Human stem cell models to study placode development, function and pathology.

Placodes are embryonic structures originating from the rostral ectoderm that give rise to highly diverse organs and tissues, comprising the anterior pituitary gland, paired sense organs and cranial sensory ganglia. Their development, including the underlying gene regulatory networks and signalling pathways, have been for the most part characterised in animal models. In this Review, we describe how placode development can be recapitulated by the differentiation of human pluripotent stem cells towards placode progenitors and their derivatives, highlighting the value of this highly scalable platform as an optimal in vitro tool to study the development of human placodes, and identify human-specific mechanisms in their development, function and pathology.

The impact of adolescent stress on nicotine use and affective disorders in rodent models.

Recent findings indicate that stress exposure during adolescence contributes to the development of both nicotine use and affective disorders, suggesting a potential shared biological pathway. One key system that may mediate the association between adolescent stress and nicotine or affective outcomes is the hypothalamic-pituitary-adrenal (HPA) axis. Here we reviewed evidence regarding the effects of adolescent stress on nicotine responses and affective phenotypes and the role of the HPA-axis in these relationships. Literature indicates that stress, possibly via HPA-axis dysfunction, is a risk factor for both nicotine use and affective disorders. In rodent models, adolescent stress modulates behavioural responses to nicotine and increases the likelihood of affective disorders. The exact role that the HPA-axis plays in altering nicotine sensitivity and affective disorder development after adolescent stress remains unclear. However, it appears likely that adolescent stress-induced nicotine use and affective disorders are precipitated by repetitive activation of a hyperactive HPA-axis. Together, these preclinical studies indicate that adolescent stress is a risk factor for nicotine use and anxiety/depression phenotypes. The findings summarized here suggest that the HPA-axis mediates this relationship. Future studies that pharmacologically manipulate the HPA-axis during and after adolescent stress are critical to elucidate the exact role that the HPA-axis plays in the development of nicotine use and affective disorders following adolescent stress.

Cocktail Napkin Presentations: Design of an Activity to Enhance Undergraduate Communication and Critical Evaluation of Neuroscience Primary Literature.

Distilling complex neuroscientific ideas in a succinct and elegant way is an art. The distilled product must have smoothly flowing logic, communicate a substantial body of knowledge, and be easily digestible by the audience. At the same time, the essence of scientific accuracy and experimental design cannot be lost in the distillation process. When undergraduates encounter primary literature for the first time, they are often stifled by its overpowering complexity and astringent technicality, but can quickly learn how exciting and interesting some of their subtle findings can be. Here, the design of a novel learning activity is presented that utilizes a cocktail napkin to synthesize the knowledge and skills required for fluidity in neuroscience primary literature. The activity was implemented within the context of an upper-level developmental neurobiology course for biology majors. The activity was designed specifically to increase neuroscience literacy and oral communication. The activity appeared to address a needed shift in students' attitudes to reading primary literature, and students additionally remarked how deeply engaged they were with the literature. When paired with mentored instruction, students' values toward neuroscience appeared to change as they learned to produce distillations that were rich in content and delightful to the scientific mind.

The strengths of the genetic approach to understanding neural systems development and function: Ray Guillery's synthesis.

The organization and function of sensory systems, especially the mammalian visual system, has been the focus of philosophers and scientists for centuries-from Descartes and Newton onward. Nevertheless, the utility of understanding development and its genetic foundations for deeper insight into neural function has been debated: Do you need to know how something is assembled-a car, for example-to understand how it works or how to use it-to turn on the ignition and drive? This review addresses this issue for sensory pathways. The pioneering work of the late Rainer W. (Ray) Guillery provides an unequivocal answer to this central question: Using genetics for mechanistic exploration of sensory system development yields essential knowledge of organization and function. Ray truly built the foundation for this now accepted tenet of modern neuroscience. His work on the development and reorganization of visual pathways in albino mammals-all with primary genetic mutations in genes for pigmentation-defined the genetic approach to neural systems development, function and plasticity. The work that followed his lead in a variety of sensory systems, including my own work in the developing olfactory system, proceeds directly from Ray's fundamental contributions.

[Early Life Stress]. / Early Life Stress.

Early Life Stress Stress and daily hassles are a normal part of day-to day-life. The amount of control that is experienced strongly contributes to resilience and coping. Children very frequently do not experience control over the stressors within their lives. Starting from pregnancy, they are subjected - via the maternal endocrine system - to a variety of stressors ranging from normal stress regarding the transition to parenthood to maternal abuse or torture. This article collects research of the last two decades regarding the influence of stress on the developing brain. Both, animal and human studies will shed light on the effect of pre- and postnatal stress demonstrating an influence of early life stressors reaching far into adulthood. A direct influence of stress on multiple developmental characteristics has been postulated and shown. The results of this review will underline the necessity of early life programs focusing stress reduction and resilience in children and their parents. Also, a need for programs targeting stress reduction in pregnancy will be demonstrated and emphasized.

[Health-related long-term effects of adverse childhood experiences - an update]. / Gesundheitliche Langzeitfolgen psychosozialer Belastungen in der Kindheit - ein Update.

In the last decade strong empirical evidence from several long-term studies supports the conclusion that physical and sexual abuse as well as emotional deprivation in childhood make people significantly more vulnerable to mental and functional disorders across their lifetime. Additionally, an increased vulnerability to several somatic disorders (cardiovascular disorders, type-2-diabetes, hepatitis, chronic obstructive pulmonary disease (COPD), immunological and pain disorders, pharynx and lung cancer) was demonstrated - most of them with a reduced life expectancy. A review of the current research will be presented that outlines the underlying developmental neurobiological and psychological mechanisms mediating these long-term effects. There is now sufficient evidence about familial risk constellations that demonstrates the well-documented impact of specific prevention strategies by several model projects. Only by establishing these strategies, future enormous health-related burdens and high economic costs (unfitness to work, early retirement) can presumably be limited.

Autism Spectrum Disorders: There Remains a Place for Psychodynamic Psychiatry through Neuroplasticity, Emotion Regulation, Caring Connections, and Hope.

There remains a role for psychodynamic psychiatry in the care of individuals with autism spectrum disorders (ASDs). Contemporary psychodynamic models are uniquely positioned to integrate today's neurobiological understandings of ASD with the subjective experience of those with ASD. Historical psychodynamic formulations of ASD struggled to appreciate the interrelatedness of biological, psychological, and social complexities in individuals with this disorder. Emotionally experienced or "illusory" environmental deprivation, early life stress, and allostatic overload, along with biological factors, current stress, and neuroplasticity, drive maladaptive coping and lead to difficulties with relationships. Fears of caring emotional connections are related to self-protective isolation and other maladaptive efforts to regulate emotions, shutting out what the child needs most-parents' love and help. In a nonlinear way, maladaptive emotion regulation further interferes with the development of the social brain. Thus, a psychodynamic defense-oriented focus upon adaptive emotion regulation provides a therapeutic avenue. Helping build the child's capacity for adaptive emotion regulation, which includes letting others help, can lead to a sense of safety and promote caring connections, a positive outcome. The authors offer guidance in the treatment of individuals with ASD in accordance with contemporary understandings of the disorder and care.

Developmental mechanisms of CPSP: Clinical observations and translational laboratory evaluations.

Understanding mechanisms that underly the transition from acute to chronic pain and identifying potential targets for preventing or minimizing this progression have specific relevance for chronic postsurgical pain (CPSP). Though it is clear that multiple psychosocial, family, and environmental factors may influence CPSP, this review will focus on parallels between clinical observations and translational laboratory studies investigating the acute and long-term effects of surgical injury on nociceptive pathways. This includes data related to alterations in sensitivity at different points along nociceptive pathways from the periphery to the brain; age- and sex-dependent mechanisms underlying the transition from acute to persistent pain; potential targets for preventive interventions; and the impact of prior surgical injury. Ongoing preclinical studies evaluating age- and sex-dependent mechanisms will also inform comparative efficacy and preclinical safety assessments of potential preventive pharmacological interventions aimed at reducing the risk of CPSP. In future clinical studies, more detailed and longitudinal peri-operative phenotyping with patient- and parent-reported chronic pain core outcomes, alongside more specialized evaluations of somatosensory function, modulation, and circuitry, may enhance understanding of individual variability in postsurgical pain trajectories and improve recognition and management of CPSP.

La compréhension des mécanismes qui sous-tendent la transition de la douleur aiguë à la douleur chronique et la détermination de cibles potentielles pour prévenir ou minimiser cette progression ont une pertinence particulière pour la douleur chronique. La détermination de cibles potentielles pour prévenir ou minimiser cette progression sont particulièrement pertinentes pour la douleur postopératoire chronique (DPOC). Bien qu'il soit clair que de multiples facteurs psychosociaux, familiaux et environnementaux peuvent influencer la DPOC, cette revue se concentrera sur les parallèles entre les observations cliniques et les études translationnelles en laboratoire qui étudient les effets aigus et à long terme d'une blessure chirurgicale sur les voies nociceptives. Cela inclut les données relatives aux altérations de la sensibilité à différents points le long des nociceptives, de la périphérie au cerveau; les mécanismes dépendant de l'âge et du sexe qui sous-tendent la transition de la douleur aiguë à la douleur persistante; les cibles potentielles des interventions préventives et l'impact d'une blessure chirurgicale antérieure. Les études précliniques en cours, qui évaluent les mécanismes dépendant de l'âge et du sexe, permettront également d'évaluer l'efficacité comparative et la sécurité préclinique d'éventuelles interventions pharmacologiques préventives potentielles visant à réduire le risque de DPOC. Dans les futures études cliniques, un phénotypage péri-opératoire plus détaillé et longitudinal avec des résultats rapportés par les patients - et les parents- ainsi que des évaluations plus spécialisées de la fonction de la modulation et des circuits somatosensoriels, pourrait améliorer la compréhension de la variabilité individuelle des trajectoires de la douleur postopératoire et améliorer la reconnaissance et la gestion de la DPOC.

The Role of Idiothetic Signals, Landmarks, and Conjunctive Representations in the Development of Place and Head-Direction Cells: A Self-Organizing Neural Network Model.

Place and head-direction (HD) cells are fundamental to maintaining accurate representations of location and heading in the mammalian brain across sensory conditions, and are thought to underlie path integration-the ability to maintain an accurate representation of location and heading during motion in the dark. Substantial evidence suggests that both populations of spatial cells function as attractor networks, but their developmental mechanisms are poorly understood. We present simulations of a fully self-organizing attractor network model of this process using well-established neural mechanisms. We show that the differential development of the two cell types can be explained by their different idiothetic inputs, even given identical visual signals: HD cells develop when the population receives angular head velocity input, whereas place cells develop when the idiothetic input encodes planar velocity. Our model explains the functional importance of conjunctive "state-action" cells, implying that signal propagation delays and a competitive learning mechanism are crucial for successful development. Consequently, we explain how insufficiently rich environments result in pathology: place cell development requires proximal landmarks; conversely, HD cells require distal landmarks. Finally, our results suggest that both networks are instantiations of general mechanisms, and we describe their implications for the neurobiology of spatial processing.

Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance.

Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo (Fmi) to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon-to-one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shapes the entire organization of the visual system.

Effects of mild intrauterine hypoperfusion in the second trimester on memory and learning function in rat offspring.

Mild intrauterine hypoperfusion (MIUH) is a serious pathological event that affects the growth and development of fetuses and offspring. MIUH can lead to growth restriction, low birth weight, neurodevelopmental disorders, and other adverse clinical outcomes. To study the effects of MIUH on learning and memory function in offspring, a model of MIUH was established by placing a coil (length 2.5 mm, diameter 0.24 mm) on the uterine artery and ovarian uterine artery of Sprague-Dawley rats in the second trimester of pregnancy (day 17). Next, 120 mg/kg lithium chloride (the MIUH + Li group) or normal saline (the MIUH group) was injected intraperitoneally into these rats. In addition, 120 mg/kg lithium chloride (the Li group) or normal saline (the SHAM group) was injected intraperitoneally into pregnant rats without coil placement. The Morris water maze was used to detect changes in learning and memory ability in the offspring at 4 weeks after birth. In the MIUH group, the escape latency and journey length before reaching the platform were both increased, and the number of times that the platform was crossed and the activity time in the target quadrant within 90 seconds were both decreased compared with the SHAM group. Immunofluorescence double staining and western blot assays demonstrated that hippocampal nestin and Ki67 (both cell-proliferation-related proteins) expression was significantly downregulated in the MIUH group compared with the SHAM group. Furthermore, western blot assays were conducted to investigate changes in related signaling pathway proteins in the brains of offspring rats, and revealed that glycogen synthase kinase 3ß (GSK3ß) expression was upregulated and ß-catenin expression was downregulated in the MIUH group compared with the SHAM group. In addition, compared with the MIUH group, the expression levels of p-GSK3ß and ß-catenin were upregulated in the MIUH + Li group. These results suggest that MIUH may affect learning and memory function in rat offspring by regulating the GSK3ß signaling pathway. The experimental procedures were approved by Animal Ethics Committee of Shengjing Hospital of China Medical University (approval No. 2018PS07K) in June 2018.

Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice.

Dendritic morphology is a critical determinant of neuronal connectivity, and calcium signaling plays a predominant role in shaping dendrites. Altered dendritic morphology and genetic mutations in calcium signaling are both associated with neurodevelopmental disorders (NDDs). In this study we tested the hypothesis that dendritic arborization and NDD-relevant behavioral phenotypes are altered by human mutations that modulate calcium-dependent signaling pathways implicated in NDDs. The dendritic morphology of pyramidal neurons in CA1 hippocampus and somatosensory cortex was quantified in Golgi-stained brain sections from juvenile mice of both sexes expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I-RYR1), a human CGG repeat expansion (170-200 CGG repeats) in the fragile X mental retardation gene 1 (FMR1 premutation), both mutations (double mutation; DM), or wildtype mice. In hippocampal neurons, increased dendritic arborization was observed in male T4826I-RYR1 and, to a lesser extent, male FMR1 premutation neurons. Dendritic morphology of cortical neurons was altered in both sexes of FMR1 premutation and DM animals with the most pronounced differences seen in DM females. Genotype also impaired behavior, as assessed using the three-chambered social approach test. The most striking lack of sociability was observed in DM male and female mice. In conclusion, mutations that alter the fidelity of calcium signaling enhance dendritic arborization in a brain region- and sex-specific manner and impair social behavior in juvenile mice. The phenotypic outcomes of these mutations likely provide a susceptible biological substrate for additional environmental stressors that converge on calcium signaling to determine individual NDD risk.

The emergent connectome in Caenorhabditis elegans embryogenesis.

The relatively new field of connectomics provides us with a unique window into nervous system function. In the model organism Caenorhabditis elegans, this promise is even greater due to the relatively small number of cells (302) in its nervous system. While the adult C. elegans connectome has been characterized, the emergence of these networks in development has yet to be established. In this paper, we approach this problem using secondary data describing the birth times of terminally-differentiated cells as they appear in the embryo and a connectomics model for nervous system cells in the adult hermaphrodite. By combining these two sources of data, we can better understand patterns that emerge in an incipient connectome. This includes identifying at what point in embryogenesis the cells of a connectome first comes into being, potentially observing some of the earliest neuron-neuron interactions, and making comparisons between the formally-defined connectome and developmental cell lineages. An analysis is also conducted to root terminally-differentiated cells in their developmental cell lineage precursors. This reveals subnetworks with different properties at 300 min of embryogenesis. Additional investigations reveal the spatial position of neuronal cells born during pre-hatch development, both within and outside the connectome model, in the context of all developmental cells in the embryo. Overall, these analyses reveal important information about the birth order of specific cells in the connectome, key building blocks of global connectivity, and how these structures correspond to key events in early development.

Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms.

Patterns of onset in Autism Spectrum Disorder, including a pattern that includes loss of previously acquired skills, have been identified since the first reports of the disorder. However, attempts to study such "regression" have been limited to clinical studies, that until recently mostly involved retrospective reports. The current report reflects discussion that occurred at an NIMH convened meeting in 2016 with the purpose of bridging clinical autism research with basic and translational work in this area. This summary describes the state of the field with respect to clinical studies, describing gaps in knowledge based on limited methods and prospective data collected. Biological mechanisms that have been shown to account for regression early in development in specific conditions are discussed, as well as potential mechanisms that have not yet been explored. Suggestions include use of model systems during the developmental period and cutting-edge methods, including non-invasive imaging that may afford opportunities for a better understanding of the neurobiological pathways that result in loss of previously-attained skills. Autism Res 2018, 11: 212-222. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Loss of previously acquired skills, or regression, has been reported in Autism Spectrum Disorder since Kanner's reports in the 1950's. The current report reflects discussion from an NIMH convened meeting in 2016 with the purpose of bridging clinical autism research with basic and translational work in this area. This summary describes the state of the field regarding clinical studies and suggests use of model systems during the developmental period and cutting-edge methods, for a better understanding of the neurobiological pathways that result in loss of previously-attained skills.

High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring.

Sevoflurane is the most commonly used volatile anesthetic during pregnancy. The viability of neural stem cells directly affects the development of the brain. However, it is unknown whether the use of sevoflurane during the second trimester affects the survival of fetal neural stem cells. Therefore, in this study, we investigated whether exposure to sevoflurane in mid-gestation induces apoptosis of neural stem cells and behavioral abnormalities. On gestational day 14, pregnant rats were anesthetized with 2% or 3.5% sevoflurane for 2 hours. The offspring were weaned at 28 days and subjected to the Morris water maze test. The brains were harvested to examine neural stem cell apoptosis by immunofluorescence and to measure Nestin and SOX-2 levels by western blot assay at 6, 24 and 48 hours after anesthesia as well as on postnatal day (P) 0, 14 and 28. Vascular endothelial growth factor (VEGF) and phosphoinositide 3-kinase (PI3K)/AKT pathway protein levels in fetal brain at 6 hours after anesthesia were assessed by western blot assay. Exposure to high-concentration (3.5%) sevoflurane during mid-gestation increased escape latency and path length to the platform, and it reduced the average duration spent in the target quadrant and platform crossing times. At 6, 24 and 48 hours after anesthesia and at P0, P14 and P28, the percentage of Nestin/terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells was increased, but Nestin and SOX-2 protein levels were decreased in the hippocampus of the offspring. At 6 hours after anesthesia, VEGF, PI3K and phospho-AKT (p-AKT) levels were decreased in the fetal brain. These changes were not observed in animals given low-concentration (2%) sevoflurane exposure. Together, our findings indicate that exposure to a high concentration of sevoflurane (3.5%) in mid-gestation decreases VEGF, PI3K and p-AKT protein levels and induces neural stem cell apoptosis, thereby causing learning and memory dysfunction in the offspring.

Toxic effect of acrylamide on the development of hippocampal neurons of weaning rats.

Although numerous studies have examined the neurotoxicity of acrylamide in adult animals, the effects on neuronal development in the embryonic and lactational periods are largely unknown. Thus, we examined the toxicity of acrylamide on neuronal development in the hippocampus of fetal rats during pregnancy. Sprague-Dawley rats were mated with male rats at a 1:1 ratio. Rats were administered 0, 5, 10 or 20 mg/kg acrylamide intragastrically from embryonic days 6-21. The gait scores were examined in pregnant rats in each group to analyze maternal toxicity. Eight weaning rats from each group were also euthanized on postnatal day 21 for follow-up studies. Nissl staining was used to observe histological change in the hippocampus. Immunohistochemistry was conducted to observe the condition of neurites, including dendrites and axons. Western blot assay was used to measure the expression levels of the specific nerve axon membrane protein, growth associated protein 43, and the presynaptic vesicle membrane specific protein, synaptophysin. The gait scores of gravid rats significantly increased, suggesting that acrylamide induced maternal motor dysfunction. The number of neurons, as well as expression of growth associated protein 43 and synaptophysin, was reduced with increasing acrylamide dose in postnatal day 21 weaning rats. These data suggest that acrylamide exerts dose-dependent toxic effects on the growth and development of hippocampal neurons of weaning rats.

Shedding new light on the origins of olfactory neurons.

Sensory neurons in the nose of the zebrafish are derived from both neural crest cells and placode cells.

Cloning and bioinformatical analysis of the N-terminus of the sonic hedgehog gene.

The sonic hedgehog protein not only plays a key role in early embryonic development, but also has essential effects on the adult nervous system, including neural stem cell proliferation, differentiation, migration and neuronal axon guidance. The N-terminal fragment of sonic hedgehog is the key functional element in this process. Therefore, this study aimed to clone and analyze the N-terminal fragment of the sonic hedgehog gene. Total RNA was extracted from the notochord of a Sprague-Dawley rat at embryonic day 9 and the N-terminal fragment of sonic hedgehog was amplified by nested reverse transcription-PCR. The N-terminal fragment of the sonic hedgehog gene was successfully cloned. The secondary and tertiary structures of the N-terminal fragment of the sonic hedgehog protein were predicted using Jpred and Phyre online.

Breast Feeding: A Neurobiologic Perspective

Breast-feeding(BF) failures are common in industrialized societies and can only partly be explained by social, psychologic, cultural and cognitive factors. The more profound causes remain unknown. This annotation presents clinical observations suggesting that several nursing care rituals in delivery rooms and maternity wards interfere with innate behavioural programs and consequently may disturb the unfolding feeding behaviour. Mother-infant interaction including BF depend on the activation of a complex network of neuronal pathways in "the old mammalian brain", as well as of certain hormonal systems especially within the neuropeptide family. Since this organization shows an evolutionary stability one can assume that it has partly been preserved in the human. Initiation and promotion of breast-feeding will benefit if the perinatal care of mother and baby supports their innate behavioural agendas. Mothers who fail often have a low confidence in their ability to breast-feed. The self-confidence is strengthened when the mother experiences that her baby all by itself can find the nipple and begin to suck within an hour of delivery. Similarly this early start helps the baby to develop an adequate sucking technique.