PREFRONTAL BARK AND STRESS: IDENTIFICATION OF SPECIFIC NEURONAL POPULATIONS AND THEIR IMPLICATION IN STRESS-INDUCED VULNERABILITY-RESILIENCE IN ADOLESCENCE (Q3135831)
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Project Q3135831 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | PREFRONTAL BARK AND STRESS: IDENTIFICATION OF SPECIFIC NEURONAL POPULATIONS AND THEIR IMPLICATION IN STRESS-INDUCED VULNERABILITY-RESILIENCE IN ADOLESCENCE |
Project Q3135831 in Spain |
Statements
121,000.0 Euro
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242,000.0 Euro
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50.0 percent
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1 January 2018
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31 December 2020
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UNIVERSIDAD AUTONOMA DE BARCELONA
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08266
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LA EXPOSICION AGUDA A SITUACIONES DE ESTRES DE GRAN INTENSIDAD (TRAUMATICAS) Y LA EXPOSICION CRONICA A SITUACIONES DE MENOR INTENSIDAD SE CONSIDERAN EN LA BASE DE MUCHAS PATOLOGIAS, ESPECIALMENTE LAS PSIQUIATRICAS. LOS ESTUDIOS EPIDEMIOLOGICOS Y CLINICOS INDICAN QUE ESTE IMPACTO ES MUCHO MAS NOTABLE SI EL ESTRES OCURRE EN ETAPAS TEMPRANAS, INCLUYENDO LA ADOLESCENCIA, Y NO HAY POSIBILIDAD DE CONTROL SOBRE EL MISMO. NO OBSTANTE, MUCHOS INDIVIDUOS SON MUY RESISTENTES AL ESTRES, EN TANTO OTROS SON MUY VULNERABLES, HABIENDOSE DESCRITO DIFERENCIAS IMPORTANTES ENTRE SEXOS. LA CORTEZA PREFRONTAL (PFC) JUEGA UN PAPEL ESENCIAL EN LA REGULACION DE LA RESPUESTA A ESTIMULOS ESTRESANTES, PERO LA DIRECCION DE LOS RESULTADOS OBTENIDOS MANIPULANDO EXPERIMENTALMENTE ESTA AREA ES CONTROVERTIDA Y NO CONOCEMOS PRACTICAMENTE NADA RESPECTO A LAS POBLACIONES NEURONALES QUE SE ACTIVAN ESPECIFICAMENTE EN RESPUESTA A ESTIMULOS EMOCIONALES DE DISTINTA NATURALEZA E INTENSIDAD. SUGERIMOS QUE LOS RESULTADOS CONTROVERTIDOS PUEDEN EXPLICARSE POR LA EXISTENCIA EN PFC DE POBLACIONES NEURONALES NO SEGREGADAS ESPACIALMENTE QUE POTENCIAN O AMORTIGUAN (EN ESTE ULTIMO CASO BAJO CIRCUSTANCIAS APROPIADAS COMO LA DISPONIBILIDAD DE CONTROL) LA RESPUESTA A LOS ESTIMULOS ESTRESANTES, SIENDO EL EQUILIBRIO ENTRE ESTAS POBLACIONES DETERMINANTE DE LA SUSCEPTILIDAD VERSUS RESILIENCIA A LOS EFECTOS DEL ESTRES. LOS OBJETIVOS DEL PRESENTE PROYECTO SON: (I) IDENTIFICAR EN RATA POBLACIONES NEURONALES DE LA PARTE MEDIAL DE PFC (MPFC) QUE SON ESPECIFICAMENTE SENSIBLES A LA NATURALEZA PARTICULAR DE LOS ESTIMULOS ESTRESANTES (TODOS ELLOS DE ELEVADA INTENSIDAD), Y A LA DISPONIBILIDAD DE CONTROL SOBRE ESTAS SITUACIONES; (II) DEMOSTRAR QUE LA ACTIVACION POSTERIOR DE DICHAS POBLACIONES NEURONALES CON TECNICAS QUIMIOGENETICAS (DESIGNED RECEPTORS SPECIFICALLY ACTIVATED BY DESIGNED DRUGS, DREADD) MIMETIZARA PARCIALMENTE LA RESPUESTA FISIOLOGICA Y CONDUCTUAL AL ESTRES Y QUE LA ACTIVACION DE LA POBLACION ESPECIFICA SENSIBLE AL CONTROL SOBRE EL ESTRES REDUCIRA LA RESPUESTA A NUEVAS SITUACIONES DE ESTRES (V.G. NADO FORZADO); (III) DEMOSTRAR QUE UNA HISTORIA PREVIA DE EXPOSICION A SITUACIONES DE ESTRES CONTROLABLES O INCONTROLABLES DURANTE LA ADOLESCENCIA PUEDE ALTERAR LA POBLACION DE NEURONAS DE MEDIAL PFC SENSIBLES AL CONTROL, PUEDIENDO ESTAS ALTERACIONES ESTAR ASOCIADAS A LAS DIFERENCIAS INDIVIDUALES O DE SEXO EN LA SUSCEPTIBILIDAD AL IMPACTO DEL ESTRES. PARA ELLO UTILIZAREMOS DOS APROXIMACIONES EXPERIMENTALES INDIVIDUALES O COMBINADAS: (A) RATAS TRANSGENICAS EN LAS QUE LA EXPRESION DE C-FOS ESTA ASOCIADA AL ENZIMA BACTERIANO B-GALACTOSIDASA, QUE CONVIERTE EL COMPUESTO DAUN02 (ADMINISTRADO LOCALMENTE) EN DAUNORUBICINA, TOXINA QUE INACTIVA DURANTE DIAS LAS NEURONAS QUE EXPRESARON C-FOS EN RESPUESTA A UN ESTIMULO PARTICULAR; (B) LA ADMINISTRACION DE VECTORES VIRALES QUE EXPRESEN LOS RECEPTORES MUSCARINICOS MODIFICADOS HM4DI O HM3DQ ASOCIADOS AL PROMOTOR DE C-FOS, RECEPTORES QUE TRAS SER ACTIVADOS POR NO-CLOZAPINA (CNO) INHIBIRAN O ESTIMULARAN, RESPECTIVAMENTE, LAS NEURONAS PREVIAMENTE ACTIVADAS. COMO VARIABLES DEPENDIENTES SE ESTUDIARA LA EXPRESION DE C-FOS COMO MARCADOR DE ACTIVACION NEURONAL, LA ACTIVIDAD DEL EJE HIPOTALAMICO-HIPOFISARIO-ADRENAL COMO MARCADOR DE ESTRES Y ASPECTOS COGNITIVOS Y EMOCIONALES QUE SON SENSIBLES A LA EXPOSICION AL ESTRES, INCLUYENDO TAREAS DEPENDIENTES DE MPFC. (Spanish)
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ACUTE EXPOSURE TO STRESSFUL SITUATIONS OF HIGH INTENSITY (TRAUMATIC) OR CHRONIC EXPOSURE TO STRESSORS OF LOWER INTENSITY IS CONSIDERED TO BE ON THE ROOT OF A HIGH NUMBER OF PATHOLOGIES, MORE PARTICULARLY PSYCHIATRIC DISEASES. EPIDEMIOLOGICAL AND CLINICAL STUDIES INDICATE THAT THIS IMPACT IS MUCH STRONGER IF STRESS OCCURS IN EARLY LIFE, INCLUDING ADOLESCENCE, AND THERE IS NO POSSIBILITY OF CONTROL OVER IT. NEVERTHELESS, SOME INDIVIDUALS ARE HIGHLY RESISTANT TO STRESS, WHEREAS OTHERS ARE HIGHLY SUSCEPTIBLE, AND IMPORTANT SEX DIFFERENCES HAVE ALSO BEEN DESCRIBED. THE PREFRONTAL CORTEX (PFC) PLAYS A CRUCIAL ROLE IN THE REGULATION OF THE RESPONSE TO EMOTIONAL STRESSORS, BUT THE DIRECTION OF THE CHANGES CAUSED BY EXPERIMENTAL MANIPULATIONS OF THIS AREA IS CONTROVERSIAL AND WE KNOW ALMOST NOTHING REGARDING THE SPECIFICITY OF NEURONAL POPULATION ACTIVATED IN RESPONSE TO EMOTIONAL STRESSORS OF DIFFERENT NATURE AND INTENSITY. WE SUGGEST THAT CONTROVERSIAL RESULTS CAN BE EXPLAINED BECAUSE THERE ARE DISTINCT NEURONAL POPULATIONS IN THE PFC NOT SEGREGATED SPACIALLY THAT CAN POTENTIATE OR BUFFER (UNDER APPROPRIATE CIRCUNSTANCES AS FOR INSTANCE WHEN THE POSSIBILITY OF CONTROL OVER THE STRESSOR IS AVAILABLE) THE RESPONSE TO STRESSORS, THE BALANCE BETWEEN THE TWO POPULATIONS DETERMINING VULNERABILITY VERSUS RESILIENCE TO THE CONSEQUENCES OF STRESS. THE PURPOSES OF THE PRESENT PROJECT ARE: (I) TO IDENTIFY IN RATS NEURONAL POPULATIONS IN THE MEDIAL PFC (MPFC) WHICH ARE SPECIFICALLY SENSITIVE TO THE PARTICULAR NATURE OF EMOTIONAL STRESSORS (ALL OF THEM OF HIGH INTENSITY), AND TO THE AVAILABILITY OF CONTROL OVER THE SITUATION; (II) TO DEMONSTRATE THAT FURTHER ACTIVATION OF THOSE NEURONAL POPULATIONS WITH CHEMIOGENETIC TECHNIQUES (DESIGNED RECEPTORS SPECIFICALLY ACTIVATED BY DESIGNED DRUGS, DREADD) WOULD PARTIALLY MIMICK THE PHYSIOLOGICAL AND BEHAVIORAL CONSEQUENCES TO THE STRESSORS, AND THAT ACTIVATION OF THOSE NEURONS SPECIFICALLY SENSITIVE TO THE CONTROL OVER THE STRESSOR WOULD REDUCE THE RESPONSE TO NOVEL STRESSORS (E.G FORCED SWIM); (III) TO DEMONSTRATE THAT A HISTORY OF PRIOR EXPOSURE TO CONTROLLABLE OR INCONTROLLABLE STRESS DURING ADOLESCENCE CAN ALTER THE NEURONAL POPULATION OF THE PFC SENSITIVE TO THE CONTROL OVER THE STRESSOR AT ADULTHOOD, THIS ALTERATION BEING ASSOCIATED WITH INDIVIDUAL OR SEX DIFFERENCES IN VULNERABILITY TO STRESS.TO THIS END, WE WILL USE, SEPARATELY OR IN COMBINATION, TWO DIFFERENT EXPERIMENTAL APPROACHES: (A) TRANSGENIC RATS IN WHICH THE EXPRESSION OF THE BACTERIAL ENZYME B-GALACTOSIDASE HAS BEEN ASSOCIATED TO THE C-FOS PROMOTER; IN ACTIVATED CELLS, THE ENZYME TRANSFORMS THE COMPOUND DAUN02 (GIVEN LOCALLY) IN DAUNORUBICIN, A TOXIN THAT INACTIVATES FOR SOME DAYS THE NEURONS PREVIOUSLY ACTIVATED BY A STIMULUS; (B) THE ADMINISTRATION OF VIRAL VECTORS IN WHICH THE EXPRESSION OF MODIFIED MUSCARINIC RECEPTORS HM4DI OR HM3DQ HAS BEEN ASSOCIATED TO THE C-FOS PROMOTOR; ACTIVATION OF THESE RECEPTORS WITH CLOZAPINE-N-OXIDE (CNO) WILL INHIBIT OR ACTIVATE, RESPECTIVELY, THOSE NEURONS PREVIOUSLY ACTIVATED BY A STIMULUS. AS DEPENDENT VARIABLES WE WILL STUDY THE EXPRESSION OF C-FOS, A MARKER OF NEURONAL ACTIVATION, THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AS A BIOLOGICAL MARKER OF STRESS, AND EMOTIONAL AND COGNITIVE TASKS THAT ARE SENSITIVE TO STRESS, INCLUDING SOME WHICH ARE MPFC-DEPENDENT. (English)
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Cerdanyola del Vallès
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Identifiers
SAF2017-83430-R
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