Excitatory versus inhibitory GABA as a divergence point in steroid-mediated sexual differentiation of the brain

Whereas adult sex differences in brain morphology and behavior result from developmental exposure to steroid hormones, the mechanism by which steroids differentiate the brain is unknown. Studies to date have described subtle sex differences in levels of proteins and neurotransmitters during brain development, but these have lacked explanatory power for the profound sex differences induced by steroids. We report here a major divergence in the response to injection of the γ-aminobutyric acid type A (GABAA) agonist, muscimol, in newborn male and female rats. In females, muscimol treatment primarily decreased the phosphorylation of cAMP response element binding protein (CREB) within the hypothalamus and the CA1 region of the hippocampus. In contrast, muscimol increased the phosphorylation of CREB in males within these same brain regions. Within the arcuate nucleus, muscimol treatment increased the phosphorylation of CREB in both females and males. Thus, the response to GABA can be excitatory or inhibitory on signal-transduction pathways that alter CREB phosphorylation depending on the sex and the region in developing brain. This divergence in response to GABA allows for a previously unknown form of steroid-mediated neuronal plasticity and may be an initial step in establishing sexually dimorphic signal-transduction pathways in developing brain.

Developmental Vitamin D-3 deficiency alters the adult rat brain

There is growing evidence that Vitamin D-3 (1,25-dihydroxyvitamin D-3) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D-3 deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D-3 deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D-3 deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D-3 deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-(alpha 4). We conclude that transient early life hypovitaminosis D-3 not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitammosis D-3 in women of child-bearing age, the public health implications of these findings warrant attention. (c) 2005 Elsevier Inc. All rights reserved.

Imaging, anatomical, and molecular analysis of callosal formation in the developing human fetal brain

A complex set of axonal guidance mechanisms are utilized by axons to locate and innervate their targets. In the developing mouse forebrain, we previously described several midline glial populations as well as various guidance molecules that regulate the formation of the corpus callosum. Since agenesis of the corpus callosum is associated with over 50 different human congenital syndromes, we wanted to investigate whether these same mechanisms also operate during human callosal development. Here we analyze midline glial and commissural development in human fetal brains ranging from 13 to 20 weeks of gestation using both diffusion tensor magnetic resonance imaging and immunohistochemistry. Through our combined radiological and histological studies, we demonstrate the morphological development of multiple forebrain commissures/decussations, including the corpus callosum, anterior commissure, hippocampal commissure, and the optic chiasm. Histological analyses demonstrated that all the midline glial populations previously described in mouse, as well as structures analogous to the subcallosal sling and cingulate pioneering axons, that mediate callosal axon guidance in mouse, are also present during human brain development. Finally, by Northern blot analysis, we have identified that molecules involved in mouse callosal development, including Slit, Robo, Netrin1, DCC, Nfia, Emx1, and GAP-43, are all expressed in human fetal brain. These data suggest that similar mechanisms and molecules required for midline commissure formation operate during both mouse and human brain development. Thus, the mouse is an excellent model system for studying normal and pathological commissural formation in human brain development. (c) 2006 Wiley-Liss, Inc.

The DVD animal model of schizophrenia: Effects of low maternal vitamin D on brain dopamine

Background: We have previously shown that the offspring of vitamin D3 depleted rats have enlarged ventricles and altered neurotrophin profiles (reduced NGF and GDNF). These findings enhance the biological plausibility that low prenatal vitamin D may be a risk factor for schizophrenia. Our recent behavioural studies have found that adult rats with developmental vitamin D deficiency (DVD) have a subtle increase in baseline locomotor activity and a heightened response to dopamine (DA) antagonists. The aim of this study was to investigate brain DA neurochemistry in the DVD model. Methods: We examined cerebrums and striatal tissue from neonates and a variety of brain tissues from the remaining littermates at adulthood. DA, DOPAC, HVA, serotonin and 5HIAA were analysed by HPLC. Single point comparisons for DA1, DA2 and NMDA receptors were also assessed in these tissues. Results: Significant increases in DA and HVA were found in brains from DVD deplete neonates (P=0.01). However, DA and its metabolites were not increased in either the neonate or adult striatum, however there was a trend towards increased DA and its metabolites in the accumbens (P=0.1). Receptor densities were unaffected by prenatal vitamin D levels. Conclusions: Although the effect of maternal diet appears to increase DA production and turnover in neonatal brain, this does not persist into adulthood. Thus other factors must underlie the increased locomotor activity noted in these animals. Future experiments will concentrate on monitoring accumbens and striatal DA release and turnover using microdialysis in pharmacologically challenged behavioural paradigms. References: Eyles D, Brown J; Mackay-Sim A, McGrath J, Feron F. (2003) Vitamin D3 and brain development. Neuroscience 118 (3) 641–653. Burne T, McGrath J, Eyles D, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. (2005) Behavioural Brain Res: 157 299–308.

The novel cytoskeleton-associated protein Neuronal protein 22: Elevated expression in the developing rat brain

Neuronal development and process targeting is mediated by proteins of the cytoskeleton. However, the signaling pathways underlying these mechanisms are complex and have not yet been fully elucidated. Neuronal protein 22 (NP22) has been identified as a cytoskeleton-associated protein. It colocalizes with microtubules and actin, the two major components of the cytoskeleton. It contains numerous signaling motifs and induces process formation in non-neuronal cells. Expression of rat NP22 (rNP22) rises incrementally at specific time points during brain development, with the greatest elevation occurring during synaptogenesis in the rat brain. its neuronal localization is primarily at the plasma membrane of the soma in the embryonic brain and progresses into homogeneous expression in the postnatal rat brain. Data suggest that NP22 may play a role in mediating the molecular events governing development of the neuronal architecture. Furthermore, its sustained expression in postnatal brain implies a function in the maintenance of neuronal morphology.

White and gray matter development in human fetal, newborn and pediatric brains

Brain anatomy is characterized by dramatic growth from the end of the second trimester through the neonatal stage. The characterization of normal axonal growth of the white matter tracts has not been well-documented to date and could provide important clues to understanding the extensive inhomogeneity of white matter injuries in cerebral palsy (CP) patients. However, anatomical studies of human brain development during this period are surprisingly scarce and histology-based atlases have become available only recently. Diffusion tensor magnetic resonance imaging (DTMRI) can reveal detailed anatomy of white matter. We acquired diffusion tensor images (DTI) of postmortem fetal brain samples and in vivo neonates and children. Neural structures were annotated in two-dimensional (2D) slices, segmented, measured, and reconstructed three-dimensionally (3D). The growth status of various white matter tracts was evaluated on cross-sections at 19-20 gestational weeks, and compared with 0-month-old neonates and 5- to 6-year-old children. Limbic, commissural, association, and projection white matter tracts and gray matter structures were illustrated in 3D and quantitatively characterized to assess their dynamic changes. The overall pattern of the time courses for the development of different white matter is that limbic fibers develop first and association fibers last and commissural and projection fibers are forming from anterior to posterior part of the brain. The resultant DTNIRI-based 3D human brain data will be a valuable resource for human brain developmental study and will provide reference standards for diagnostic radiology of premature newborns. (c) 2006 Elsevier Inc. All rights reserved.

The ‘first three years’ movement and the infant brain:a review of critiques

This article reviews a particular aspect of the critique of the increasing focus on the brain and neuroscience; what has been termed by some, 'neuromania'. It engages with the growing literature produced in response to the 'first three years' movement: an alliance of child welfare advocates and politicians that draws on the authority of neuroscience to argue that social problems such as inequality, poverty, educational underachievement, violence and mental illness are best addressed through 'early intervention' programmes to protect or enhance emotional and cognitive aspects of children's brain development. The movement began in the United States in the early 1990s and has become increasingly vocal and influential since then, achieving international legitimacy in the United States, Canada, New Zealand, Australia, the UK and elsewhere. The movement, and the brain-based culture of expert-led parent training that has grown with it, has been criticised for claiming scientific authority whilst taking a cavalier approach to scientific method and evidence; for being overly deterministic about the early years of life; for focusing attention on individual parental failings rather than societal or structural problems, for adding to the expanding anxieties of parents and strengthening the intensification of parenting and, ultimately, for redefining the parent-child relationship in biologised, instrumental and dehumanised terms. © 2014 John Wiley & Sons Ltd.

Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior

There is a growing recognition of the importance of the commensal intestinal microbiota in the development and later function of the central nervous system. Research using germ-free mice (mice raised without any exposure to microorganisms) has provided some of the most persuasive evidence for a role of these bacteria in gut-brain signalling. Key findings show that the microbiota is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition. Furthermore, the microbiota maintains central nervous system homeostasis by regulating immune function and blood brain barrier integrity. Studies have also found that the gut microbiota influences neurotransmitter, synaptic, and neurotrophic signalling systems and neurogenesis. The principle advantage of the germ-free mouse model is in proof-of-principle studies and that a complete microbiota or defined consortiums of bacteria can be introduced at various developmental time points. However, a germ-free upbringing can induce permanent neurodevelopmental deficits that may deem the model unsuitable for specific scientific queries that do not involve early-life microbial deficiency. As such, alternatives and complementary strategies to the germ-free model are warranted and include antibiotic treatment to create microbiota-deficient animals at distinct time points across the lifespan. Increasing our understanding of the impact of the gut microbiota on brain and behavior has the potential to inform novel management strategies for stress-related gastrointestinal and neuropsychiatric disorders.

Girl in the Shadows and resilience and coping strategies in contemporary young adult fiction

The novel manuscript Girl in the Shadows tells the story of two teenage girls whose friendship, safety and sanity are pushed to the limits when an unexplained phenomenon invades their lives. Sixteen-year-old Tash has everything a teenage girl could want: good looks, brains and freedom from her busy parents. But when she looks into her mirror, a stranger’s face stares back at her. Her best friend Mal believes it’s an evil spirit and enters the world of the supernatural to find answers. But spell books and ouija boards cannot fix a problem that comes from deep within the soul. It will take a journey to the edge of madness for Tash to face the truth inside her heart and see the evil that lurks in her home. And Mal’s love and courage to pull her back into life. The exegesis examines resilience and coping strategies in adolescence, in particular, the relationship of trauma to brain development in children and teenagers. It draws on recent discoveries in neuroscience and psychology to provide a framework to examine the role of coping strategies in building resilience. Within this broader context, it analyses two works of contemporary young adult fiction, Freaky Green Eyes by Joyce Carol Oates and Sonya Hartnett’s Surrender, their use of the split persona as a coping mechanism within young adult fiction and the potential of young adult literature as a tool to help build resilience in teen readers.

Implications of lipid biology for the pathogenesis of schizophrenia

Objective: Preclinical and clinical data suggest that lipid biology is integral to brain development and neurodegeneration. Both aspects are proposed as being important in the pathogenesis of schizophrenia. The purpose of this paper is to examine the implications of lipid biology, in particular the role of essential fatty acids (EFA), for schizophrenia. Methods: Medline databases were searched from 1966 to 2001 followed by the crosschecking of references. Results: Most studies investigating lipids in schizophrenia described reduced EFA, altered glycerophospholipids and an increased activity of a calcium-independent phospholipase A2 in blood cells and in post-mortem brain tissue. Additionally, in vivo brain phosphorus-31 Magnetic Resonance Spectroscopy (31P-MRS) demonstrated lower phosphomonoesters (implying reduced membrane precursors) in first- and multi-episode patients. In contrast, phosphodiesters were elevated mainly in first-episode patients (implying increased membrane breakdown products), whereas inconclusive results were found in chronic patients. EFA supplementation trials in chronic patient populations with residual symptoms have demonstrated conflicting results. More consistent results were observed in the early and symptomatic stages of illness, especially if EFA with a high proportion of eicosapentaenoic acid was used. Conclusion: Peripheral blood cell, brain necropsy and 31P-MRS analysis reveal a disturbed lipid biology, suggesting generalized membrane alterations in schizophrenia. 31P-MRS data suggest increased membrane turnover at illness onset and persisting membrane abnormalities in established schizophrenia. Cellular processes regulating membrane lipid metabolism are potential new targets for antipsychotic drugs and might explain the mechanism of action of treatments such as eicosapentaenoic acid.

Expression Profiles of Mitochondrial Genes in the Frontal Cortex and the Caudate Nucleus of Developing Humans and Mice Selectively Bred for High and Low Fear

A growing body of evidence suggests that mitochondrial function may be important in brain development and psychiatric disorders. However, detailed expression profiles of those genes in human brain development and fear-related behavior remain unclear. Using microarray data available from the public domain and the Gene Ontology analysis, we identified the genes and the functional categories associated with chronological age in the prefrontal cortex (PFC) and the caudate nucleus (CN) of psychiatrically normal humans ranging in age from birth to 50 years. Among those, we found that a substantial number of genes in the PFC (115) and the CN (117) are associated with the GO term: mitochondrion (FDR qv <0.05). A greater number of the genes in the PFC (91%) than the genes in the CN (62%) showed a linear increase in expression during postnatal development. Using quantitative PCR, we validated the developmental expression pattern of four genes including monoamine oxidase B (MAOB), NADH dehydrogenase flavoprotein (NDUFV1), mitochondrial uncoupling protein 5 (SLC25A14) and tubulin beta-3 chain (TUBB3). In mice, overall developmental expression pattern of MAOB, SLC25A14 and TUBB3 in the PFC were comparable to the pattern observed in humans (p<0.05). However, mice selectively bred for high fear did not exhibit normal developmental changes of MAOB and TUBB3. These findings suggest that the genes associated with mitochondrial function in the PFC play a significant role in brain development and fear-related behavior.

Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear

Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain. The CB1, not the CB2, mRNA levels in the PFC gradually decrease during postnatal development ranging in age from birth to 50 years (r 2 > 0.6 & adj. p < 0.05). The CB1 levels in the PFC of major depression patients were higher when compared to the age-matched controls (adj. p < 0.05). In mice, the CB1, not the CB2, levels in the PFC were positively correlated with freezing behavior in classical fear conditioning (p < 0.05). These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders

Analysis of kinase gene expression in the frontal cortex of suicide victims: Implications of fear and stress

Suicide is a serious public health issue that results from an interaction between multiple risk factors including individual vulnerabilities to complex feelings of hopelessness, fear, and stress. Although kinase genes have been implicated in fear and stress, including the consolidation and extinction of fearful memories, expression profiles of those genes in the brain of suicide victims are less clear. Using gene expression microarray data from the Online Stanley Genomics Database 1 and a quantitative PCR, we investigated the expression profiles of multiple kinase genes including the calcium calmodulin-dependent kinase (CAMK), the cyclin-dependent kinase, the mitogen-activated protein kinase (MAPK), and the protein kinase C (PKC) in the prefrontal cortex (PFC) of mood disorder patients died with suicide (N = 45) and without suicide (N = 38). We also investigated the expression pattern of the same genes in the PFC of developing humans ranging in age from birth to 49 year (N = 46). The expression levels of CAMK2B, CDK5, MAPK9, and PRKCI were increased in the PFC of suicide victims as compared to non-suicide controls (false discovery rate, FDR-adjusted p < 0.05, fold change >1.1). Those genes also showed changes in expression pattern during the postnatal development (FDR-adjusted p < 0.05). These results suggest that multiple kinase genes undergo age-dependent changes in normal brains as well as pathological changes in suicide brains. These findings may provide an important link to protein kinases known to be important for the development of fear memory, stress associated neural plasticity, and up-regulation in the PFC of suicide victims. More research is needed to better understand the functional role of these kinase genes that may be associated with the pathophysiology of suicide

Neurodevelopmental animal models of schizophrenia: Effects on prepulse inhibition

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.