Efectos del cuidado materno temprano en el desarrollo del sistema nervioso

Ambientes adversos tempranos pueden afectar el desarrollo del sistema nervioso e incluso favorecer la aparición de desórdenes del estado de ánimo como la depresión y ansiedad. Esta hipótesis ha sido corroborada a través de modelos animales. En un estudio reciente de nuestro laboratorio comparamos crías de ratas que recibieron de sus madres un bajo nivel de cuidado durante sus primeros días de vida con otras que recibieron un alto nivel de cuidado. Cuando alcanzaron la adolescencia, las primeras presentaron mayores niveles de ansiedad y una mayor adquisición de conductas que se han relacionado con la depresión. Este estudio permitió también observar cambios neurofisiológicos en los mismos animales. Los resultados obtenidos confirman la influencia del cuidado materno en el desarrollo y sus efectos a largo plazo.UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de MedicinaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN

Individual differences in animal models: an approach to study neurobiological factors related to depression

El estudio de las diferencias individuales en la prueba de nado forzado (PNF) en ratas permite la identificación de factores de susceptibilidad o de resistencia en el desarrollo conductas relacionadas con la depresión. Para estudiar estas diferencias, varios grupos de ratas fueron sometidos a la PNF; posteriormente, los animales con baja y alta inmovilidad fueron comparados, lo que permitió identificar una serie de características que podrían estar actuando como factores de riesgo o de protección. Así, factores neurobiológicos como la expresión diferencial en el núcleo accumbens del receptor 1 para el factor liberador de corticotropina (CRFR1), una tasa diferencial de recambio de dopamina en esa misma región y la cinética de expresión diferencial del factor neurotrófico derivado del cerebro (BDNF) en la corteza prefrontal, podrían jugar un papel importante en la modulación de conductas depresivas. La presente revisión resume nuestros resultados más importantes en esta línea de investigación.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de MedicinaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN

The environmental enrichment model revisited: A translatable paradigm to study the stress of our modern lifestyle

Mounting evidence shows that physical activity, social interaction and sensorimotor stimulation provided by environmental enrichment (EE) exert several neurobehavioural effects traditionally interpreted as enhancements relative to standard housing (SH) conditions. However, this evidence rather indicates that SH induces many deficits, which could be ameliorated by exposing animals to an environment vaguely mimicking some features of their wild habitat. Rearing rodents in social isolation (SI) can aggravate such deficits, which can be restored by SH or EE. It is not surprising, therefore, that most preclinical stress models have included severe and unnatural stressors to produce a stress response prominent enough to be distinguishable from SH or SI—frequently used as control groups. Although current stress models induce a stress-related phenotype, they may fail to represent the stress of our urban lifestyle characterized by SI, poor housing and working environments, sedentarism, obesity and limited access to recreational activities and exercise. In the following review, we discuss the stress of living in urban areas and how exposures to and performing activities in green environments are stress relievers. Based on the commonalities between human and animal EE, we discuss how models of housing conditions (e.g., SI–SH– EE) could be adapted to study the stress of our modern lifestyle. The housing conditions model might be easy to implement and replicate leading to more translational results. It may also contribute to accomplishing some ethical commitments by promoting the refinement of procedures to model stress, diminishing animal suffering, enhancing animal welfare and eventually reducing the number of experimental animals needed.Universidad de Costa Rica/[723-B9-197]/UCR/Costa RicaUniversidad de Costa Rica/[837-B8-123]/UCR/Costa RicaUniversidad de Costa Rica/[837-B7-603]/UCR/Costa RicaUniversidad de Costa Rica/[837-C0-606]/UCR/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

Environmental Enrichment and Physical Exercise Attenuate the Depressive-Like Effects Induced by Social Isolation Stress in Rats

We assessed the antidepressant-like effects of environmental enrichment (EE) and physical exercise (PE) compared with the selective serotonin reuptake inhibitor fluoxetine against the depression-related neurobehavioral alterations induced by postweaning social isolation (SI) in rats. After 1 month of SI, rats were submitted to PE (treadmill), EE, or fluoxetine (10 mg/kg), which were compared with naïve SI and grouphoused rats. After 1 month, behavior was analyzed in the open field (OFT), the sucrose preference (SPT), and the forced swimming (FST) tests. Afterward, the hippocampal serotonin contents, its metabolite, and turnover were measured. SI induced a depressionrelated phenotype characterized by a marginal bodyweight gain, anxiety, anhedonia, behavioral despair, and alterations of serotonin metabolism. EE produced the widest and largest antidepressive-like effect, followed by PE and fluoxetine, which were almost equivalent. The treatments, however, affected differentially the neurobehavioral domains investigated. EE exerted its largest effect on anhedonia and was the only treatment inducing anxiolytic-like effects. Fluoxetine, in contrast, produced its largest effect on serotonin metabolism, followed by its anti-behavioral despair action. PE was a middleground treatment with broader behavioral outcomes than fluoxetine, but ineffective to reverse the serotonergic alterations induced by SI. The most responsive test to the treatments was the FST, followed closely by the SPT. Although OFT locomotion and body weight varied considerably between groups, they were barely responsive to PE and fluoxetine. From a translational standpoint, our data suggest that exercise and recreational activities may have broader health benefits than antidepressants to overcome confinement and the consequences of chronic stress.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Medicin

Neurobehavioral Effects of Restricted and Unpredictable Environmental Enrichment in Rats

To study how motivational factors modulate experience-dependent neurobehavioral plasticity, we modify a protocol of environmental enrichment (EE) in rats. We assumed that the benefits derived from EE might vary according to the level of incentive salience attributed to it. To enhance the rewarding properties of EE, access to the EE cage varied randomly from 2 to 48 h for 30 days (REE). The REE group was enriched only 50% of the time and was compared to standard housing and continuous EE (CEE) groups. As behavioral readout, we analyzed the spontaneous activity and the ultrasonic vocalizations (USVs) within the EE cage weekly, and in the open field test at the end of the experiment. In the cage, REE increased the utilization of materials, physical activity, and the rate of appetitive USVs. In the OF, the CEE-induced enhancements in novelty habituation and social signaling were equaled by the REE. At the neural level, we measured the expression of genes related to neural plasticity and epigenetic regulations in different brain regions. In the dorsal striatum and hippocampus, REE upregulated the expression of the brain-derived neurotrophic factor, its tropomyosin kinase B receptor, and the DNA methyltransferase 3A. Altogether, our results suggest that the higher activity within the cage and the augmented incentive motivation provoked by the REE boosted its neurobehavioral effects equaling or surpassing those observed in the CEE condition. As constant exposures to treatments or stimulating environments are virtually impossible for humans, restricted EE protocols would have greater translational value than traditional ones.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP

Neurobiología de la depresión

La depresión es una enfermedad compleja que afecta a un porcentaje considerable de la población mundial (17-20%). Aunque todavía no se han identificado los circuitos cerebrales específicos, investigaciones utilizando neuroimagen, estudios post mortem y modelos animales señalan regiones importantes para la fisiopatología de la enfermedad. Al mismo tiempo, se han identificado procesos como la respuesta al estrés, la respuesta inmune, la transmisión sináptica y la plasticidad neuronal que participan en el desarrollo de la enfermedad. Así, una serie de procesos neurohormonales, neuronales y neurotróficos son objeto de intensa investigación con el objetivo de comprender el surgimiento y progreso de la depresión. Entre los factores estudiados se encuentran el eje hipotalámico-hipofisiario-suprarrenal, la transmisión monoaminérgica, los mecanismos neurotróficos, la neurogénesis y las citoquinas. Investigaciones recientes sugieren que el ambiente ejerce un efecto determinante en el funcionamiento de estos procesos. Situaciones adversas ocurridas durante etapas tempranas del desarrollo son capaces de modificar la expresión génica a través de mecanismos epigenéticos, convirtiéndose en factores de susceptibilidad. Por su parte, el enriquecimiento ambiental también es capaz de modificar diversos procesos neurológicos, adquiriendo un papel relevante en el desarrollo de la enfermedad.Instituto de Investigaciones en Salud, Universidad de Costa Rica/[]/INISA/Costa RicaUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de MedicinaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN

The individual differences approach in the study of neurobiological factors related to the development of depression and anxiety

La investigación de las diferencias individuales en la conducta de inmovilidad en la prueba de nado forzado en ratas, facilita la identificación de sustratos biológicos y mecanismos relacionados con la depresión. En una serie de estudios usando este enfoque encontramos que animales con baja inmovilidad presentaron mayores niveles de CRFR1 en el NAc en comparación con animales con alta inmovilidad. Además, la tasa de recambio de DA en NAc también fue mayor en animales juveniles con baja inmovilidad, aunque esta diferencia fue opuesta en animales adultos. Con respecto a la cinética neuroquímica observamos que animales con baja inmovilidad presentaron una disminución de BDNF en corteza prefrontal más rápida, comparados con ratas con alta inmovilidad. También se observó una respuesta diferencial al efecto del enriquecimiento ambiental en lo referente a la expresión de CRF y CRFR1 en el NAc. Finalmente, el enfoque de las diferencias individuales aplicado al estudio del cuido materno, nos permitió identificar varios factores que pueden ser modificados por el ambiente temprano, entre los cuales destaca la expresión del receptor TrkB. Estas observaciones podrían representar un conjunto de factores de susceptibilidad o resistencia, por lo que se perfilan como blancos importantes en el estudio de la depresión.The study of individual differences in the immobility behavior using the forced swimming test in rats facilitates the identification of biological substrates and mechanisms related to depression. By means of the individual differences approach we found that animals with low immobility showed higher CRFR1 levels in the NAc compared with animals with high immobility. Furthermore, accumbal DA turnover was also significantly higher in juvenile animals with low immobility. In adult rats, a significant difference was also observed for accumbal DA turnover, but in an opposite direction. In regard to neurochemical kinetics, we found that animals with low immobility showed a faster decrease of the BDNF expression in the prefrontal cortex, compared with rats with high immobility. On the other hand, a differential response in the accumbal CRF or CRFR1 expression profiles in response to environmental enrichment was observed. Finally, the individual differences approach used in the study of maternal care allowed us to identify a number of factors susceptible of modification by early environments, e.g., the expression of TrkB receptor. Taken together, these findings may represent a set of features conferring susceptibility or resilience to the display of depression-related behaviors, emerging as key targets in the study of the disease.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN

Age-dependent differences on neurochemistry and behavior in rats raised with low and high levels of maternal care

In laboratory rats, naturally-occurring variations in maternal care have been used to study the neurobehavioral consequences of maternal nursing and to model the early-life adversity associated with many psychiatric disorders. This study aimed to determine the role of maternal care on behavior and monoamine concentrations at the prepubertal and young adulthood ages. We observed the licking/grooming (LG) behavior of Sprague-Dawley (SD) dams and assigned the litter to either low (LLG) or high (HLG) LG groups. Behavioral testing in the male offspring consisted of the open-field test, the elevated plus-maze, and the forced swimming test. Afterward, neurotransmitters contents were measured in the prefrontal cortex, the nucleus accumbens, the amygdala, and the hippocampus. We found that at the prepubertal stage, the effects of maternal care were only noticeable in the elevated plus-maze and the serotonin concentration in the nucleus accumbens. At adulthood, body weight and monoamines contents increased substantially in LLG rats. Specifically, they showed higher serotonin contents with a reduced turnover in almost all brain regions, followed by higher contents of norepinephrine and dopamine, especially in the nucleus accumbens. Changes in monoamines concentrations seem to be independent of the behavioral phenotype shaped by variations in maternal care, as behavioral effects were somewhat weak in both experiments. If higher monoamines contents in LLG rats represent an adaptive mechanism to deal with further adverse events, the behavioral paradigms used here were insufficiently challenging to bring out noticeable differences, at least in SD rats.Universidad de Costa Rica/[837-B5-184]/UCR/Costa RicaUniversidad de Costa Rica/[837-B5-185]/UCR/Costa RicaUniversidad de Costa Rica/[742-B4-240]/UCR/Costa RicaUniversidad de Costa Rica/[723-B7-610]/UCR/Costa RicaUniversidad de Costa Rica/[723-B3-110]/UCR/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

Individual Differences In The Forced Swimming Test And The Effect Of Environmental Enrichment: Searching For An Interaction

artículo -- Universidad de Costa Rica, Centro de Investigación en Neurociencias e Instituto de Investigaciones en Salud. 2014. Este documento es privado debido a limitaciones de derechos de autor.Animals with low and high immobility in the forced swimming test (FST) differ in a number of neurobehavioral factors. A growing body of evidence suggests that the exposure to enriched environments mediates a number of changes in the brain. Therefore, we studied if animals’ individuality can somehow modulate the response to environmental stimuli. Male rats were classified according to their immobility time scores in theFSTtest session as animals with low, medium or high immobility. Then, rats from groups with low and high immobility were randomly distributed in two groups to be reared in different housing conditions (i.e., enriched and standard conditions) during 8 weeks. Animals were subjected to the open field test (OFT) before and 6 weeks after the start of housing protocol. Rats with high immobility in the FST also showed high ambulation and high rearing time in the first OFT. Such findings were not observed in the second OFT. Conversely, an effect of environmental enrichment was found in the second OFT where enriched animals showed lower ambulation and higher grooming time than the standard control group. Rats were sacrificed after the housing protocol and neurochemical content and/or gene expression were studied in three different brain regions: the prefrontal cortex, the hippocampus and the nucleus accumbens. Rats with low immobility showed significantly higher accumbal 5-HT levels than animals with high immobility, whereas no neurochemical differences were observed between enriched and standard animals. Regarding expression data, however, an effect of enrichment on accumbal corticotropin-releasing factor (CRF) and its receptor 1 (CRFR1) levels was observed, and such effect depended on immobility levels. Thus, our results not only allowed us to identify a number of differences between animals with low and high immobility or animals housed in standard and enriched conditions, but also suggested that animals’ individuality modulated in some way the response to environmental stimuli.Universidad de Costa Rica.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN

Maternal behavior as an early modulator of neurobehavioral offspring responses by Sprague-Dawley rats

Maternal care plays an important role as an early modeler of neurodevelopment and brain function, and its effects remain until adulthood. Such modeling or programming has shown to influence the stress response and represents a key susceptibility factor in the development of mood disorders. In order to characterize such process which is still not clear, male offspring were classified in animals with low, medium and high licking/grooming (LG) according to the maternal behavior. Juvenile animals were subjected to the open field test (OFT) and the forced swimming test (FST), and offspring of low and high LG mothers were compared. Seven days after the FST, neurochemical and gene expression analyses were carried out in order to identify possible changes on relevant targets. Maternal care did determine locomotor behaviors in the OFT, supporting an anxiogenic effect of low maternal investment. This effect seems to be associated with the serotonergic systems in both nucleus accumbens (NAc) and hippocampus (HPC), since offspring of low LG mothers showed decreased 5-HT neurotransmission in those brain regions compared with animals of high LG mothers. Furthermore, TrkB expression was higher in offspring of high LG compared to the group of low LG mothers, supporting its influence as a mechanistic intermediate of such effect, at least in the NAc. Taken together, these findings strongly support the influence of differential maternal care on the neurodevelopment and responsivity of juvenile ratsUniversidad de Costa Rica/[VI-422-A9-607]/UCR/Costa RicaConsejo Nacional para Investigaciones Científicas y Tecnológicas/[FI-293-2009]/CONICIT/Costa RicaUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de MedicinaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN