RESUMEN
Even though the etiology of Alzheimer's disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Tronco Encefálico/patología , Metilación de ADN , Epigénesis Genética , Animales , Tronco Encefálico/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/patología , HumanosRESUMEN
Abnormal brain-derived neurotrophic factor (BDNF) signaling seems to have a central role in the course and development of various neurological and psychiatric disorders. In addition, positive effects of psychotropic drugs are known to activate BDNF-mediated signaling. Although the BDNF gene has been associated with several diseases, molecular mechanisms other than functional genetic variations can impact on the regulation of BDNF gene expression and lead to disturbed BDNF signaling and associated pathology. Thus, epigenetic modifications, representing key mechanisms by which environmental factors induce enduring changes in gene expression, are suspected to participate in the onset of various psychiatric disorders. More specifically, various environmental factors, particularly when occurring during development, have been claimed to produce long-lasting epigenetic changes at the BDNF gene, thereby affecting availability and function of the BDNF protein. Such stabile imprints on the BDNF gene might explain, at least in part, the delayed efficacy of treatments as well as the high degree of relapses observed in psychiatric disorders. Moreover, BDNF gene has a complex structure displaying differential exon regulation and usage, suggesting a subcellular- and brain region-specific distribution. As such, developing drugs that modify epigenetic regulation at specific BDNF exons represents a promising strategy for the treatment of psychiatric disorders. Here, we present an overview of the current literature on epigenetic modifications at the BDNF locus in psychiatric disorders and related animal models.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Epigénesis Genética/fisiología , Interacción Gen-Ambiente , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/psicología , Humanos , Modelos GenéticosRESUMEN
Brain-derived neurotrophic factor (BDNF) signaling has been implicated in the onset of depression and in antidepressant efficacy, although the exact role of this neurotrophin in the pathophysiology of depression remains to be elucidated. Also, the interaction between chronic stress, which may precede depression, corticosteroids and BDNF is not fully understood. The present study aimed at investigating whether long-lasting, recurrent tethering of sows during a period of 1.5 or 4.5 years leads to enduring effects on measures that may be indicative of chronic stress, compared with animals kept in a group housing system ('loose' sows). Immediately after slaughter, the frontal cortex, dorsal and ventral hippocampus were dissected and protein levels of BDNF and its receptors were analyzed and compared with plasma cortisol levels and adrenal weights. Results indicate that tethering stress reduced BDNF protein levels in the dorsal hippocampus and the frontal cortex, but not in the ventral hippocampus. In addition, levels of TrkB, the high affinity receptor for BDNF, were increased in the dorsal hippocampus. Plasma cortisol levels and adrenal weight were increased after tethering. These stress effects on BDNF levels were more pronounced after 4.5 years of recurrent tethering and negatively correlated in particular in the frontal cortex with cortisol levels and adrenal weight. This suggests that the stress effect of tethered housing on neurotrophin levels may be mediated via cortisol. Taken together, these data indicate that recurrent tethering stress in sows over 4.5 years results in a loss of neurotrophic support by BDNF, mediated by an overactive neuroendocrine system.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Estrés Psicológico/metabolismo , Glándulas Suprarrenales/anatomía & histología , Animales , Depresión/metabolismo , Depresión/psicología , Modelos Animales de Enfermedad , Femenino , Hidrocortisona/sangre , Receptor trkB/análisis , Porcinos/metabolismo , Porcinos/psicologíaRESUMEN
Recent studies have suggested that DNA methylation is implicated in age-related changes in gene expression as well as in cognition. DNA methyltransferase 3a (Dnmt3a), which catalyzes DNA methylation, is essential for memory formation and underlying changes in neuronal and synaptic plasticity. Because caloric restriction (CR) and upregulation of antioxidants have been suggested as strategies to attenuate age-related alterations in the brain, we hypothesized that both a diet restricted in calories and transgenic overexpression of normal human Cu/Zn superoxide dismutase 1 (SOD) attenuate age-related changes in Dnmt3a in the aging mouse hippocampus. For this purpose, we performed qualitative and quantitative analyses of Dnmt3a-immunoreactivity (IR) for the hippocampal dentate gyrus (DG), CA3 and CA1-2 regions in 12- and 24-month-old mice from 4 groups, i.e. (1) wild-type (WT) mice on a control diet (WT-CD), (2) SOD-CD mice, (3) WT mice on CR (WT-CR), and (4) SOD-CR. Qualitative analyses revealed two types of Dnmt3a immunoreactive cells: type I cells--present throughout all hippocampal cell layers showing moderate levels of nuclear Dnmt3a-IR, and type II cells--a subpopulation of hippocampal cells showing very intense nuclear Dnmt3a-IR, and colocalization with Bromodeoxyuridine. Quantitative analyses indicated that the age-related increase in Dnmt3a-IR within the CA3 and CA1-2 in type I cells was attenuated by CR, but not by SOD overexpression. In contrast, the density of type II Dnmt3a immunoreactive cells showed an age-related reduction, without significant effects of both CR and SOD. These changes in Dnmt3a levels in the mouse hippocampus may have a significant impact on gene expression and associated cognitive functioning.
Asunto(s)
Envejecimiento/fisiología , Restricción Calórica , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Hipocampo/enzimología , Superóxido Dismutasa/metabolismo , Animales , ADN Metiltransferasa 3A , Metabolismo Energético/fisiología , Femenino , Regulación de la Expresión Génica/fisiología , Hipocampo/citología , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regulación hacia ArribaRESUMEN
Real-time reverse transcription PCR (qPCR) normalized to an internal reference gene (RG), is a frequently used method for quantifying gene expression changes in neuroscience. Although RG expression is assumed to be constant independent of physiological or experimental conditions, several studies have shown that commonly used RGs are not expressed stably. The use of unstable RGs has a profound effect on the conclusions drawn from studies on gene expression, and almost universally results in spurious estimation of target gene expression. Approaches aimed at selecting and validating RGs often make use of different statistical methods, which may lead to conflicting results. Based on published RG validation studies involving hypoxia the present study evaluates the expression of 5 candidate RGs (Actb, Pgk1, Sdha, Gapdh, Rnu6b) as a function of hypoxia exposure and hypothermic treatment in the neonatal rat cerebral cortex-in order to identify RGs that are stably expressed under these experimental conditions-using several statistical approaches that have been proposed to validate RGs. In doing so, we first analyzed RG ranking stability proposed by several widely used statistical methods and related tools, i.e. the Coefficient of Variation (CV) analysis, GeNorm, NormFinder, BestKeeper, and the ΔCt method. Using the Geometric mean rank, Pgk1 was identified as the most stable gene. Subsequently, we compared RG expression patterns between the various experimental groups. We found that these statistical methods, next to producing different rankings per se, all ranked RGs displaying significant differences in expression levels between groups as the most stable RG. As a consequence, when assessing the impact of RG selection on target gene expression quantification, substantial differences in target gene expression profiles were observed. Altogether, by assessing mRNA expression profiles within the neonatal rat brain cortex in hypoxia and hypothermia as a showcase, this study underlines the importance of further validating RGs for each individual experimental paradigm, considering the limitations of the statistical methods used for this aim.
Asunto(s)
Encéfalo/metabolismo , Perfilación de la Expresión Génica/métodos , Genes Esenciales , Hipotermia/genética , Hipoxia Encefálica/genética , Animales , Animales Recién Nacidos , Expresión Génica , Hipotermia/metabolismo , Hipoxia Encefálica/metabolismo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reproducibilidad de los ResultadosRESUMEN
Human pluripotent stem cell (PSC) technology and direct somatic cell reprogramming have opened up a promising new avenue in the field of neuroscience. These recent advances allow researchers to obtain virtually any cell type found in the human brain, making it possible to produce and study functional neurons in laboratory conditions for both scientific and medical purposes. Although distinct approaches have shown to be successful in directing neuronal cell fate in vitro, their refinement and optimization, as well as the search for alternative approaches, remains necessary to help realize the full potential of the eventually derived neuronal populations. Furthermore, we are currently limited in the number of neuronal subtypes whose induction is fully established, and different cultivation protocols for each subtype exist, making it challenging to increase the reproducibility and decrease the variances that are observed between different protocols. In this review, we summarize the progress that has been made in generating various neuronal subtypes from PSCs and somatic cells, with special emphasis on chemically defined systems, transcription factor-mediated reprogramming and epigenetic-based approaches. We also discuss the efforts that are being made to increase the efficiency of current protocols and address the potential for the use of these cells in disease modelling, drug discovery and regenerative medicine.
Asunto(s)
Reprogramación Celular/fisiología , Neuronas/fisiología , Células Madre Pluripotentes/fisiología , Células Madre Pluripotentes/trasplante , Animales , Diferenciación Celular/efectos de los fármacos , Epigenómica/métodos , Técnicas In Vitro , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Behavioral testing provides an essential approach in further developing our understanding of brain structure and function. The aim of our study was to outline a more expanded approach to cognition- and anxiety-related behavior in the rabbit. METHODS: Twenty-one 70-day old rabbits (13 female, 8 male) were exposed to open field test, dark-light box test and object recognition testing with variations in inter-trial-interval, olfactory recognition and object location testing. Independent T-tests were used to compare data by individual baseline characteristics, i.e. birth weight, weight at testing, sex, litter #, litter size. RESULTS: In the open field test, median time spent in the center was 3.64â¯s (0.84-41.36) for the 9 rabbits who entered the center; median distance moved in the arena was 874.42â¯cm (54.20-3444.83). In the dark light box test, 12 rabbits entered the light compartment. In the object recognition task, rabbits spent significantly less time exploring the familiar object compared to the novel (0.40â¯s [0-2.8] vs. 3.17â¯s [1.30-32.69]; Pâ¯=â¯0.003) when using a 30-min inter-trial interval, as well with a 90-min inter-trial interval: 0.87â¯s [0-7.8] vs. 7.65â¯s [0-37.6] (Pâ¯=â¯0.008). However, recognition was lost when using a 24-h inter-trial interval (time spent exploring the familiar object: 3.33 [0-10.90]; novel object:3.87 [1.15-48.53]; n.s). In the object location task and in olfactory object recognition task, median discrimination indexes were 0.69 (-1 to 1) and 0.37 (-0.38 to 0.78) respectively, higher than level expected by chance (Pâ¯<â¯0.001). Litter size >3 during the neonatal period was associated with increased explorative behavior in the dark light box test (Pâ¯=â¯0.046) and in the visual object recognition task (Pâ¯=â¯0.005), whereas body weight and sex were not. CONCLUSIONS: Settings and outcome measures for multiple behavioral tests, providing reference values and considerations for future developmental studies are reported. Discrimination and memory in the rabbit appear to relate to litter characteristics, although a larger sample size is needed to confirm our findings.
Asunto(s)
Conducta Exploratoria , Tamaño de la Camada , Reconocimiento en Psicología , Animales , Escala de Evaluación de la Conducta , Discriminación en Psicología , Femenino , Masculino , Actividad Motora , Percepción Olfatoria , Conejos , Proyectos de InvestigaciónRESUMEN
Hypoxic-ischemic encephalopathy remains a common cause of brain damage in neonates. Preterm infants have additional complications, as prematurity by itself increases the risk of encephalopathy. Currently, therapy for this subset of asphyxiated infants is limited to supportive care. There is an urgent need for therapies in preterm infants - and for representative animal models for preclinical drug development. In 1991, a novel rodent model of global asphyxia in the preterm infant was developed in Sweden. This method was based on the induction of asphyxia during the birth processes itself by submerging pups, still in the uterine horns, in a water bath followed by C-section. This insult occurs at a time-point when the rodent brain maturity resembles the brain of a 22-32 week old human fetus. This model has developed over the past 25 years as an established model of perinatal global asphyxia in the early preterm brain. Here we summarize the knowledge gained on the short- and long-term neuropathological and behavioral effects of asphyxia on the immature central nervous system.
Asunto(s)
Asfixia , Encéfalo , Animales , Asfixia Neonatal , Femenino , Humanos , Hipoxia-Isquemia Encefálica , Recien Nacido Prematuro , Embarazo , RatasRESUMEN
Chronic or repeated stress during human fetal brain development has been associated with various learning, behavioral, and/or mood disorders, including depression in later life. The mechanisms accounting for these effects of prenatal stress are not fully understood. The aim of this study was to investigate the effects of prenatal stress on early postnatal brain development, a disturbance of which may contribute to this increased vulnerability to psychopathology. We studied the effects of prenatal stress on fetal growth, stress-induced corticosterone secretion, brain cell proliferation, caspase-3-like activity and brain-derived neurotrophic factor protein content in newborn Fischer 344 rats. In addition to a slight reduction in birth weight, prenatal stress was associated with elevated corticosterone levels (33.8%) after 1 h of maternal deprivation on postnatal day 1, whereas by postnatal day 8 this pattern was reversed (-46.5%). Further, prenatal stress resulted in an approximately 50% decrease in brain cell proliferation just after birth in both genders with a concomitant increase in caspase-3-like activity within the hippocampus at postnatal day 1 (36.1%) and at postnatal day 5 (females only; 20.1%). Finally, brain-derived neurotrophic factor protein content was reduced in both the olfactory bulbs (-24.6%) and hippocampus (-28.2%) of prenatally stressed male offspring at postnatal days 1 and 5, respectively. These detrimental central changes observed may partly explain the increased susceptibility of prenatally stressed subjects to mood disorders including depression in later life.
Asunto(s)
Encéfalo/embriología , Desarrollo Fetal/fisiología , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico/fisiopatología , Animales , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Caspasa 3 , Caspasas/metabolismo , Proliferación Celular , Corticosterona/sangre , Femenino , Masculino , Embarazo , Ratas , Ratas Endogámicas F344 , Restricción Física/efectos adversosRESUMEN
Exposure of a pregnant woman to physical and/or psychological stress might affect her offspring by promoting the development of various learning, behavioral and/or mood disorders in later life. The 5-HT1A and 5-HT2A receptors are prominently implicated in the modulation of anxiety and mood-related behaviors. Using a semi-quantitative radiolabel immunocytochemical analysis (immunobinding), we studied the effect of prenatal stress on binding of these two receptor subtypes in the hippocampus of 4-week-old male and female Fischer 344 rats. Levels of 5-HT1A immunobinding in the ventral hippocampus, which is primarily implicated in emotional processing, were significantly decreased in male offspring after prenatal stress. A trend towards a decrease was observed in the ventral hippocampus of females. In contrast, 5-HT1A immunobinding within the dorsal hippocampus, which is mainly related to learning and memory, was not affected by prenatal stress in offspring of either gender. Likewise, no significant differences between control and prenatally stressed rats were observed for levels of 5-HT2A immunobinding in either part of the hippocampus or gender. The observed reduction in hippocampal 5-HT1A receptor binding in male offspring after prenatal stress may have important consequences for adult anxiety- and depressive-like behavior.
Asunto(s)
Hipocampo/fisiopatología , Trastornos del Humor/etiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/deficiencia , Estrés Fisiológico/metabolismo , Animales , Trastornos de Ansiedad/etiología , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Sitios de Unión/fisiología , Unión Competitiva/fisiología , Trastorno Depresivo/etiología , Trastorno Depresivo/metabolismo , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Aprendizaje/fisiología , Masculino , Trastornos del Humor/metabolismo , Trastornos del Humor/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Endogámicas F344 , Receptor de Serotonina 5-HT2A/metabolismo , Estrés Fisiológico/fisiopatología , Transmisión Sináptica/fisiologíaRESUMEN
The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dióxido de Carbono/farmacología , Modelos Animales de Enfermedad , Miedo/efectos de los fármacos , Ratones , Trastorno de Pánico/psicología , Pánico/efectos de los fármacos , Adolescente , Adulto , Animales , Presión Sanguínea/efectos de los fármacos , Capnografía , Dióxido de Carbono/efectos adversos , Femenino , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Trastorno de Pánico/fisiopatología , Adulto JovenRESUMEN
Growing evidence indicates that impairment of the stress response, in particular the negative feedback regulation mechanism exerted by the hypothalamo-pituitary-adrenal (HPA) axis, might be responsible for the hippocampal atrophy observed in depressed patients. Antidepressants, possibly through the activation of BDNF signaling, may enhance neuroplasticity and restore normal hippocampal functions. In this context, glucocorticoid receptor-impaired (GR-i) mice-a transgenic mouse model of reduced GR-induced negative feedback regulation of the HPA axis-were used to investigate the role of BDNF/TrkB signaling in the behavioral and neurochemical effects of the new generation antidepressant drug, agomelatine. GR-i mice exhibited marked alterations in depressive-like and anxiety-like behaviors, together with a decreased cell proliferation and altered levels of neuroplastic and epigenetic markers in the hippocampus. GR-i mice and their wild-type littermates were treated for 21 days with vehicle, agomelatine (50mg/kg/day; i.p) or the TrkB inhibitor Ana-12 (0.5mg/kg/day, i.p) alone, or in combination with agomelatine. Chronic treatment with agomelatine resulted in antidepressant-like effects in GR-i mice and reversed the deficit in hippocampal cell proliferation and some of the alterations of mRNA plasticity markers in GR-i mice. Ana-12 blocked the effect of agomelatine on motor activity as well as its ability to restore a normal hippocampal cell proliferation and expression of neurotrophic factors. Altogether, our findings indicate that agomelatine requires TrkB signaling to reverse some of the molecular and behavioral alterations caused by HPA axis impairment.
Asunto(s)
Acetamidas/farmacología , Antidepresivos/farmacología , Trastorno Depresivo/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Receptor trkB/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Azepinas/farmacología , Benzamidas/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proliferación Celular/efectos de los fármacos , Trastorno Depresivo/metabolismo , Trastorno Depresivo/patología , Modelos Animales de Enfermedad , Miedo/efectos de los fármacos , Miedo/fisiología , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Receptor trkB/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Método Simple Ciego , Conducta SocialRESUMEN
The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders.
Asunto(s)
Conducta Animal/efectos de los fármacos , Factor Neurotrófico Ciliar/genética , Fluoxetina/farmacología , Hipocampo , Efectos Adversos a Largo Plazo , Transferrina/genética , Regulación hacia Arriba/efectos de los fármacos , Animales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Hipocampo/metabolismo , Hipocampo/patología , Efectos Adversos a Largo Plazo/diagnóstico , Efectos Adversos a Largo Plazo/etiología , Efectos Adversos a Largo Plazo/metabolismo , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/genética , Farmacogenética , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed.
Asunto(s)
Encéfalo/fisiopatología , Dióxido de Carbono/metabolismo , Homeostasis/fisiología , Trastorno de Pánico/fisiopatología , Serotonina/metabolismo , Animales , Humanos , Concentración de Iones de HidrógenoRESUMEN
Exposure to prenatal stress (PS) can predispose individuals to the development of psychopathology later in life. We examined the effects of unpredictable chronic mild stress (CMS) exposure during adolescence on a background of PS in male and female Sprague-Dawley rats. PS induced more anxiety-like behavior in the elevated zero maze in both sexes, an effect that was normalized by subsequent exposure to CMS. Moreover, PS was associated with increased depression-like behavior in the forced swim test in males only. Conversely, sucrose intake was increased in PS males, whilst being decreased in females when consecutively exposed to PS and CMS. Hypothalamo-pituitary-adrenal (HPA) axis reactivity was affected in males only, with higher stress-induced plasma corticosterone levels after PS. Markedly, CMS normalized the effects of PS on elevated zero maze behavior as well as basal and stress-induced plasma corticosterone secretion. At the neurochemical level, both PS and CMS induced various sex-specific alterations in serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) immunoreactivity in the dorsal raphe nucleus, hippocampus and prefrontal cortex with, in line with the behavioral observations, more profound effects in male offspring. In conclusion, these findings show that prenatal maternal stress in Sprague-Dawley rats induces various anxiety- and depression-related behavioral and neuroendocrine changes, as well as alterations in central 5-HT and TPH2 function, predominantly in male offspring. Moreover, CMS exposure partially normalized the effects of previous PS experience, suggesting that the outcome of developmental stress exposure largely depends on the environmental conditions later in life and vice versa.
Asunto(s)
Alostasis , Ansiedad/etiología , Depresión/etiología , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Neuronas Serotoninérgicas/metabolismo , Estrés Fisiológico , Animales , Ansiedad/sangre , Ansiedad/prevención & control , Conducta Animal , Depresión/sangre , Depresión/prevención & control , Femenino , Hipocampo/enzimología , Hipocampo/metabolismo , Hipocampo/patología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Proteínas del Tejido Nervioso/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Corteza Prefrontal/enzimología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/psicología , Núcleos del Rafe/enzimología , Núcleos del Rafe/metabolismo , Núcleos del Rafe/patología , Ratas , Ratas Sprague-Dawley , Neuronas Serotoninérgicas/enzimología , Neuronas Serotoninérgicas/patología , Caracteres Sexuales , Triptófano Hidroxilasa/metabolismoRESUMEN
Phosphodiesterase type 4 inhibitors (PDE4-Is) have received increasing attention as cognition-enhancers and putative treatment strategies for Alzheimer's disease (AD). By preventing cAMP breakdown, PDE4-Is can enhance intracellular signal transduction and increase the phosphorylation of cAMP response element-binding protein (CREB) and transcription of proteins related to synaptic plasticity and associated memory formation. Unfortunately, clinical development of PDE4-Is has been seriously hampered by emetic side effects. The new isoform-specific PDE4D-I, GEBR-7b, has shown to have beneficial effects on memory at non-emetic doses. The aim of the current study was to investigate chronic cognition-enhancing effects of GEBR-7b in a mouse model of AD. To this extent, 5-month-old (5M) APPswe/PS1dE9 mice received daily subcutaneous injections with GEBR-7b (0.001 mg/kg) or vehicle for a period of 3 weeks, and were tested on affective and cognitive behavior at 7M. We demonstrated a cognition-enhancing potential in APPswe/PS1dE9 mice as their spatial memory function at 7M in the object location test was improved by prior GEBR-7b treatment. APPswe/PS1dE9 mice displayed lower levels of CREB phosphorylation, which remained unaltered after chronic GEBR-7b treatment, and higher levels of tau in the hippocampus. Hippocampal brain-derived neurotrophic factor levels and synaptic densities were not different between experimental groups and no effects were observed on hippocampal GSK3ß and tau phosphorylation or Aß levels. In conclusion, GEBR-7b can enhance spatial memory function in the APPswe/PS1dE9 mouse model of AD. Although the underlying mechanisms of its cognition-enhancing potential remain to be elucidated, PDE4D inhibition appears an interesting novel therapeutic option for cognitive deficits in AD.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Hipocampo/efectos de los fármacos , Iminas/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Morfolinas/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large , Guanilato-Quinasas/metabolismo , Hipocampo/metabolismo , Iminas/uso terapéutico , Proteínas de la Membrana/metabolismo , Ratones , Morfolinas/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Fosforilación/efectos de los fármacosRESUMEN
Plastic changes in the adult mammal hippocampus can be altered by many factors and perhaps the most well-documented is stress. Stress and elevated corticosterone levels have been shown to decrease hippocampal neurogenesis and decrease the complexity of CA3 pyramidal neurons. However, the extent of these changes in relation to low and moderately elevated levels of corticosterone has yet to be fully investigated. Therefore, the aim of the present study was to determine how low to moderately elevated circulating corticosterone levels affect dendritic morphology of CA3 pyramidal cells and hippocampal neurogenesis in adult male rats. To do this, three groups of adult male Wistar rats were used: (1) Sham-operated, (2) Adrenalectomized (ADX), and (3) ADX+corticosterone replacement. Primary results show that adrenalectomy, but not moderately elevated levels of corticosterone replacement, resulted in significant atrophy of CA3 pyramidal neurons. Interestingly, moderate corticosterone replacement resulted in significantly more surviving new cells in the dentate gyrus when compared to sham controls. This work shows that circulating levels of corticosterone differentially affect plasticity in the CA3 region and the dentate gyrus.
Asunto(s)
Adrenalectomía , Región CA3 Hipocampal/citología , Corticosterona/farmacología , Dendritas/efectos de los fármacos , Terapia de Reemplazo de Hormonas , Animales , Antimetabolitos , Bromodesoxiuridina , Región CA3 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/ultraestructura , Supervivencia Celular/efectos de los fármacos , Dendritas/ultraestructura , Giro Dentado/citología , Giro Dentado/efectos de los fármacos , Implantes de Medicamentos , Hipocampo/citología , Inmunohistoquímica , Masculino , Células Piramidales/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Adverse life events during pregnancy may impact upon the developing fetus, predisposing prenatally stressed offspring to the development of psychopathology. In the present study, we examined the effects of prenatal restraint stress (PS) on anxiety- and depression-related behavior in both male and female adult Sprague-Dawley rats. In addition, gene expression profiles within the hippocampus and frontal cortex (FC) were examined in order to gain more insight into the molecular mechanisms that mediate the behavioral effects of PS exposure. PS significantly increased anxiety-related behavior in male, but not female offspring. Likewise, depression-related behavior was increased in male PS rats only. Further, male PS offspring showed increased basal plasma corticosterone levels in adulthood, whereas both PS males and females had lower stress-induced corticosterone levels when compared to controls. Microarray-based profiling of the hippocampus and FC showed distinct sex-dependent changes in gene expression after PS. Biological processes and/or signal transduction cascades affected by PS included glutamatergic and GABAergic neurotransmission, mitogen-activated protein kinase (MAPK) signaling, neurotrophic factor signaling, phosphodiesterase (PDE)/ cyclic nucleotide signaling, glycogen synthase kinase 3 (GSK3) signaling, and insulin signaling. Further, the data indicated that epigenetic regulation is affected differentially in male and female PS offspring. These sex-specific alterations may, at least in part, explain the behavioral differences observed between both sexes, i.e. relative vulnerability versus resilience to PS in male versus female rats, respectively. These data reveal novel potential targets for antidepressant and mood stabilizing drug treatments including PDE inhibitors and histone deacetylase (HDAC) inhibitors.
Asunto(s)
Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Complicaciones del Embarazo/fisiopatología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Estrés Fisiológico , Estrés Psicológico/fisiopatología , Animales , Ansiedad/sangre , Ansiedad/etiología , Ansiedad/metabolismo , Conducta Animal , Corticosterona/sangre , Depresión/sangre , Depresión/etiología , Depresión/metabolismo , Susceptibilidad a Enfermedades , Epigénesis Genética , Femenino , Lóbulo Frontal/enzimología , Regulación de la Expresión Génica , Hipocampo/enzimología , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neuronas/enzimología , Neuronas/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/etiología , Ratas , Ratas Sprague-Dawley , Restricción Física , Caracteres Sexuales , Transducción de SeñalRESUMEN
Fetal asphyxic insults in the brain are known to be associated with developmental and neurological problems like neuromotor disorders and cognitive deficits. Little is known, however, about the long-term consequences of fetal asphyxia contributing to the development of different neurological diseases common in the adult or the aging brain. For that reason the present study aimed to investigate the long-term effects of fetal asphyxia on synaptic organization within the adult rat brain. Fetal asphyxia was induced at embryonic day 17 by 75-min clamping of the uterine and ovarian arteries. Presynaptic bouton densities and numbers were analyzed in the striatum and prefrontal cortex at the age of 19 months. A substantial decrease in presynaptic bouton density and number was observed in the striatum of fetal asphyxia rats compared to control rats, while an increase was found in the fifth layer of the prefrontal cortex. These results suggest that fetal asphyxia can have long-lasting effects on synaptic organization that might contribute to a developmental etiology of different neurological disorders and aging.