RESUMEN
The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.
Asunto(s)
Cuerpo Estriado/fisiología , Dopamina/fisiología , Trastornos Psicóticos/fisiopatología , Esquizofrenia/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Neurobiología , Esquizofrenia/diagnósticoRESUMEN
There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l-1. Compared with the 25OHD sufficient group (25OHD>50 nmol l-1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, ß=0.06, P<0.001; cord blood n=1712, ß=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.
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Trastorno Autístico/etiología , Deficiencia de Vitamina D/complicaciones , Adulto , Niño , Estudios de Cohortes , Suplementos Dietéticos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Madres , Países Bajos , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Vitamina D/análogos & derivados , Vitamina D/análisis , Vitamina D/sangreRESUMEN
Vitamin D deficiency has adverse health effects in young children. Our aims were to determine predictors of vitamin D status and then to use these factors to develop a practical tool to predict low 25(OH)D concentrations in preschool New Zealand children. A cross-sectional sample of 1329 children aged 2 to <5 years were enrolled from throughout New Zealand in late-winter to spring 2012. 25-Hydroxyvitamin D (25(OH)D) was measured on dried blood spot (DBS) samples collected using finger-prick sampling. Caregivers completed a questionnaire. Mean (SD) DBS 25(OH)D concentration was 52(19)nmol/L. 25(OH)D < 25 nmol/L was present in 86(7%), 25(OH)D < 50 nmol/L in 642(48%), 25(OH)D 50- < 75 nmol/L in 541(41%) and 25(OH)D > 75 nmol/L in 146(11%) of children. Factors independently associated with the risk of 25(OH)D < 25 nmol/L were female gender (OR 1.92,95%CI 1.17-3.14), other non-European ethnicities (not including Maori or Pacific) (3.51,1.89-6.50), had olive-dark skin colour (4.52,2.22-9.16), did not take vitamin D supplements (2.56,1.06-6.18), had mothers with less than secondary-school qualifications (5.00,2.44-10.21) and lived in more deprived households (1.27,1.06-1.53). Children who drank toddler milk (vitamin D fortified cow's milk formula marketed to young children) had a zero risk of 25(OH)D < 25 nmol/L. The predictive tool identified children at risk of 25(OH)D < 25 nmol/L with sensitivity 42%, specificity 97% and ROC area-under-curve 0.76(95%CI 0.67-0.86, p < 0.001). Predictors of low vitamin D status were consistent with those identified in previous studies of New Zealand children. The tool had insufficient predictive ability for use in clinical situations, and suggests a need to promote safe, inexpensive testing to determine vitamin D status in preschool children.
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Alimentos Fortificados , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Vitamina D/administración & dosificación , Vitamina D/sangre , Animales , Preescolar , Estudios Transversales , Suplementos Dietéticos , Femenino , Humanos , Masculino , Leche/química , Nueva Zelanda/epidemiología , Estado Nutricional , Instituciones Académicas , Estaciones del Año , Pigmentación de la PielRESUMEN
BACKGROUND: Research on the psychological experiences of parents of infants within pediatric oncology is sparse. This study examined rates and indicative risk factors for psychological distress in parents where there is either an infant patient or infant sibling of a patient. METHODS: Participants were mothers (n = 41) and fathers (n = 25) of infants under 2 years who either had a cancer diagnosis (n = 37; infant patients) or was an infant sibling of an older child with cancer (n = 29; infant siblings) recruited from a single oncology center. There were 21 couple dyads. Parents completed the Depression Anxiety Stress Scales short form and the Posttraumatic Stress Disorder Checklist. RESULTS: Mothers (47.5%) and fathers (37.5%) reported elevated, cancer-related posttraumatic stress symptoms. Rates of depression (12.2% of mothers and 12.0% of fathers) and anxiety symptoms (17.1% of mothers and 8.0% of fathers) were lower. Compared with parents of infant patients, parents of infant siblings reported significantly higher rates of depressive symptoms and trends toward higher rates of posttraumatic stress symptoms and anxiety symptoms. Parent anxiety was higher with increased time post diagnosis. No demographic or illness-related variables were associated with psychological distress, with the exception of the number of children in the family. CONCLUSIONS: Parent-child relationships are of fundamental importance during infancy. This study provides novel data highlighting the psychological impact for parents when a cancer diagnosis is made during this critical developmental period, including the contribution of family structure to parental distress. Results provide further support for applying a traumatic stress framework when exploring parent experiences of pediatric cancer. Copyright © 2016 John Wiley & Sons, Ltd.
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Depresión/psicología , Neoplasias/psicología , Relaciones Padres-Hijo , Padres/psicología , Estrés Psicológico/psicología , Adaptación Psicológica , Adulto , Ansiedad/psicología , Preescolar , Depresión/etiología , Padre/psicología , Femenino , Humanos , Lactante , Masculino , Madres/psicología , Neoplasias/terapia , Factores de Riesgo , Hermanos , Estrés Psicológico/etiologíaRESUMEN
BACKGROUND: Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma. OBJECTIVE: We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children. METHODS: We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6. RESULTS: Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]. CONCLUSION AND CLINICAL RELEVANCE: Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences.
Asunto(s)
Asma/sangre , Madres , Vitamina D/análogos & derivados , Adulto , Niño , Preescolar , Cromatografía Liquida , Estudios de Cohortes , Femenino , Feto , Estudios de Seguimiento , Humanos , Masculino , Estudios Prospectivos , Pruebas de Función Respiratoria , Espectrometría de Masas en Tándem , Vitamina D/sangreRESUMEN
BACKGROUND/OBJECTIVES: Maternal vitamin D deficiency during pregnancy may influence offspring kidney health. We aimed to examine the associations of 25-hydroxyvitamin D (25(OH)D) blood levels during fetal life with kidney outcomes at school age. SUBJECTS/METHODS: This study was embedded in a population-based prospective cohort study among 4212 mother-child pairs. We measured maternal second trimester (18-25 weeks) and fetal cord blood (at birth) 25(OH)D levels. At a median age of 6.0 years, we measured children's combined kidney volume, glomerular filtration rate (eGFR) from creatinine and cystatin C serum levels, and microalbuminuria from albumin and creatinine urine levels. RESULTS: Of all mothers, 21.9% had severely deficient levels (25(OH)D <25.0 nmol/l), 25.7% had deficient levels (25.0-49.9 nmol/l), 25% had sufficient levels (50.0-74.9 nmol/l) and 27.4% had optimal levels (⩾75.0 nmol/l). Maternal 25(OH)D levels were not consistently associated with childhood combined kidney volume. Higher maternal 25(OH)D levels were associated with lower childhood eGFR (difference -0.94 ml/min per 1.73 m(2) (95% confidence interval, -1.73; -0.15) per 1 standard deviation (s.d.) increase in 25(OH)D). Maternal 25(OH)D levels were not associated with microalbuminuria. Cord blood 25(OH)D levels were not associated with childhood kidney outcomes. The associations of maternal 25(OH)D levels with childhood eGFR were partly explained by childhood vitamin D status. CONCLUSIONS: Our findings suggest that maternal 25(OH)D levels during pregnancy may influence childhood kidney outcomes. These results should be considered hypothesis generating. Further studies are needed to replicate the observations, to examine the underlying mechanisms and to identify the long-term clinical consequences.
Asunto(s)
Riñón/fisiopatología , Complicaciones del Embarazo/sangre , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Deficiencia de Vitamina D/sangre , Vitamina D/análogos & derivados , Adulto , Niño , Femenino , Sangre Fetal/química , Humanos , Pruebas de Función Renal , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Embarazo , Complicaciones del Embarazo/etiología , Efectos Tardíos de la Exposición Prenatal/etiología , Estudios Prospectivos , Vitamina D/sangre , Deficiencia de Vitamina D/complicacionesRESUMEN
Vitamin D is a neuroactive steroid. Its genomic actions are mediated via the active form of vitamin D, 1,25(OH)2D3, binding to the vitamin D receptor (VDR). The VDR emerges in the rat mesencephalon at embryonic day 12, representing the peak period of dopaminergic cell birth. Our prior studies reveal that developmental vitamin D (DVD)-deficiency alters the ontogeny of dopaminergic neurons in the developing mesencephalon. There is also consistent evidence from others that 1,25(OH)2D3 promotes the survival of dopaminergic neurons in models of dopaminergic toxicity. In both developmental and toxicological studies it has been proposed that 1,25(OH)2D3 may modulate the differentiation and maturation of dopaminergic neurons; however, to date there is lack of direct evidence. The aim of the current study is to investigate this both in vitro using a human SH-SY5Y cell line transfected with rodent VDR and in vivo using a DVD-deficient model. Here we show that in VDR-expressing SH-SY5Y cells, 1,25(OH)2D3 significantly increased production of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. This effect was dose- and time-dependent, but was not due to an increase in TH-positive cell number, nor was it due to the production of trophic survival factors for dopamine neurons such as glial-derived neurotrophic factor (GDNF). In accordance with 1,25(OH)2D3's anti-proliferative actions in the brain, 1,25(OH)2D3 reduced the percentage of dividing cells from approximately 15-10%. Given the recently reported role of N-cadherin in the direct differentiation of dopaminergic neurons, we examined here whether it may be elevated by 1,25(OH)2D3. We confirmed this in vitro and more importantly, we showed DVD-deficiency decreases N-cadherin expression in the embryonic mesencephalon. In summary, in our in vitro model we have shown 1,25(OH)2D3 increases TH expression, decreases proliferation and elevates N-cadherin, a potential factor that mediates these processes. Accordingly all of these findings are reversed in the developing brain in our DVD-deficiency model. Remarkably our findings in the DVD-deficiency model phenocopy those found in a recent model where N-cadherin was regionally ablated from the mesencephalon. This study has, for the first time, shown that vitamin D directly modulates TH expression and strongly suggests N-cadherin may be a plausible mediator of this process both in vitro and in vivo. Our findings may help to explain epidemiological data linking DVD deficiency with schizophrenia.
Asunto(s)
Antígenos CD/metabolismo , Cadherinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Esteroides/administración & dosificación , Tirosina 3-Monooxigenasa/metabolismo , Vitamina D/administración & dosificación , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Humanos , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transfección , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/metabolismoRESUMEN
Apart from its role in regulating calcium there is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. Vitamin D induces its genomic effects through its nuclear receptor the vitamin D receptor (VDR). Although there is abundant evidence for this receptor's presence in the mammalian brain from studies employing immunohistochemistry, Western blot or quantitative RNA studies there remains some dispute regarding the validity of these studies. In this study we provide unambiguous confirmation for the VDR in adult rodent brain using proteomic techniques. However Western blot experiments show that compared to more classic target organs such as the gut and kidney, VDR expression is quantitatively lower in the brain. In addition we have examined VDR subcellular distribution in the gut, kidney and brain from both embryonic and adult tissues. We show that in all embryonic tissues VDR distribution is mostly nuclear, however by adulthood it appears that at least in the gut and kidney, VDR presence in the plasma membrane is more prominent perhaps reflecting some change in VDR function with the maturation of these tissues. Finally the subcellular distribution of VDR in the embryo did not appear to be altered by vitamin D deficiency indicating that perhaps there are other mechanisms at play in vivo to stabilize this receptor in the absence of its ligand.
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Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Espacio Intracelular/metabolismo , Receptores de Calcitriol/metabolismo , Deficiencia de Vitamina D/metabolismo , Animales , Western Blotting , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Electroforesis , Tracto Gastrointestinal/crecimiento & desarrollo , Tracto Gastrointestinal/metabolismo , Inmunoprecipitación , Riñón/crecimiento & desarrollo , Riñón/metabolismo , Proteómica/métodos , Ratas Sprague-DawleyRESUMEN
There is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. In particular, there is evidence from rodent models that prenatal vitamin D deficiency alters the development of dopaminergic pathways and this disruption is associated with altered behavior and neurochemistry in the adult brain. Although the presence of the vitamin D receptor (VDR) has been noted in the human substantia nigra, there is a lack of direct evidence showing that VDR is present in dopaminergic cells. Here we confirm that the VDR is present in the nucleus of tyrosine hydroxylase (TH)-positive neurons in both the human and rat substantia nigra, and it emerges early in development in the rat, between embryonic day 12 (E12) and E15. Consistent evidence based on immunohistochemistry, real-time PCR and western blot confirmed a pattern of increasing VDR expression in the rat midbrain until weaning. The nuclear expression of VDR in TH-positive neurons during critical periods of brain development suggests that alterations in early life vitamin D status may influence the orderly development of dopaminergic neurons.
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Neuronas Dopaminérgicas/metabolismo , Mesencéfalo/crecimiento & desarrollo , Mesencéfalo/metabolismo , Receptores de Calcitriol/metabolismo , Sustancia Negra/crecimiento & desarrollo , Sustancia Negra/metabolismo , Adolescente , Adulto , Animales , Western Blotting , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the "dopamine ontogeny hypothesis of schizophrenia". To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Dopamina/genética , Neuronas Dopaminérgicas/patología , Efectos Tardíos de la Exposición Prenatal , Esquizofrenia/etiología , Percepción Visual/genética , Análisis de Varianza , Animales , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/genética , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Dopamina/metabolismo , Dopaminérgicos/farmacología , Drosophila melanogaster , Electrofisiología/métodos , Femenino , Masculino , Microscopía Confocal , Embarazo , Esquizofrenia/genéticaRESUMEN
During foetal development, calcium requirements are met as a consequence of maternal adaptations independent of vitamin D status. In contrast, after birth, dependency on vitamin D appears necessary for calcium metabolism and skeletal health. We used a rodent model (Sprague-Dawley rats), to determine if maternal vitamin D deficiency during pregnancy had a deleterious effect on bone structure at birth. Vitamin D deplete females were maintained under deplete conditions until birth of the pups, whereupon all dams were fed a vitamin D replete diet. Offspring were harvested at birth, and 140 days of age. Bones were analyzed using micro-computed tomography and strength tested to study differences in bone structure, density and strength and subjected to elemental analysis using plasma mass spectrometry to determine strontium, barium and calcium contents. Offspring from deplete mothers displayed altered trabecular parameters in the femur at birth and 140 days of age. In addition, at 140 days of age there was evidence of premature mineralization of the secondary ossification centre of the femoral head. Elemental analysis showed increased strontium uptake in the femur of the developmentally vitamin D-deficient offspring. Vitamin D depletion during development in the offspring may have a long-lasting effect, despite repletion of vitamin D from birth. This may have consequences for human health given the low vitamin D levels seen during pregnancy and current lifestyle of sun avoidance due to the risk of skin cancer.
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Densidad Ósea/fisiología , Huesos/fisiología , Efectos Tardíos de la Exposición Prenatal/etiología , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/fisiopatología , Análisis de Varianza , Animales , Bario/análisis , Fenómenos Biomecánicos , Huesos/anatomía & histología , Huesos/química , Calcio/análisis , Femenino , Espectrometría de Masas , Embarazo , Ratas , Ratas Sprague-Dawley , Estroncio/análisis , Microtomografía por Rayos XRESUMEN
The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as 'Risk factors for schizophrenia--all roads lead to dopamine' or 'The dopamine hypothesis of schizophrenia--the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.
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Encéfalo/fisiopatología , Citocinas/fisiología , Modelos Animales de Enfermedad , Dopamina/fisiología , Intercambio Materno-Fetal/fisiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Esquizofrenia/fisiopatología , Transducción de Señal/fisiología , Deficiencia de Vitamina D/fisiopatología , Animales , Atención/fisiología , Femenino , Inductores de Interferón/farmacología , Intercambio Materno-Fetal/inmunología , Ratones , Actividad Motora/fisiología , Poli I-C/farmacología , Embarazo , Ratas , Filtrado Sensorial/fisiologíaRESUMEN
While the research community has accepted the value of rodent models as informative research platforms, there is less awareness of the utility of other small vertebrate and invertebrate animal models. Neuroscience is increasingly turning to smaller, non-rodent models to understand mechanisms related to neuropsychiatric disorders. Although they can never replace clinical research, there is much to be learnt from 'small brains'. In particular, these species can offer flexible genetic 'tool kits' that can be used to explore the expression and function of candidate genes in different brain regions. Very small animals also offer efficiencies with respect to high-throughput screening programs. This review provides a concise overview of the utility of models based on worm, fruit fly, honeybee and zebrafish. Although these species may have small brains, they offer the neuropsychiatric research community opportunities to explore some of the most important research questions in our field.
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Trastornos Mentales/metabolismo , Modelos Animales , Proteínas del Tejido Nervioso/metabolismo , Neuropsiquiatría/métodos , Animales , Ensayos Analíticos de Alto Rendimiento/métodos , Trastornos Mentales/fisiopatologíaRESUMEN
The offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. In light of the evidence implicating copy number variants (CNVs) with schizophrenia and autism, we used a mouse model to explore the hypothesis that the offspring of older males have an increased risk of de novo CNVs. C57BL/6J sires that were 3- and 12-16-months old were mated with 3-month-old dams to create control offspring and offspring of old sires, respectively. Applying genome-wide microarray screening technology, 7 distinct CNVs were identified in a set of 12 offspring and their parents. Competitive quantitative PCR confirmed these CNVs in the original set and also established their frequency in an independent set of 77 offspring and their parents. On the basis of the combined samples, six de novo CNVs were detected in the offspring of older sires, whereas none were detected in the control group. Two of the CNVs were associated with behavioral and/or neuroanatomical phenotypic features. One of the de novo CNVs involved Auts2 (autism susceptibility candidate 2), and other CNVs included genes linked to schizophrenia, autism and brain development. This is the first experimental demonstration that the offspring of older males have an increased risk of de novo CNVs. Our results support the hypothesis that the offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism by generation of de novo CNVs in the male germline.
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Variaciones en el Número de Copia de ADN/genética , Variación Genética/genética , Edad Paterna , Animales , Trastorno Autístico/genética , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la Polimerasa , Esquizofrenia/genéticaRESUMEN
It has been known for more than 20 years that vitamin D exerts marked effects on immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed attention since it has been shown that diminished levels of vitamin D induce immune-mediated symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases. For example, it has been demonstrated that vitamin D (i) modulates the production of several neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most prevalent neurological and inflammatory disease in the young adult population. Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor (VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/Grp58. In this article, we review some of the mechanisms that may underlie the role of vitamin D in various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a range of adult disorders, including brain pathologies (Parkinson's disease, epilepsy, depression) and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are now required to fully appreciate the complex role of vitamin D in mammal metabolism.
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Enfermedades Autoinmunes/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Neuroinmunomodulación/fisiología , Vitamina D/fisiología , Animales , Enfermedades del Sistema Nervioso Central/metabolismo , Humanos , Trastornos Mentales/metabolismo , Modelos Biológicos , Modelos Inmunológicos , Neurotransmisores/inmunología , Neurotransmisores/fisiologíaRESUMEN
There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the "Biological Plausibility" of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that vitamin D acts as a neurosteroid with direct effects on brain development.
Asunto(s)
Encéfalo/embriología , Deficiencia de Vitamina D/psicología , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Humanos , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/etiología , Neurotransmisores/fisiología , Esquizofrenia/epidemiología , Esquizofrenia/etiología , Vitamina D/fisiología , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
Epidemiology has highlighted the links between season of birth, latitude and the prevalence of brain disorders such as multiple sclerosis and schizophrenia. In line with these data, we have hypothesized that "imprinting" with low prenatal vitamin D could contribute to the risk of these two brain disorders. Previously, we have shown that transient developmental hypovitaminosis D induces permanent changes in adult nervous system. The aim of this study was to examine the impact of prenatal hypovitaminosis D on gene expression in the adult rat brain. Vitamin D deficient female rats were mated with undeprived males and the offspring were fed with a control diet after birth. At Week 10, gene expression in the progeny's brain was compared with control animals using Affymetrix gene microarrays. Prenatal hypovitaminosis D causes a dramatic dysregulation of several biological pathways including oxidative phosphorylation, redox balance, cytoskeleton maintenance, calcium homeostasis, chaperoning, post-translational modifications, synaptic plasticity and neurotransmission. A computational analysis of these data suggests that impaired synaptic network may be a consequence of mitochondrial dysfunction. Since disruptions of mitochondrial metabolism have been associated with both multiple sclerosis and schizophrenia, developmental vitamin D deficiency may be a heuristic animal model for the study of these two brain diseases.
Asunto(s)
Encéfalo/metabolismo , Citoesqueleto/metabolismo , Regulación de la Expresión Génica/genética , Mitocondrias/metabolismo , Neuronas/metabolismo , Proteínas/metabolismo , Deficiencia de Vitamina D/metabolismo , Envejecimiento/fisiología , Animales , Femenino , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas/genética , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Biología de Sistemas , Factores de Tiempo , Transcripción Genética/genética , Deficiencia de Vitamina D/genéticaAsunto(s)
Neoplasias Encefálicas/epidemiología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Estaciones del Año , Deficiencia de Vitamina D/epidemiología , Vitamina D/metabolismo , Adulto , Animales , Apoptosis/genética , Encéfalo/fisiopatología , Neoplasias Encefálicas/fisiopatología , Causalidad , Proliferación Celular , Transformación Celular Neoplásica/genética , Niño , Modelos Animales de Enfermedad , Femenino , Trastornos Nutricionales en el Feto/metabolismo , Trastornos Nutricionales en el Feto/fisiopatología , Predisposición Genética a la Enfermedad/genética , Humanos , Recién Nacido , Embarazo , Ratas , Tiempo , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
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-A(alpha4). 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 hypovitaminosis D(3) in women of child-bearing age, the public health implications of these findings warrant attention.