Papel del receptor del ácido lisofosfatídico LPA1 en la neurogénesis hipocampal adulta y la memoria espacial en situaciones de estrés crónico

Este estudio muestra que los ratones carentes del receptor del ácido lisofosfatídico LPA1 (LPA1-nulos) presentan déficit de memoria espacial. Además, el efecto del estrés crónico sobre la neurogénesis hipocampal adulta y la memoria espacial es más severo en los LPA1-nulos que en animales normales, demostrándose que la ausencia del receptor agrava las consecuencias del estrés. La modulación de la señalización mediada por el LPA1 podría intervenir en la patología asociada al estrés y al hipocampo

Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on Learning-Related Brain Regions

This chapter will review the altered brain structure and function associated to drug addiction, with a focus on brain regions involved in learning and motivated behavior. As evidenced by both clinical and preclinical studies, repeated drug exposure affects whole brain neuroplasticity including the mesolimbic system which is a main locus for reward, an action-control center such as the dorsal striatum, and limbic brain regions such as the prefrontal cortex, the hippocampus, and the amygdala that are involved in behavioral control, memory, and mood. In this way, the drug-seeking actions that were initially intentional responses become involuntary habits governed by the dorsal striatum. Drug addiction may also curse with a reduced ability to experience rewards that are unrelated to drugs and emotional dysregulation, while the impairment on limbic regions contributes to generate cognitive symptoms. These entail persistent memories for previous experiences with the drug contrasting with a global cognitive decline that may hamper the acquisition of new, adaptive learnings. Overall, these features promote a desire for the drug, leading to relapse in drug use. Further drug exposure, in turn, aggravates its consequences on the brain and behavior, creating the harmful “addiction cycle.

Estudio del cacao como potenciador de la neurogénesis y la función hipocampal en ratones adultos

Introducción: La formación de nuevas neuronas es un fenómeno neuroplástico esencial que se produce en el cerebro adulto, concretamente en el giro dentado del hipocampo (neurogénesis hipocampal adulta, NHA). Numerosos estudios demuestran que la inhibición de NHA en roedores conduce al deterioro cognitivo, mientras que su aumento potencia la adquisición, consolidación y actualización de los recuerdos dependientes del hipocampo. Estudios recientes destacan el papel de los polifenoles del cacao en la potenciación de la memoria, sin embargo, no existen evidencias concluyentes sobre su efecto en la NHA. Objetivos: En este proyecto, proponemos estudiar la modulación de la NHA mediante la dieta, empleando el cacao como una nueva intervención nutricional que podría potenciar la NHA mediante la acción de los polifenoles. Se emplearán ratones macho y hembra (aproximadamente 3 meses de edad), que recibirán una dieta estándar (grupos “control”) o una dieta enriquecida en cacao (10 %) durante ocho semanas. Se evaluará el efecto del cacao en la función cognitiva y emocional mediante distintas pruebas comportamentales que incluyen tareas para evaluar la ansiedad (laberinto en cruz), la exploración (campo abierto), la indefensión (test de natación forzada) y la memoria (reconocimiento de objeto y laberinto acuático). Se estudiará la NHA mediante la administración de bromodesoxiuridina y técnicas de inmunohistoquímica y microscopía, así como la expresión del factor neurotrófico brain derived neurotrophic factor (BDNF) en el hipocampo mediante western blot. Resultados esperados: Mediante este estudio se espera obtener una mejora del rendimiento cognitivo, debido principalmente a la potenciación de la plasticidad cerebral (incremento de la NHA y BDNF) trasla ingesta de cacao.Proyecto I+D+i PID2020-114374RB-100, financiado por MCIN/AEI/10.13039/501100011033/ Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Perfil neuropsicológico de paciente con trastorno por uso de sustancias.

Aunque los Trastornos por Uso de Sustancias (TUS) no se han considerado un componente esencial en la etiología de la demencia durante mucho tiempo, el DSM-5 ha introducido recientemente el trastorno neurocognitivo leve y mayor inducido por sustancias, y la OMS ha incluido la demencia alcohólica como una de las consecuencias del consumo problemático de alcohol. Sin embargo, este conocimiento no ha tenido impacto en la práctica clínica y la neuropsicología aún no forma parte del tratamiento de las adicciones. Por lo tanto, la detección y el seguimiento del deterioro cognitivo en pacientes con TUS sigue siendo un gran desafío clínico, sobre todo cuando se requiere un diagnóstico precoz. El objetivo del presente estudio fue estudiar el efecto del consumo crónico de sustancias sobre el rendimiento cognitivo y su correlación con variables relacionadas con el consumo de sustancias (inicio del consumo, desarrollo de la dependencia, abstinencia, años del trastorno, número de recaídas). Participaron 61 pacientes con TUS reclutados de Proyecto Hombre-Málaga en tratamiento y se compararon con 38 controles sanos. Los participantes fueron evaluados mediante la entrevista PRISM, MoCA, D2-R, TESEN, TAVEC, ROCF, Dígitos, anillas, Stroop y M-WCST. Los resultados se analizaron mediante los programas estadísticos SPSS versión 25.0 y GraphPad Prism 8. Un valor p<0.05 fue considerado como estadísticamente significativo. Cuando fueron comparados con los sujetos controles, los pacientes TUS mostraron amplias alteraciones cognitivas en dominios como la atención, la memoria y el aprendizaje y las funciones ejecutivas. Además, estas disfunciones cognitivas se correlacionaron con variables relacionadas con el consumo de sustancias. La detección temprana del deterioro cognitivo en los dispositivos de tratamiento de adicciones es fundamental ya que el grado de disfunción cognitiva se ha considerado como un predictor fiable de una menor adherencia al tratamiento y un mayor riesgo de recaída.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The presence of a social stimulus reduces cocaine seeking in a place preference conditioning paradigm.

BACKGROUND: One challenge in the treatment of substance use disorders is to re-engage the interest toward non-drug-related activities. Among these activities, social interaction has had a prominent role due to its positive influence on treatment outcome. AIMS AND METHODS: Our aim was to study whether the presence of a social stimulus during the cocaine-induced conditioned place preference test was able to reduce the time spent in the drug-paired compartment. For that purpose, mice were trained for four days on a conditioned place preference task with one compartment paired with cocaine and the opposite with saline. On the test day, we introduced an unfamiliar juvenile male mouse into the saline-conditioned compartment (inside a pencil cup) to analyse the animal preference towards the two rewarding stimuli (cocaine vs mouse). Additionally, to discard the possible effect of novelty, as well as the housing condition (social isolation) on social preference, we decided to include a novel object during the test session, as well as perform the same conditioned place preference protocol with a group of animals in social housing conditions. RESULTS: The social stimulus was able to reduce the preference for cocaine and enhance the active interaction with the juvenile mouse (sniffing) compared to the empty pencil cup paired with the drug. The introduction of a novel object during the test session did not reduce the preference for the cocaine-paired compartment, and interestingly, the preference for the social stimulus was independent of the housing condition. c-Fos immunohistochemistry revealed a different pattern of activation based on cocaine-paired conditioning or the presence of social stimulus. CONCLUSIONS: These results suggest that social interaction could constitute a valuable component in the treatment of substance use disorders by reducing the salience of the drug.Plan Propio 2017 – ‘Ayudas para proyectos dirigidos por jóvenes investigadores’, PPIT.UMA.B1.2017/38. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Effects of palmitoylethanolamide in cocaine-induced behaviours

Aims. Cocaine addiction is a chronically relapsing disorder characterized by the compulsion to seek and take the drug. Previous investigations have demonstrated that several drugs of abuse, as cocaine, can alter the levels of lipid-based signalling molecules such as the N-acylethanolamines (NAEs). In addition, NAEs levels in the brain are sensitive to cocaine self-administration and extinction training. In this context, this study aimed to investigate the effect of repeated and acute palmitoylethanolamide (PEA), an endogenous NAE, on the behavioural effects of cocaine using mouse models of conditioned reward and psychomotor activation. Methods. Using male C57BL/6J mice, the ability of repeated PEA injections (1 or 10 mg/kg i.p) to modulate the development of a conditioned place preference (CPP) and behavioural sensitization (BS) induced by cocaine (20 mg/kg i.p.) was evaluated. In addition, the expression of cocaine-induced CPP and BS after acute PEA administration was also studied. Results. PEA (1 and 10 mg/kg i.p) significantly reduced the development of cocaine-induced BS, but did not modify the acquisition of cocaine-induced CPP. Furthermore, both doses of PEA were able to reduce the expression of BS and CPP. Conclusions. Altogether, these findings show that exogenous administration of PEA attenuated psychomotor activation and impaired the expression of CPP induced by cocaine. Our results may be relevant in order to understand the role of NAEs in the development and treatment of cocaine addiction.Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tech. PSI2013-44901-P, AP2010-2044, FPU13/04819, CD12/0045

Reduction of adult hippocampal neurogenesis modifies brain functional connectivity and enhances cocaine-seeking in mice

Recently, adult hippocampal neurogenesis has been proposed as a putative neuroplastic mechanism involved in those behavioural processes. In this work, we studied the effect of the inhibition of adult hippocampal neurogenesis using the DNA alkylating agent temozolomide (TMZ), in cocaine-induced conditioned place preference (CPP) behaviour. In a first experiment, we investigated both CPP acquisition/expression and the functional brain circuits underlying CPP expression in control and neurogenesis-reduced conditions by analysing c-Fos immunoreactivity (c-Fos IR) in hippocampal and extrahippocampal addiction-related areas. A second experiment was designed to study the involvement of adult-born neurons in the extinction and cocaine-induced reinstatement of drug-seeking in the CPP model. We performed two independent studies where adult hippocampal neurogenesis was inhibited either before or after the CPP was acquired. Our results showed that TMZ treatment had no effect on the acquisition of the cocaine-induced CPP, but c-Fos IR associated to the test trial (CPP expression) revealed an increased activity in some of the analysed brain areas in the CPP-TMZ mice. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain network associated with CPP expression. However, mice with reduced neurogenesis showed an alternative brain circuit. The results of the second experiment revealed that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug seeking behaviour. However, when neurogenesis was inhibited after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that the role of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition.Universidad de Málaga. Andalucía Tech, Campus de Excelencia Internacional. Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to L.J.S.; Subprograma RETICS Red de Trastornos Adictivos RD12/0028/0001, to F.R.F.). Author E.C-O. holds a ‘Sara Borrell’ research contract from the Spanish Carlos III Health Institute, Spanish Ministry of Economy and Competitiviness (grant number CD12/00455). Author D.L.G-M. holds a ‘FPU’ grant from the Spanish Ministry of Education, Culture and Sports (grant number FPU13/04819)

Behavioral traits predicting cocaine-conditioned place reference in mice: role of anxiety adn the basolateral amygdala

Aims. The individual susceptibility to cocaine addiction, a factor of interest in the understanding and prevention of this disorder, may be predicted by certain behavioral traits. However, these are not usually taken into account in research, making it difficult to identify whether they are a cause or a consequence of drug use. Methods. Male C57BL/6J mice underwent a battery of behavioral tests (elevated plus maze, hole-board, novelty preference in the Y maze, episodic-like object recognition memory and forced swimming test), followed by a cocaine-conditioned place preference (CPP) training to assess the reinforcing effect of the drug. In a second study, we aimed to determine the existence of neurobiological differences between the mice expressing high or low CPP by studying the number of neurons in certain addiction-related structures: the medial prefrontal cortex, the basolateral amygdala and the ventral tegmental area. Results. Anxiety-like behaviors in the elevated plus maze successfully predicted the cocaine-CPP behavior, so that the most anxious mice were also more likely to search for cocaine in a CPP paradigm. In addition, these mice exhibited an increased number of neurons in the basolateral amygdala, a key structure in emotional response including anxiety expression, without differences in the others regions analyzed. Conclusions. Our results suggest a relevant role of anxiety as a psychological risk factor for cocaine vulnerability, with the basolateral amygdala as potential common neural center for both anxiety and addiction.Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tech. PSI2013-44901-P, FPU13/04819, CD12/00455, Red de Trastornos Adictivo

Educación superior y emociones, bases epistemológicas de Maturana

I Plan Propio de Investigación, Transferencia y Divulgación Científica; Plan Propio Integral de Docencia de la Universidad de Málaga.Introducción. Las emociones serán entendidas como las disposiciones corporales que especifican el dominio de acción en que ese mueve el organismo. Son el fundamento de muchos aspectos de la vida y la educación es parte de esta influencia. La educación es un proceso para toda la vida y con cambios graduales de transformación. Es progresiva, pues la educación primaria y secundaria incidirá en la educación superior del sujeto. Es en la educación superior donde se da valor a lo que el estudiante pudo aprender a aceptar y respetar al otro en esos espacios de convivencia primarios. Objetivos. El objetivo de este trabajo es reflexionar sobre la obra de Humberto Maturana y relacionar sus postulados a la educación superior. Método La metodología utilizada ha sido de carácter cualitativa derivada de dos obras sobre educación y emociones. Resultados. Los resultados de este estudio nos dicen que es en la educación superior donde damos valor o no al aprendizaje de valores, al respeto por el otro, a la legitimación del otro, a la reflexión metódica, a desincentivar la competitividad y a colaborar en procesos de aprendizajes sin subordinación. Conclusión. Hay mucho por hacer. La competitividad se mantiene en muchos entornos, los espacios reflexivos aún son insuficientes, también el aprender a escuchar al otro y enseñar a escuchar, las relaciones de poder se mantienen rígidas durante años, y esto nos lleva a fomentar relaciones de subordinación. Lo importante es la confianza en los estudiantes y el profesorado. Lo emocional es la clave, y con qué emoción vivo la relación dentro del aula, ¿de poder o de mutuo respeto? Promover a los estudiantes al cambio o crear contextos de cambios y mirar la diferencia como un valor y no como un problema.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Role of the LPA1 receptor in mood and emotional regulation

Depression is a debilitating psychiatric condition characterized by anhedonia and behavioural despair among others symptoms. Despite the high prevalence and devastating impact of depression, underlying neurobiological mechanisms of mood disorders are still not well known. Regardless its complexity, central features of this disease can be modelled in rodents in order to better understand the potential mechanisms underlying. On the other hand, the lack of LPA1 receptor compromises the morphological and functional integrity of the limbic circuit and the neurogenesis in hippocampus, induces cognitive alterations on hippocampal-dependent tasks and dysfunctional coping of chronic stress, provokes exaggerated endocrine responses to emotional stimuli and impairs adaptation of the hypothalamic-pituitary-adrenal axis after chronic stress. Factors, which all have been related with depression. Here, we sought to establish the involvement of the LPA1 receptor in regulation of mood and emotion. To this end, in wild-type and maLPA1-null mice active coping responses to stress were examined using the forced swimming test (FST). To assess hedonic behaviour saccharine preference test and female urine sniffing test were used. Our data indicated that the absence of the LPA1 receptor significantly affected to coping strategies. Thus, while null mice displayed less immobility than wt in FST, exhibited more climbing and less swimming behaviour, responses that could be interpreted as an emotional over-reaction (i.e., a panic-like response) to stress situations. Concerning hedonic behaviour, the lack of the LPA1 receptor diminished saccharin preference and female urine sniffing time. Overall, these data supports the role of LPA1 receptor in mood and emotional regulation. Specially, the lack of this receptor induced emotional dysregulation and anhedonic behaviour, a core symptom of depression.Universidad de Málaga, Campus de Excelencia Andalucía Tech. Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ-1863; CTS643) and of Health (PI-0234-2013; Nicolas Monardes Programme), MINECO (PSI2013-44901-P) and National Institute of Health Carlos III (Sara Borrel)