BACK TO FRONT: PARTICIPATION OF THE CEREBELO-CORTEZA INFRALIMBICA IN THE FORMATION OF INCENTIVE HABITS INDUCED BY ADDICTIVE DRUGS (Q3144763)
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Project Q3144763 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | BACK TO FRONT: PARTICIPATION OF THE CEREBELO-CORTEZA INFRALIMBICA IN THE FORMATION OF INCENTIVE HABITS INDUCED BY ADDICTIVE DRUGS |
Project Q3144763 in Spain |
Statements
42,350.0 Euro
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84,700.0 Euro
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50.0 percent
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1 January 2019
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31 December 2021
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UNIVERSIDAD JAUME I
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39°59'9.71"N, 0°2'15.86"W
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12040
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ADDICTION IS A CHRONIC BRAIN DISORDER CHARACTERISED BY COMPULSIVE DRUG CONSUMPTION AND HIGH RISK OF RELAPSE. IT HAS BEEN HYPOTHESISED THAT COMPULSIVE BEHAVIOUR MAY RESULT FROM AN ABERRANT HABIT FORMATION. IN FACT, PATIENTS SUFFERING FROM COMPULSIVE DISORDERS INCLUDING OCD, DRUG ADDICTION, AND TOURETTE SYNDROME HAVE DEMONSTRATED TO DEVELOP HABITS MORE EASILY THAN NORMAL CONTROLS, AFTER REDUCED BEHAVIOURAL TRAINING. INTERESTINGLY, THE MAJORITY OF THE STUDIES ABOUT COMPULSIVE DISORDERS HAVE SHOWN SMALLER CEREBELLAR SIZE AND REDUCED ACTIVITY IN RESTING STATE. HABITS CONSIST IN OVERLEARNED, REPETITIVE, SEQUENTIAL BEHAVIOURS THAT ARE PERFORMED AUTOMATICALLY AND TRIGGERED BY ASSOCIATED ENVIRONMENTAL SIGNALS. DURING ACQUISITION OF HABITS, THERE IS A SHIFT FROM GOAL-DIRECTED BEHAVIOUR REGULATED BY AN ACTION-OUTCOME PROCESS (RESPONSE-OUTCOME; R-O) TO AUTOMATIZED BEHAVIOUR TRIGGERED BY THE ASSOCIATED STIMULUS (STIMULUS-RESPONSE; S-R). REMARKABLY, BOTH REPRESENTATIONS (R-O AND S-R) SURVIVE IN PARALLEL AND PREDOMINATE OVER EACH OTHER DEPENDING ON INTERNAL AND EXTERNAL CONDITIONS. WITH EXTENDED DRUG EXPERIENCE, THE BALANCE BETWEEN FLEXIBLE (R-O) AND AUTOMATIC (S-R) BEHAVIOURAL PATTERNS CAN BE BIASED TOWARDS HABITS. _x000D_ THE INFRALIMBIC CORTEX (IL) HAS DEMONSTRATED TO BE A KEY REGION IN THE FORMATION OF HABITS. REPEATED OPTOGENETIC INHIBITION OF THE IL DURING OVERTRAINING DISRUPTS HABIT FORMATION. THE CEREBELLUM ALSO PARTICIPATES IN THE ESTABLISHMENT OF HABITS. IT HAS BEEN DESCRIBED THAT REGIONALISED CEREBELLAR LESIONS PREVENT THE DEVELOPMENT OF HABITS. VERY RECENT FINDINGS FORM OUR LABORATORY INDICATE THAT THE CEREBELLUM CAN CONTROL COCAINE-DEPENDENT ACTIVITY AND PLASTICITY IN THE IL. A LESION OF THE CEREBELLUM INCREASED ACTIVITY AND PERINEURONAL EXPRESSION IN THE IL. IN SEARCHING FOR A NEUROANATOMICAL MODEL TO EXPLAIN THESE RESULTS, A TRACING STUDY USING ANTEROGRADE AND RETROGRADE TRACERS REVEALED A DIRECT PATHWAY FROM THE LATERAL CEREBELLAR NUCLEUS TO THE CONTRALATERAL VTA. _x000D_ THEREFORE, THE MAIN GOAL OF THE PRESENT PROPOSAL IS TO INVESTIGATE THE CONTRIBUTION OF THE CEREBELLUM-INFRALIMBIC PATHWAY TO THE DEVELOPMENT OF DRUG-INDUCED HABITS USING INNOVATIVE METHODOLOGIES SUCH AS DREADDS (DESIGNER RECEPTOR EXCLUSIVELY ACTIVATED BY DESIGNER DRUG), ELECTROPHYSIOLOGY AND OPTOGENETICS. THIS PROJECT WILL HAVE 3 INTERCONNECTED AND COMPLEMENTARY AIMS THAT WILL ANSWER THE FOLLOWING 3 MAIN QUESTIONS: 1) AIM 1. DOES THE STIMULATION OF THE CEREBELLAR CORTEX REDUCE THE HABIT BIAS THAT DRUGS INDUCE IN NATURAL-REWARDED BEHAVIOUR? 2) AIM 2. DOES THE CEREBELLUM MODULATE THE FUNCTION OF IL IN DRUG-INDUCED HABIT FORMATION? 3) AIM 3. IS THE CEREBELLAR CONTRIBUTION TO HABIT FORMATION MEDIATED THROUGH THE VTA AND DOPAMINERGIC ACTIVITY? TAKEN TOGETHER, THE OBJECTIVES OF THE PRESENT PROPOSAL AIM TO TEST THE HYPOTHESIS THAT BY MODULATING ACTIVITY IN THE CEREBELLUM IS POSSIBLE TO CHANGE THE BALANCE BETWEEN FLEXIBLE GOAL-DIRECTED AND HABITUAL BEHAVIOURAL PATTERNS. IN ADDITION, WE HYPOTHESISE THAT RESTORING NORMAL ACTIVITY IN THE CEREBELLUM-IL PATHWAY WOULD RESULT IN THE REDUCED PROPENSITY TO EXHIBIT DRUG-RELATED BEHAVIOUR INSENSITIVE TO DEVALUATION. THIS PROPOSAL HAS BEEN DESIGNED IN COLLABORATION WITH ONE OF THE MOST IMPORTANT INSTITUTIONS IN NEUROSCIENCE IN THE WORLD, THE ALBERT EINSTEIN COLLEGE OF MEDICINE. (Spanish)
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LA ADICCION ES UN TRASTORNO CEREBRAL CRONICO CARACTERIZADO POR EL CONSUMO COMPULSIVO DE DROGAS Y UN ALTO RIESGO DE RECAIDA. EL COMPORTAMIENTO COMPULSIVO PUEDE SER EL RESULTADO DE UNA PROPENSION ANORMAL A LA FORMACION DE HABITOS. DE HECHO, LOS PACIENTES QUE SUFREN DE TRASTORNOS COMPULSIVOS COMO EL TOC, LA DROGADICCION Y EL SINDROME DE TOURETTE DESARROLLAN HABITOS MAS FACILMENTE QUE LOS CONTROLES NORMALES CON POCO ENTRENAMIENTO. CABE RESALTAR QUE LA MAYORIA DE LOS ESTUDIOS SOBRE TRASTORNOS COMPULSIVOS HAN MOSTRADO UN TAMAÑO MENOR DEL CEREBELO Y UNA ACTIVIDAD CEREBELAR REDUCIDA EN ESTADO DE REPOSO. LOS HABITOS CONSISTEN EN COMPORTAMIENTOS SOBRE-APRENDIDOS, REPETITIVOS Y SECUENCIALES. DURANTE LA ADQUISICION DE HABITOS, SE PASA DE UN COMPORTAMIENTO REGULADO POR EL VALOR DE LA META (RESPUESTA-CONSECUENCIA; R-C) A UN PATRON DESENCADENADO DIRECTAMENTE POR EL ESTIMULO (ESTIMULO-RESPUESTA; E-S). NO OBSTANTE, AMBAS REPRESENTACIONES SOBREVIVEN EN PARALELO Y PREDOMINAN UNA SOBRE LA OTRA DEPENDIENDO DE LAS CONDICIONES INTERNAS Y EXTERNAS. ES SABIDO QUE EL CONSUMO CRONICO DE DROGAS SESGA EL EQUILIBRIO EXISTENTE ENTRE LOS PATRONES CONDUCTUALES FLEXIBLES (R-C) Y AUTOMATICOS (E-R), HACIA EL HABITO. LA CORTEZA INFRALIMBICA (IL) ES UNA REGION CLAVE EN LA FORMACION DE HABITOS TANTO EN CONDUCTAS REFORZADAS NATURALMENTE COMO CON DROGAS ADICTIVAS. LA FORMACION DEL HABITO SE BLOQUEA SI SE INHIBE MEDIANTE OPTOGENETICA LA CORTEZA IL. SE SABE QUE EL CEREBELO TAMBIEN PARTICIPA EN EL ESTABLECIMIENTO DE HABITOS. DE HECHO, LESIONES REGIONALIZADAS EN EL CEREBELO INTERRUMPEN LA FORMACION DEL HABITO. NUESTROS RESULTADOS INDICAN QUE EL CEREBELO PUEDE CONTROLAR LA ACTIVIDAD NEURONAL Y LA PLASTICIDAD INDUCIDAS POR UNA EXPERIENCIA REPETIDA CON COCAINA EN LA CORTEZA IL. UNA LESION DEL CEREBELO AUMENTA LA ACTIVIDAD Y LA EXPRESION DE LAS REDES PERINEURONALES EN ESTA REGION DE LA CORTEZA MEDIAL PREFRONTAL. BUSCANDO UN MODELO NEUROANATOMICO PARA EXPLICAR ESTOS RESULTADOS, NUESTROS ESTUDIOS HAN REVELADO UNA VIA DIRECTA DESDE EL NUCLEO CEREBELOSO LATERAL HASTA EL VTA CONTRALATERAL. ASI PUES, EL OBJETIVO PRINCIPAL DE LA PRESENTE PROPUESTA ES INVESTIGAR LA CONTRIBUCION DE LA VIA CEREBELO-CORTEZA IL AL DESARROLLO DE HABITOS INDUCIDOS POR DROGAS, UTILIZANDO METODOLOGIAS INNOVADORAS COMO DREADDS (RECEPTOR DE DISEÑO ACTIVADO EXCLUSIVAMENTE POR LA DROGA DE DISEÑO), ELECTROFISIOLOGIA Y OPTOGENETICA. ESTE PROYECTO TENDRA 3 OBJETIVOS INTERCONECTADOS Y COMPLEMENTARIOS QUE RESPONDERAN A LAS SIGUIENTES 3 PREGUNTAS: OBJETIVO 1: ¿LA ESTIMULACION DE LA CORTEZA CEREBELOSA REDUCE LA FORMACION DE HABITOS INDUCIDOS POR DROGAS DE ABUSO? OBJETIVO 2: ¿EL CEREBELO MODULA LA FUNCION DE LA CORTEZA IL EN LA FORMACION DE HABITOS INDUCIDOS POR DROGAS DE ABUSO? OBJETIVO 3: ¿LA CONTRIBUCION CEREBELOSA A LA FORMACION DE HABITOS ESTA MEDIADA POR EL AREA TEGMENTO VENTRAL Y LA ACTIVIDAD DOPAMINERGICA? ESTOS OBJETIVOS PRETENDEN PONER A PRUEBA LA HIPOTESIS GENERALSEGUN LA CUAL SE PUEDE CAMBIAR EL EQUILIBRIO ENTRE LOS PATRONES DE COMPORTAMIENTO FLEXIBLES Y LOS HABITUALES MEDIANTE LA MODULACION DE LA ACTIVIDAD DEL CEREBELO. ADEMAS, SE PLANTEA LA HIPOTESIS DE QUE EL RESTABLECIMIENTO DE LA ACTIVIDAD NORMAL EN LA VIA CEREBELO-IL DARA LUGAR A UNA MENOR PROPENSION A EXHIBIR CONDUCTAS INSENSIBLES A LA DEVALUACION RELACIONADAS CON LAS DROGAS. ESTA PROPUESTA HA SIDO DISEÑADA EN COLABORACION CON UNA DE LAS INSTITUCIONES EN NEUROCIENCIA MAS IMPORTANTES DEL MUNDO, EL DEPARTAMENTO DE NEUROCIENCIA-ALBERT EINSTEIN COLLEGE OF MEDICINE (English)
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Castellón de la Plana/Castelló de la Plana
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Identifiers
PGC2018-095980-B-I00
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