Teacher-Child Racial Congruence and Young Children's Preschool Adjustment.

The purpose of this study was to explore how adjusted preschoolers were to preschool when their teachers were either racially congruent or racially incongruent and whether gender moderated these associations. In this study, 259 preschoolers (50% boys; Mage = 53.84 months; 63% White, 37% Black) in 44 classrooms at 16 federally- and privately-funded centers/preschools were rated for their adjustment to preschool using teacher (N = 44; 100% women, 52% White, 38% Black, 2% Asian, 5% American Indian/Alaskan Native, 2% Latine) reports and direct child assessments. Multi-level structural equation modeling was used to simultaneously address the non-independence of the data by estimating higher-level variance components (i.e., variance on a total of six preschool adjustment outcomes out due to the classroom and due to the center) as well as correlated outcomes. Accounting for classroom-level variance as well as school-, classroom-, and child-level covariates, these analyses revealed main effects for gender and teacher-child racial congruence, and not for race, but higher-order interactions were significant. White girls with White teachers scored higher than White girls with Black teachers on four outcomes. Black girls with Black teachers scored higher than Black girls with White teachers on three outcomes and lower on two outcomes. White boys with White teachers scored lower than White boys with Black teachers on three outcomes. Black boys with Black teachers scored lower than Black boys with White teachers on five outcomes and higher on one outcome. Magnitudes of associations found ranged from small to large across the analyses. These findings add to the growing literature concerning teacher racial congruence suggesting its association with preschool adjustment may be moderated by race and gender of the child. More research is needed to understand the mechanisms accounting for these associations.

Rostral spread of lumbosacral epidural volumes of dye and contrast medium calculated using body weight or length of the vertebral column in dog cadavers.

The objective of this study was to compare the rostral spread of lumbosacral epidural volumes of a mixture of dye and contrast medium, calculated using body weight (BW) or vertebral column length (LE), in 22 dog cadavers. The dogs weighed 4.6 to 52.0 kg. Dogs were paired within a < 10% difference for BW and LE and with the same body condition score (BCS). Pairs of dogs were injected while in sternal recumbency through an epidural catheter with a volume mixture of iopamidol and dye, calculated based on BW: 0.2 mL/kg in one of the cadavers and based on LE: 0.05 mL/cm (< 50 cm), 0.07 mL/cm (50 to < 70 cm), 0.08 mL/cm (70 to < 80 cm), and 0.11 mL/cm (≥ 80 cm) in the other cadaver. The extent of rostral spread was determined using computed tomography for iopamidol and anatomical dissection for dye. Comparisons for dye and iopamidol within each dog, and for BW and LE within matched pairs, were completed with mixed linear models (P < 0.05). The number of vertebrae reached by dye was greater than the number reached by iopamidol in both BW and LE, but the rostral spread was not significantly different between BW and LE for all pairs. In conclusion, dye tends to spread further than iopamidol and therefore, these two methods should not be considered interchangeable when used in research studies.

L'objectif de cette étude était de comparer l'étalement rostral des volumes épiduraux lombo-sacrés d'un mélange de colorant et de produit de contraste, calculé en utilisant le poids corporel (PC) ou la longueur de la colonne vertébrale (LE), chez 22 cadavres de chiens. Les chiens pesaient de 4,6 à 52,0 kg. Les chiens ont été appariés avec une différence < 10 % pour PC et LE et avec le même score d'état corporel (PCS). Des paires de chiens ont reçu une injection alors qu'ils étaient en décubitus sternal à travers un cathéter péridural avec un mélange volumique d'iopamidol et de colorant, calculé sur la base du poids corporel : 0,2 mL/kg dans l'un des cadavres et sur la base de la LE : 0,05 mL/cm (< 50 cm), 0,07 mL/cm (50 à < 70 cm), 0,08 mL/cm (70 à < 80 cm) et 0,11 mL/cm (≥ 80 cm) dans l'autre cadavre. L'étendue de la propagation rostrale a été déterminée par tomodensitométrie pour l'iopamidol et dissection anatomique pour le colorant. Les comparaisons pour le colorant et l'iopamidol au sein de chaque chien, et pour PC et LE au sein de paires appariées, ont été complétées avec des modèles linéaires mixtes (P < 0,05). Le nombre de vertèbres atteintes par le colorant était supérieur au nombre atteint par l'iopamidol dans PC et LE, mais la propagation rostrale n'était pas significativement différente entre PC et LE pour toutes les paires. En conclusion, le colorant a tendance à se propager plus loin que l'iopamidol et, par conséquent, ces deux méthodes ne doivent pas être considérées comme interchangeables lorsqu'elles sont utilisées dans des études de recherche.(Traduit par Docteur Serge Messier).

Comparison of rostral spread of lumbosacral epidural volume calculated by body weight or length of the vertebral column in small-sized anesthetized dogs.

The first objective of this prospective, randomized, crossover experimental trial was to compare the rostral spread of lumbosacral epidural volume calculated by body weight (BW) or vertebral column length (LE) in 6 small, isoflurane-anesthetized female beagle dogs (BW: 7.5 to 10.2 kg; LE measured from the occipital crest to the sacrococcygeal space: 46 to 56 cm). The second objective was to assess the response to a noxious stimulus once the dogs recovered from anesthesia and to determine the effects of the injection on cardiopulmonary variables. While in sternal position, dogs were injected through an epidural catheter with a volume mixture of bupivacaine 0.25% and iopamidol 15% based on BW: 0.2 mL/kg or LE: 0.05 mL/cm (< 50 cm) or 0.07 mL/cm (50 to < 70 cm). Rostral spread was determined by counting the number of vertebrae reached by iopamidol using computed tomography. After anesthesia, cardiopulmonary variables, motor function, and responses to nociceptive stimuli were evaluated. Comparisons were completed with mixed linear models and 2-way analysis of variance (ANOVA) (P < 0.05). The volume of injectate (3.29 ± 0.74 versus 1.81 ± 0.21 mL; mean ± SD) and the number of vertebrae (22 ± 2 versus 19 ± 2 vertebrae) reached by iopamidol were significantly greater for LE than for BW. Response to nociception, time to return of pain sensation, motor function, and cardiopulmonary variables were similar between groups. In conclusion, dosing based on LE resulted in larger rostral spread than when based on BW in dogs of small size.

Le premier objectif de cet essai expérimental croisé prospectif randomisé était de comparer la propagation rostrale du volume épidural lombo-sacré calculé en fonction du poids corporel (PC) ou de la longueur de la colonne vertébrale (LE) chez 6 petites chiennes beagle anesthésiées à l'isoflurane (PC : 7,5 à 10,2 kg; LE mesuré de la crête occipitale à l'espace sacro-coccygien : 46 à 56 cm). Le deuxième objectif était d'évaluer la réponse à un stimulus nocif une fois que les chiens se sont remis de l'anesthésie et de déterminer les effets de l'injection sur les variables cardiopulmonaires. En position sternale, les chiens ont reçu une injection via un cathéter péridural d'un mélange volumique de bupivacaïne à 0,25 % et d'iopamidol à 15 % basé sur le poids corporel : 0,2 mL/kg ou LE : 0,05 mL/cm (< 50 cm) ou 0,07 mL/cm (50 à < 70 cm). La propagation rostrale a été déterminée en comptant le nombre de vertèbres atteintes par l'iopamidol en utilisant la tomodensitométrie. Après l'anesthésie, les variables cardiopulmonaires, la fonction motrice et les réponses aux stimuli nociceptifs ont été évaluées. Les comparaisons ont été complétées avec des modèles linéaires mixtes et une analyse de variance à 2 facteurs (ANOVA) (P < 0,05). Le volume d'injectat (3,29 ± 0,74 versus 1,81 ± 0,21 mL; moyenne ± SD) et le nombre de vertèbres (22 ± 2 versus 19 ± 2 vertèbres) atteints par l'iopamidol étaient significativement plus élevés pour LE que pour BW. La réponse à la nociception, le temps de retour de la sensation de douleur, la fonction motrice et les variables cardiopulmonaires étaient similaires entre les groupes. En conclusion, le dosage basé sur LE a entraîné une plus grande propagation rostrale que lorsqu'il était basé sur BW chez les chiens de petite taille.(Traduit par Docteur Serge Messier).

Human factors and ergonomics.

Human factors and ergonomics in healthcare is an important discipline that considers both the physical and mental characteristics of healthcare workers, as well as the complex interactions within which organisations exist.

Cortical dopamine D5 receptors regulate neuronal circuit oscillatory activity and memory in rats.

INTRODUCTION: The dopamine D5 receptor (D5R) shows high expression in cortical regions, yet the role of the receptor in learning and memory remains poorly understood. This study evaluated the impact of prefrontal cortical (PFC) D5R knockdown in rats on learning and memory and assessed the role of the D5R in the regulation of neuronal oscillatory activity and glycogen synthase kinase-3 (GSK-3ß), processes integral to cognitive function. MATERIALS AND METHODS: Using an adeno-associated viral (AAV) vector, male rats were infused with shRNA to the D5R bilaterally into the PFC. Local field potential recordings were taken from freely moving animals and spectral power and coherence were evaluated in, and between, the PFC, orbitofrontal cortex (OFC), hippocampus (HIP), and thalamus. Animals were then assessed in object recognition, object location, and object in place tasks. The activity of PFC GSK-3ß, a downstream effector of the D5R, was evaluated. RESULTS: AAV-mediated knockdown of the D5R in the PFC induced learning and memory deficits. These changes were accompanied by elevations in PFC, OFC, and HIP theta spectral power and PFC-OFC coherence, reduced PFC-thalamus gamma coherence, and increased PFC GSK-3ß activity. CONCLUSION: This work demonstrates a role for PFC D5Rs in the regulation of neuronal oscillatory activity and learning and memory. As elevated GSK-3ß activity has been implicated in numerous disorders of cognitive dysfunction, this work also highlights the potential of the D5R as a novel therapeutic target via suppression of GSK-3ß.

The Development of Cognitive Reappraisal From Early Childhood Through Adolescence: A Systematic Review and Methodological Recommendations.

Cognitive reappraisal is an important emotion regulation strategy that shows considerable developmental change in its use and effectiveness. This paper presents a systematic review of the evidence base regarding the development of cognitive reappraisal from early childhood through adolescence and provides methodological recommendations for future research. We searched Scopus, PsycINFO, and ERIC for empirical papers measuring cognitive reappraisal in normative samples of children and youth between the ages of 3 and 18 years published in peer-reviewed journals through August 9th, 2018. We identified 118 studies that met our inclusion criteria. We first present a quantitative review of the methodologies used to investigate cognitive reappraisal in children and adolescents, with attention to variations in methodologies by the sample age range. We then present a qualitative review of findings with attention to: (1) the age at which children begin to effectively use cognitive reappraisal to regulate their emotions, and (2) developmental changes in cognitive reappraisal from early childhood through adolescence. We consider how methodological differences may contribute to inconsistencies in findings, highlight gaps in the literature that remain to be addressed, and make recommendations for future directions.

Human cerebral spheroids undergo 4-aminopyridine-induced, activity associated changes in cellular composition and microrna expression.

Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis.

Teachers' Consistency of Emotional Support Moderates the Association Between Young Children's Regulation Capacities and Their Preschool Adjustment.

Objectives: Preschool teachers' consistency of warm, sensitive, and responsive interactions with children may be more important than average levels and may moderate the association between children's cognitive and emotion regulation and their preschool adjustment. Methods: A sample of 312 boys and girls aged 32 to 68 months in 44 classrooms at 16 privately-funded centers and Head Starts completed assessments of emotional and cognitive regulation and were rated by their teachers using measures of social-emotional functioning. Teacher-child interactions were rated for emotional support. Multilevel structural equation modeling was used to simultaneously explore three aspects of preschool adjustment. Results: Children who were the least regulated were more adjusted to preschool in classrooms where teachers were more consistent in their emotional support, over and above mean emotional support and after controlling for child- and preschool-level covariates. Conclusions: Consistency matters for children's preschool adjustment perhaps even more so than average levels of emotional support.

Brain-Generated 17ß-Estradiol Modulates Long-Term Synaptic Plasticity in the Primary Auditory Cortex of Adult Male Rats.

Neuron-derived 17ß-estradiol (E2) alters synaptic transmission and plasticity in brain regions with endocrine and non-endocrine functions. Investigations into a modulatory role of E2 in synaptic activity and plasticity have mainly focused on the rodent hippocampal formation. In songbirds, E2 is synthesized by auditory forebrain neurons and promotes auditory signal processing and memory for salient acoustic stimuli; however, the modulatory effects of E2 on memory-related synaptic plasticity mechanisms have not been directly examined in the auditory forebrain. We investigated the effects of bidirectional E2 manipulations on synaptic transmission and long-term potentiation (LTP) in the rat primary auditory cortex (A1). Immunohistochemistry revealed widespread neuronal expression of the E2 biosynthetic enzyme aromatase in multiple regions of the rat sensory and association neocortex, including A1. In A1, E2 application reduced the threshold for in vivo LTP induction at layer IV synapses, whereas pharmacological suppression of E2 production by aromatase inhibition abolished LTP induction at layer II/III synapses. In acute A1 slices, glutamate and γ-aminobutyric acid (GABA) receptor-mediated currents were sensitive to E2 manipulations in a layer-specific manner. These findings demonstrate that locally synthesized E2 modulates synaptic transmission and plasticity in A1 and suggest potential mechanisms by which E2 contributes to auditory signal processing and memory.

Enhanced electrical conductivity of anticorrosive coatings by functionalized carbon nanotubes: effect of hydrogen bonding.

Carbon nanotubes and nanofibers (CNFs) are well-known nano additives to produce coating materials with high electrical and thermal conductivity and corrosion resistance. In this paper, coating materials incorporating hydrogen bonding offered significantly lower electrical resistance. The hydrogen bonding formed between functionalized carbon nanotubes and ethanol helped create a well-dispersed carbon nanotube network as the electron pathways. Electrical resistivity as low as 6.8 Ω cm has been achieved by adding 4.5 wt% functionalized multiwalled carbon nanotubes (MWNT-OH) to 75%polyurethane/25%ethanol. Moreover, the thermal conductivity of polyurethane was improved by 332% with 10 wt% addition of CNF. Electrochemical methods were used to evaluate the anti-corrosion properties of the fabricated coating materials. 75%polyurethane/25%ethanol with the addition of 3.0 wt% of MWNT-OH showed an excellent corrosion rate of 5.105 × 10-3mm year-1, with a protection efficiency of 99.5% against corrosive environments. The adhesion properties of the coating materials were measured following ASTM standard test methods. 75%polyurethane/25%ethanol with 3.0 wt% of MWNT-OH belonged to class 5 (ASTM D3359), indicating the outstanding adhesion of the coating to the substrate. These nanocoatings with enhanced electrical, thermal, and anti-corrosion properties consist of a choice of traditional coating materials, such as polyurethane, yielding coating durability with the ability to tailor the electrical and thermal properties to fit the desired application.

Developmental age and biological sex influence muscarinic receptor function and neuron morphology within layer VI of the medial prefrontal cortex.

Acetylcholine (ACh) neurotransmission within the medial prefrontal cortex (mPFC) plays an important modulatory role to support mPFC-dependent cognitive functions. This role is mediated by ACh activation of its nicotinic (nAChR) and muscarinic (mAChR) classes of receptors, which are both present on mPFC layer VI pyramidal neurons. While the expression and function of nAChRs have been characterized thoroughly for rodent mPFC layer VI neurons during postnatal development, mAChRs have not been characterized in detail. We employed whole-cell electrophysiology with biocytin filling to demonstrate that mAChR function is greater during the juvenile period of development than in adulthood for both sexes. Pharmacological experiments suggest that each of the M1, M2, and M3 mAChR subtypes contributes to ACh responses in these neurons in a sex-dependent manner. Analysis of dendrite morphology identified effects of age more often in males, as the amount of dendrite matter was greatest during the juvenile period. Interestingly, a number of positive correlations were identified between the magnitude of ACh/mAChR responses and dendrite morphology in juvenile mice that were not present in adulthood. To our knowledge, this work describes the first detailed characterization of mAChR function and its correlation with neuron morphology within layer VI of the mPFC.

The Dendrite Arbor of Purkinje Cells Is Altered Following to Tail Regeneration in the Leopard Gecko.

Purkinje cells of the cerebellum have a complex arborized arrangement of dendrites and are among the most distinctive cell types of the nervous system. Although the neuromorphology of Purkinje cells has been well described for some mammals and teleost fish, for most vertebrates less is known. Here we used a modified Golgi-Cox method to investigate the neuromorphology of Purkinje cells from the lizard Eublepharis macularius, the leopard gecko. Using Sholl and Branch Structure Analyses, we sought to investigate whether the neuromorphology of gecko Purkinje cells was altered in response to tail loss and regeneration. Tail loss is an evolved mechanism commonly used by geckos to escape predation. Loss of the tail represents a significant and sudden change in body length and mass, which is only partially recovered as the tail is regenerated. We predicted that tail loss and regeneration would induce a quantifiable change in Purkinje cell dendrite arborization. Post hoc comparisons of Sholl analyses data showed that geckos with regenerated tails have significant changes in dendrite diameter and the number of dendrite intersections in regions corresponding to the position of parallel fiber synapses. We propose that the neuromorphological alterations observed in gecko Purkinje cells represent a compensatory response to tail regrowth, and perhaps a role in motor learning.

Emotion regulation, pain interference and affective symptoms in children and adolescents with sickle cell disease.

BACKGROUND: The ability to regulate emotion is associated with affective disorders and the experience of pain. However, little is known about emotion regulation in youth with Sickle Cell Disease (SCD), a population that regularly experiences pain and symptoms of depression and anxiety. This study examines the relationship between emotion regulation and symptoms of depression, anxiety, and pain interference in youth with SCD. METHODS: Participants ages 8-20 at a university-based pediatric sickle cell clinic completed the Emotion Regulation Questionnaire (ERQ) and the Cognitive Emotion Regulation Questionnaire (CERQ), self-report measures assessing use of emotion regulation strategies. Participants also completed the Patient-Reported Outcomes Measurement Information System (PROMIS), measures for symptoms of anxiety, depression, and pain interference. Multiple regression models tested associations between use of emotion regulation strategies and symptoms of depression, anxiety, and pain interference. RESULTS: Participants were 51 patients with SCD, 30 female and 21 male, with a mean age of 13.02 years (SD = 0.47, mid-max = 8-20). Use of maladaptive emotion regulation strategies was associated with increased symptoms of depression (r = .58), anxiety (r = .45) and pain interference (r = .30) in youth with SCD. LIMITATIONS: Potential limitations of our study include small sample size, use of youth self-report measures, and participant selection contingent on the ability to attend an outpatient appointment. CONCLUSION: Identifying maladaptive emotion regulation strategies in youth with SCD may provide clinicians with targeted pathways for improving emotional and psychological functioning.

Self-Regulation in Preschool: Examining Its Factor Structure and Associations With Pre-academic Skills and Social-Emotional Competence.

Self-regulation in early childhood is an important predictor of success across a variety of indicators in life, including health, well-being, and earnings. Although conceptually self-regulation has been defined as multifaceted, previous research has not investigated whether there is conceptual and empirical overlap between the factors that comprise self-regulation or if they are distinct. In this study, using a bifactor model, we tested the shared and unique variance among self-regulation constructs and prediction to pre-academic and social-emotional skills. The sample included 932 preschool children (M age = 48 months, SD = 6.55; 49% female), their parents, and their teachers in the United States. Children's self-regulation was assessed using measures of executive function, behavioral self-regulation, and emotion regulation. The bifactor model demonstrated a common overarching self-regulation factor, as well as distinct executive function and emotion regulation factors. The common overarching self-regulation factor and executive function predicted children's pre-academic (i.e., mathematics and literacy) and social-emotional skills. The emotion regulation factor predicted children's social-emotional skills. Identifying the shared and unique aspects of self-regulation may have important implications for supporting children's regulatory skills as well as their success in school.

Preclinical methodological approaches investigating of the effects of alcohol on perinatal and adolescent neurodevelopment.

Despite much evidence of its economic and social costs, alcohol use continues to increase. Much remains to be known as to the effects of alcohol on neurodevelopment across the lifespan and in both sexes. We provide a comprehensive overview of the methodological approaches to ethanol administration when using animal models (primarily rodent models) and their translational relevance, as well as some of the advantages and disadvantages of each approach. Special consideration is given to early developmental periods (prenatal through adolescence), as well as to the types of research questions that are best addressed by specific methodologies. The zebrafish is used increasingly in alcohol research, and how to use this model effectively as a preclinical model is reviewed as well.

Teaching emotion regulation in schools: Translating research into practice with the RULER approach to social and emotional learning.

Emotion regulation skills are critical to young children's school readiness and later academic achievement, as well as educators' efficacy, stress, and job satisfaction. In this article, we demonstrate how the science of emotion regulation can be translated into practical steps for educating teachers and students in schools. We begin with the crucial role of supporting educators in developing their own emotion regulation skills. We also discuss concrete and accessible tools that can be used to support both educators' own skill development and that of their students. We demonstrate how educators can integrate the teaching of emotion regulation through direct instruction, its integration into existing curricula, and daily practices and routines. The examples we provide are part of RULER, an evidence-based, whole school approach to social and emotional learning (SEL) that was developed at the Yale Center for Emotional Intelligence. RULER is grounded in the theory of emotional intelligence, which emphasizes the critical role of emotion regulation in healthy development. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Serotonin Induces Structural Plasticity of Both Extrinsic Modulating and Intrinsic Mediating Circuits In Vitro in Aplysia Californica.

Long-term sensitization of the gill withdrawal reflex in Aplysia requires heterosynaptic, modulatory input that is mediated in part by the growth of new synaptic connections between sensory neurons and their follower cells (intrinsic mediating circuit). Whether modulatory interneurons (the extrinsic modulatory circuit) also display learning-related structural synaptic plasticity remains unknown. To test this idea, we added a bona fide serotonergic modulatory neuron, the metacerebral cell (MCC), to sensory-motor neuron co-cultures and examined the modulating presynaptic varicosities of MCCs before and after repeated pulses of serotonin (5-HT) that induced long-term facilitation (LTF). We observed robust growth of new serotonergic varicosities that were positive for serotonin and capable of synaptic recycling. Our findings demonstrate that, in addition to structural changes in the intrinsic mediating circuit, there are also significant learning-related structural changes in the extrinsic modulating circuit, and these changes might provide a cellular mechanism for savings and for spread of memory.

Determination of gastrointestinal passage rate using three different markers in laying hens.

The titanium dioxide (TiO2 ) marker technique is currently widely practiced as a method to evaluate gastrointestinal (GI) passage rate in poultry. However, this method requires sacrificing the animal to obtain digesta samples, is labour-intensive and eliminates the possibility of follow-up studies with the same individual. The aim of this study was to evaluate whether the radiographic methods barium-impregnated polyethylene spheres (BIPS) and barium sulphate (BaSO4 ) suspension are in agreement with the TiO2 technique and can be used as an alternative method for GI passage rate determination in laying hens. Whole-body radiographs were taken at different time points. Hens of group 3 (n = 55) were orally inoculated with 5 g of feed mixed with 0.15 g TiO2 , 5 hens per time point sacrificed, and whole gastrointestinal organs (crop, proventriculus, gizzard, small intestine and large intestine) were collected and analysed for TiO2 content. The average marker passage rate of hens administered BaSO4 was significantly faster than those administered BIPS (gizzard: 15.2 hr vs. 43.2 hr; small intestine: 15.2 hr vs. 38.4 hr, respectively). A greater percentage of BIPS remained in the crop at 0, 0.5, 2, 3 and 8 hr post-inoculation (p.i.) and in the gizzard at 2, 24, 36 and 48 hr p.i. (all p < 0.05) compared to TiO2 . In conclusion, the evaluation of the GI transit time is feasible using BIPS, TiO2 and BaSO4 . The evaluation of the GI transit time using BIPS and BaSO4 needs further investigation.

Axonal pathology in hPSC-based models of Parkinson's disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus.

While mutations in the SNCA gene (α-synuclein [α-syn]) are causal in rare familial forms of Parkinson's disease (PD), the prevalence of α-syn aggregates in the cortices of sporadic disease cases emphasizes the need to understand the link between α-syn accumulation and disease pathogenesis. By employing a combination of human pluripotent stem cells (hPSCs) that harbor the SNCA-A53T mutation contrasted against isogenic controls, we evaluated the consequences of α-syn accumulation in human A9-type dopaminergic (DA) neurons (hNs). We show that the early accumulation of α-syn in SNCA-A53T hNs results in changes in gene expression consistent with the expression profile of the substantia nigra (SN) from PD patients, analyzed post mortem. Differentially expressed genes from both PD patient SN and SNCA-A53T hNs were associated with regulatory motifs transcriptionally activated by the antioxidant response pathway, particularly Nrf2 gene targets. Differentially expressed gene targets were also enriched for gene ontologies related to microtubule binding processes. We thus assessed the relationship between Nrf2-mediated gene expression and neuritic pathology in SNCA-A53T hNs. We show that SNCA-mutant hNs have deficits in neuritic length and complexity relative to isogenic controls as well as contorted axons with Tau-positive varicosities. Furthermore, we show that mutant α-syn fails to complex with protein kinase C (PKC), which, in turn, results in impaired activation of Nrf2. These neuritic defects result from impaired Nrf2 activity on antioxidant response elements (AREs) localized to a microtubule-associated protein (Map1b) gene enhancer and are rescued by forced expression of Map1b as well as by both Nrf2 overexpression and pharmaceutical activation in PD neurons.

The Clock Mechanism Influences Neurobiology and Adaptations to Heart Failure in Clock∆19/∆19 Mice With Implications for Circadian Medicine.

In this study we investigated the role of the circadian mechanism on cognition-relevant brain regions and neurobiological impairments associated with heart failure (HF), using murine models. We found that the circadian mechanism is an important regulator of healthy cognitive system neurobiology. Normal Clock∆19/∆19 mice had neurons with smaller apical dendrite trees in the medial prefrontal cortex (mPFC), and hippocampus, showed impaired visual-spatial memory, and exhibited lower cerebrovascular myogenic tone, versus wild types (WT). We then used the left anterior descending coronary artery ligation model to investigate adaptations in response to HF. Intriguingly, adaptations to neuron morphology, memory, and cerebrovascular tone occurred in differing magnitude and direction between Clock∆19/∆19 and WT mice, ultimately converging in HF. To investigate this dichotomous response, we performed microarrays and found genes crucial for growth and stress pathways that were altered in Clock∆19/∆19 mPFC and hippocampus. Thus these data demonstrate for the first time that (i) the circadian mechanism plays a role in neuron morphology and function; (ii) there are changes in neuron morphology and function in HF; (iii) CLOCK influences neurobiological gene adaptations to HF at a cellular level. These findings have clinical relevance as patients with HF often present with concurrent neurocognitive impairments. There is no cure for HF, and new understanding is needed to reduce morbidity and improve the quality of life for HF patients.