Modelos animales para el estudio de factores de vulnerabilidad en el contexto de desórdenes neuropsiquiátricos y de adicción a drogas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 11/12/2013Fac. de Ciencias BiológicasTRUEunpu

Cannabinoid Drugs-Related Neuroprotection as a Potential Therapeutic Tool Against Chemotherapy-Induced Cognitive Impairment

In recent years, and particularly associated with the increase of cancer patients’ life expectancy, the occurrence of cancer treatment sequelae, including cognitive impairments, has received considerable attention. Chemotherapy-induced cognitive impairments (CICI) can be observed not only during pharmacological treatment of the disease but also long after cessation of this therapy. The lack of effective tools for its diagnosis together with the limited treatments currently available for alleviation of the side-effects induced by chemotherapeutic agents, demonstrates the need of a better understanding of the mechanisms underlying the pathology. This review focuses on the comprehensive appraisal of two main processes associated with the development of CICI: neuroinflammation and oxidative stress, and proposes the endogenous cannabinoid system (ECS) as a new therapeutic target against CICI. The neuroprotective role of the ECS, well described in other cognitive-related neuropathologies, seems to be able to reduce the activation of pro-inflammatory cytokines involved in the neuroinflammatory supraspinal processes underlying CICI. This review also provides evidence supporting the role of cannabinoid-based drugs in the modulation of oxidative stress processes that underpin cognitive impairments, and warrant the investigation of endocannabinoid components, still unknown, that may mediate the molecular mechanism behind this neuroprotective activity. Finally, this review points forward the urgent need of research focused on the understanding of CICI and the investigation of new therapeutic targets.LB and AL-B are supported by the Irish Research Council (IRCL/ 2017/78). RA is supported by Ministerio de Ciencia, Innovación y Universidades (PID2019-111510RB-I00) and Universidad Rey Juan Carlos

Un modelo animal de separación materna para el estudio de los efectos de �programación� neurometabólica del estrés neonatal

La aplicación de modelos animales en diversos campos de las neurociencias, incluyendo la psiquiatría, es a pesar de sus limitaciones una herramienta fundamental para la investigación de los mecanismos neurobiológicos subyacentes a diversas enfermedades desde una perspectiva traslacional. En este artículo presentamos y discutimos los datos procedentes de un modelo animal de estrés en etapas tempranas del desarrollo. En particular, exponemos evidencias acerca de diversas alteraciones psiconeuroinmunoendocrinas que aparecen, a lo largo de la vida, como consecuencia de someter a ratas Wistar neonatales a un episodio de estrés por separación materna de 24 horas a día postnatal 9. Discutimos la utilidad de este protocolo como modelo de alteraciones no solo neuropsiquiátricas, sino también metabólicas e inmunológicas, con base en el desarrollo. Finalmente, proponemos una hipótesis-modelo de trabajo en el que la leptina podría considerarse como nexo de unión entre los cambios neurales, metabólicos e inmunológicos encontrados en los animales separados de la madr

Neonatal treatment with a pegylated leptin antagonist induces sexually dimorphic effects on neurones and glial cells, and on markers of synaptic plasticity in the developing rat hippocampal formation

The present study aimed to better understand the role of the neonatal leptin surge, which peaks on postnatal day (PND)9–10, on the development of the hippocampal formation. Accordingly, male and female rats were administered with a pegylated leptin antagonist on PND9 and the expression of neurones, glial cells and diverse markers of synaptic plasticity was then analysed by immunohistochemistry in the hippocampal formation. Antagonism of the actions of leptin at this specific postnatal stage altered the number of glial fibrillary acidic protein positive cells, and also affected type 1 cannabinoid receptors, synaptophysin and brain-derived neurotrophic factor (BDNF), with the latter effect being sexually dimorphic. The results indicate that the physiological leptin surge occurring around PND 9–10 is critical for hippocampal formation development and that the dynamics of leptin activity might be different in males and females. The data obtained also suggest that some but not all the previously reported effects of maternal deprivation on hippocampal formation development (which markedly reduces leptin levels at PND 9–10) might be mediated by leptin deficiency in these animals

Neonatal treatment with a pegylated leptin antagonist induces sexually dimorphic effects on neurones and glial cells, and on markers of synaptic plasticity in the developing rat hippocampal formation

The present study aimed to better understand the role of the neonatal leptin surge, which peaks on postnatal day (PND)9–10, on the development of the hippocampal formation. Accordingly, male and female rats were administered with a pegylated leptin antagonist on PND9 and the expression of neurones, glial cells and diverse markers of synaptic plasticity was then analysed by immunohistochemistry in the hippocampal formation. Antagonism of the actions of leptin at this specific postnatal stage altered the number of glial fibrillary acidic protein positive cells, and also affected type 1 cannabinoid receptors, synaptophysin and brain-derived neurotrophic factor (BDNF), with the latter effect being sexually dimorphic. The results indicate that the physiological leptin surge occurring around PND 9–10 is critical for hippocampal formation development and that the dynamics of leptin activity might be different in males and females. The data obtained also suggest that some but not all the previously reported effects of maternal deprivation on hippocampal formation development (which markedly reduces leptin levels at PND 9–10) might be mediated by leptin deficiency in these animals.Ministerio de Economía y Competitividad (MINECO)Universidad Complutense de Madrid-Banco de SantanderInstituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en SaludDepto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

The maternal deprivation animal model revisited

Early life stress, in the form of MD (24 h at pnd 9), interferes with brain developmental trajectories modifying both behavioral and neurobiochemical parameters. MD has been reported to enhance neuroendocrine responses to stress, to affect emotional behavior and to impair cognitive function. More recently, changes in body weight gain, metabolic parameters and immunological responding have also been described. Present data give support to the fact that neuronal degeneration and/or astrocyte proliferation are present in specific brain regions, mainly hippocampus, prefrontal cortex and hypothalamus, which are particularly vulnerable to the effects of neonatal stress. The MD animal model arises as a valuable tool for the investigation of the brain processes occurring at the narrow time window comprised between pnd 9 and 10 that are critical for the establishment of brain circuitries critical for the regulation of behavior, metabolism and energy homeostasis. In the present review we will discuss three possible mechanisms that might be crucial for the effects of MD, namely, the rapid increase in glucocorticoids, the lack of the neonatal leptin surge, and the enhanced endocannabinoid signaling during the specific critical period of MD. A better understanding of the mechanisms underlying the detrimental consequences of MD is a concern for public health and may provide new insights into mental health prevention strategies and into novel therapeutic approaches in neuropsychiatry.Sin financiación8.580 JCR (2015) Q1, 3/51 Behavioral Sciences, 16/256 NeurosciencesUE

Pharmacological blockade of PPAR isoforms increases conditioned fear responding in the presence of nociceptive tone

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPAR¿, PPARß/¿, PPAR¿) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPAR¿ (GW6471), PPARß/¿ (GSK0660) or PPAR¿ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPAR¿ and PPARß/¿ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPAR¿ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPAR¿ and PPARß/¿ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPAR¿ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.This research was funded by Conselho Nacional de Pesquisa (CNPq)—Brazil (#207530/2014-9) and Science Foundation Ireland (10/IN.1/B2976). JCG was funded by a PhD scholarship from Conselho Nacional de Pesquisa (CNPq)—Brazil, ALB was funded by Government of Ireland Postdoctoral Research Fellowship from the Irish Research Councilpeer-reviewe