 type I impacts on hippocampal gene expression and structure in a multifaceted and partly age-related way, complementing the evidence implicating Nrg1 signaling in aspects of hippocampal function. The findings are also relevant to the possible role of NRG1 signaling in the pathophysiology of schizophrenia or other disorders affecting this brain region.

Introduction: Rotary wing pilot neck strain is increasing in prevalence due to the combined effects of head supported mass (e.g., Night Vision Goggles, head mounted displays) and whole-body vibration. This study examined the physiological responses of pilots during exposure to whole-body vibration (WBV) representative of the National Research Council's Bell 412 helicopter in forward flight. WBV levels were measured and evaluated using the ISO-2631-1-1997 WBV standards., Methods: Twelve pilots (aged 20-59 yr, 7 of the 12 with 20+ years flight experience) underwent six 15-min vibration trials on a human rated shaker platform. Participants were exposed to three vibration levels (-25%, normal, and +25% amplitude; Levels 1-3, respectively) while seated on an Original Equipment Manufacturer (OEM) or vibration mitigating (MIT) cushion. Upper back and neck electromyography (EMG) and acceleration were continuously recorded., Results: Normalized EMG amplitude was higher using the OEM compared to the MIT during Level 2 (0.18 vs. -0.27) and Level 3 (0.24 vs. -0.14) for the anterior neck muscles. Health weighted vibration amplitude at the head (Mean of 3 levels: OEM = 1.19 and MIT = 1.11 m · s-2) was larger than the vibration amplitude at the seat (Mean of 3 levels: OEM = 0.77 and MIT = 0.70 m · s-2)., Discussion: The amplification of head vibration relative to the seat, and the significant effects of vibration level, as well as the vibration mitigation cushion, on neck EMG amplitude support the need for revisions to the ISO-2631-1 standard to account for the head and neck response to whole-body vibration.Wright Beatty HE, Law AJ, Thomas JR, Wickramasinghe V. Amplified pilot head vibration and the effects of vibration mitigation on neck muscle strain. Aerosp Med Hum Perform. 2018; 89(6):510-519.

Psychiatric genetic studies have identified genome-wide significant loci for schizophrenia. The AKT3/1q44 locus is a principal risk region and gene-network analyses identify AKT3 polymorphisms as a constituent of several neurobiological pathways relevant to psychiatric risk; the neurobiological mechanisms remain unknown. AKT3 shows prenatal enrichment during human neocortical development and recurrent copy number variations involving the 1q43-44 locus are associated with cortical malformations and intellectual disability, implicating an essential role in early brain development. Here, we investigated the role of AKT3 as it relates to aspects of learning and memory and behavioral function, relevant to schizophrenia and cognitive disability, utilizing a novel murine model of Akt3 genetic deficiency. Akt3 heterozygous (Akt3-/+) or null mice (Akt3-/-) were assessed in a comprehensive test battery. Brain biochemical studies were conducted to assess the impact of Akt3 deficiency on cortical Akt/mTOR signaling. Akt3-/+ and Akt3-/- mice exhibited selective deficits of temporal order discrimination and spatial memory, tasks critically dependent on intact prefrontal-hippocampal circuitry, but showed normal prepulse inhibition, fear conditioned learning, memory for novel objects and social function. Akt3 loss-of-function, reduced brain size and dramatically impaired cortical Akt Ser473 activation in an allele-dose dependent manner. Such changes were observed in the absence of altered Akt1 or Akt2 protein expression. Concomitant reduction of the mTORC2 complex proteins, Rictor and Sin1 identifies a potential mechanism. Our findings provide novel insight into the neurodevelopmental role of Akt3, identify a non-redundant role for Akt3 in the development of prefrontal cortical-mediated cognitive function and show that Akt3 is potentially the dominant regulator of AKT/mTOR signaling in brain.

Objective: Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I-IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined., Method: NRG3 isoform classes I-IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined., Results: NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3., Conclusions: Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development.

Neurexin 1 (NRXN1), a presynaptic cell adhesion molecule, is implicated in several neurodevelopmental disorders characterized by synaptic dysfunction including autism, intellectual disability and schizophrenia. To gain insight into NRXN1's involvement in human cortical development we used quantitative real-time PCR to examine the expression trajectories of NRXN1, and its predominant isoforms, NRXN1-α and NRXN1-β, in prefrontal cortex from fetal stages to aging. In addition, we investigated whether prefrontal cortical expression levels of NRXN1 transcripts are altered in schizophrenia or bipolar disorder in comparison with non-psychiatric control subjects. We observed that all three NRXN1 transcripts were highly expressed during human fetal cortical development, markedly increasing with gestational age. In the postnatal dorsolateral prefrontal cortex, expression levels were negatively correlated with age, peaking at birth until ~3 years of age, after which levels declined markedly to be stable across the lifespan. NRXN1-β expression was modestly but significantly elevated in the brains of patients with schizophrenia compared with non-psychiatric controls, whereas NRXN1-α expression was increased in bipolar disorder. These data provide novel evidence that NRXN1 expression is highest in human dorsolateral prefrontal cortex during critical developmental windows relevant to the onset and diagnosis of a range of neurodevelopmental disorders, and that NRXN1 expression may be differentially altered in neuropsychiatric disorders.

Objective: α7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at α7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness., Method: The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children's behavior at 40 months of age, using the Child Behavior Checklist., Results: At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The children's behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns., Conclusions: CHRNA7, the α7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the α7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness.

Unlabelled: Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110δ, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110δ reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110δ as a target for antipsychotic drug development., Significance Statement: Schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia., (Copyright © 2016 the authors 0270-6474/16/364860-17$15.00/0.)

Pioneering studies demonstrated that novel degrees of freedom could be controlled individually by directly encoding the firing rate of single motor cortex neurons, without regard to each neuron's role in controlling movement of the native limb. In contrast, recent brain-computer interface work has emphasized decoding outputs from large ensembles that include substantially more neurons than the number of degrees of freedom being controlled. To bridge the gap between direct encoding by single neurons and decoding output from large ensembles, we studied monkeys controlling one degree of freedom by comodulating up to four arbitrarily selected motor cortex neurons. Performance typically exceeded random quite early in single sessions and then continued to improve to different degrees in different sessions. We therefore examined factors that might affect performance. Performance improved with larger ensembles. In contrast, other factors that might have reflected preexisting synaptic architecture-such as the similarity of preferred directions-had little if any effect on performance. Patterns of comodulation among ensemble neurons became more consistent across trials as performance improved over single sessions. Compared with the ensemble neurons, other simultaneously recorded neurons showed less modulation. Patterns of voluntarily comodulated firing among small numbers of arbitrarily selected primary motor cortex (M1) neurons thus can be found and improved rapidly, with little constraint based on the normal relationships of the individual neurons to native limb movement. This rapid flexibility in relationships among M1 neurons may in part underlie our ability to learn new movements and improve motor skill., (Copyright © 2014 the American Physiological Society.)

Objective: Neuregulin 1 (NRG1) is a multifunctional neurotrophin that mediates neurodevelopment and schizophrenia risk. The NRG1 gene undergoes extensive alternative splicing, and association of brain NRG1 type IV isoform expression with the schizophrenia-risk polymorphism rs6994992 is a potential mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain tissue. The authors investigated the temporal dynamics of transcription of NRG1-IVNV, compared with the major NRG1 isoforms, across human prenatal and postnatal prefrontal cortical development, and they examined the association of rs6994992 with NRG1-IVNV expression., Method: NRG1 type I-IV and NRG1-IVNV isoforms were evaluated with quantitative real-time polymerase chain reaction in human postmortem prefrontal cortex tissue samples at 14 to 39 weeks gestation and postnatal ages 0-83 years. The association of rs6994992 genotype with NRG1-IVNV expression and the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms were also determined., Results: Expression of NRG1 types I, II, and III was temporally regulated during prenatal and postnatal neocortical development. NRG1-IVNV was expressed from 16 weeks gestation until age 3. Homozygosity for the schizophrenia risk allele (T) of rs6994992 conferred lower cortical NRG1-IVNV levels. Assays showed that NRG1-IVNV is a novel nuclear-enriched, truncated NRG1 protein resistant to proteolytic processing., Conclusions: To the authors' knowledge, this study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging. It identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins.

Neuregulin 3 (NRG3), a specific ligand for ErbB4 and a neuronal-enriched neurotrophin is implicated in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including Alzheimer's disease, autism and schizophrenia. Genetic studies in schizophrenia demonstrate that risk variants in NRG3 are associated with cognitive and psychotic symptom severity, accompanied by increased expression of prefrontal cortical NRG3. Despite our expanding knowledge of genetic involvement of NRG3 in neurological disorders, little is known about the neurodevelopmental mechanisms of risk. Here we exploited the fact that a paralog of NRG3, NRG1, readily penetrates the murine blood brain barrier (BBB). In this study we synthesized the bioactive epidermal growth factor (EGF) domain of NRG3, and using previously validated in-vivo peripheral injection methodologies in neonatal mice, demonstrate that NRG3 successfully crosses the BBB, where it activates its receptor ErbB4 and downstream Akt signaling at levels of bioactivity comparable to NRG1. To determine the impact of NRG3 overexpression during one critical developmental window, C57BL/6 male mice were subcutaneously injected daily with NRG1-EGF, NRG3-EGF or vehicle from postnatal days 2-10. Mice were tested in adulthood using a comprehensive battery of behavioral tasks relevant to neurocognitive and psychiatric disorders. In agreement with previous studies, developmental overexposure to NRG1 induced multiple non-CNS mediated peripheral effects as well as severely disrupting performance of prepulse inhibition of the startle response. In contrast, NRG3 had no effect on any peripheral measures investigated or sensorimotor gating. Specifically, developmental NRG3 overexposure produced an anxiogenic-like phenotype and deficits in social behavior in adulthood. These results provide primary data to support a role for NRG3 in brain development and function, which appears to be distinct from its paralog NRG1. Furthermore we demonstrate how perturbations in NRG3 expression at distinct developmental stages may contribute to the neurological deficits observed in brain disorders such as schizophrenia and autism.

Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.

Early in development, GABA, an inhibitory neurotransmitter in adults, is excitatory. NKCC1 (SLC12A2) encodes one of two cation chloride cotransporters mediating the conversion of GABA from excitatory to inhibitory. Using 3' and 5' RACE and PCR, we verified previously characterized alternative transcripts of NKCC1a (1-27) and NKCC1b (1-27(Δ21)), identified new NKCC1 transcripts, and explored their expression patterns during human prefrontal cortical development. A novel ultra-short transcript (1-2a) was expressed preferentially in the fetus. Expression of NKCC1b and 1-2a were decreased in schizophrenia compared with controls (NKCC1b: 0.8-fold decrease, p = 0.013; 1-2a: 0.8-fold decrease, p = 0.006). Furthermore, the expression of NKCC1b was associated with NKCC1 polymorphism rs3087889. The minor allele at rs3087889, associated with reduced NKCC1b expression (homozygous for major allele: N = 37; homozygous for minor allele: N = 15; 1.5-fold decrease; p < 0.01), was also associated with a modest increase in schizophrenia risk in a case-control sample (controls: N = 435; cases: N = 397, OR = 1.5). This same allele was then found associated with cognitive (n = 369) and fMRI (n = 313) intermediate phenotypes associated with schizophrenia-working memory (Cohen's d = 0.35), global cognition or g (d = 0.18), and prefrontal inefficiency (d = 0.36) as measured by BOLD fMRI during a working memory task. Together, these preclinical and clinical results suggest that variation in NKCC1 may increase risk for schizophrenia via alterations of mRNA expression at the molecular level and impairment of optimal prefrontal function at the macro or systems level.

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS., Methods: Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m)RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing., Results: There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3' untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3' untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 "T" mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals., Conclusions: Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone., (Copyright © 2014 Society of Biological Psychiatry. All rights reserved.)

The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1(tg-type I)) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1(tg-type I) mice showed normal memory performance, but in older NRG1(tg-type I) mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1(tg-type I) mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1(tg-type I) mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform.

To examine the spatiotemporal distribution of discriminable information about reach-to-grasp movements in the primary motor cortex upper extremity representation, we implanted four microelectrode arrays in the anterior bank and lip of the central sulcus in each of two monkeys. We used linear discriminant analysis to compare information, quantified as decoding accuracy, contained in various neurophysiological signals. For all signal types, decoding accuracy increased immediately after the movement cue, peaked around movement onset, and declined during the static hold. Spike recordings and local field potential (LFP) time domain amplitude provided more discriminable information than LFP frequency domain power. Discriminable information on movement type was distributed evenly across recording sites by LFP amplitude and 1-4 Hz power but unevenly by 100-170 Hz power and spike recordings. These latter two signal types provided higher decoding accuracies closer to the hemispheric surface than deep in the anterior bank and also provided accuracies that varied along the central sulcus. This variation in the distribution of movement-type information may be related to differences in the rostral versus caudal regions of the primary motor cortex and to its underlying somatotopic organization. The even distribution of information by LFP amplitude and 1-4 Hz power compared with the more localized distribution by 100-170 Hz power and spikes suggest that these different neurophysiological signals reflect different underlying processes that distribute information through the motor cortex during reach-to-grasp movements.

NRG1-ErbB4 signaling controls inhibitory circuit development in the mammalian cortex through ErbB4-dependent regulation of GABAergic interneuron connectivity. Common genetic variation in ErbB4 (rs7598440) has been associated with ErbB4 messenger RNA levels in the human cortex and risk for schizophrenia. Recent work demonstrates that Erbb4 is expressed exclusively on inhibitory interneurons, where its presence on parvalbumin-positive cells mediates the effects of NRG1 on inhibitory circuit formation in the cortex. We therefore hypothesized that genetic variation in ErbB4 at rs7598440 would impact indices of GABA concentration in the human cortex. We tested this hypothesis in 116 healthy volunteers by measuring GABA and GLX (glutamate + glutamine) with proton magnetic resonance spectroscopy in the dorsal anterior cingulate gyrus. ErbB4 rs7598440 genotype significantly predicted cortical GABA concentration (p = 0.014), but not GLX (p = 0.51), with A allele carriers having higher GABA as predicted by the allelic impact on ErbB4 expression. These data establish an association of ErbB4 and GABA in human brain and have implications for understanding the pathogenesis of schizophrenia and other psychiatric disorders.