DEVELOPMENT OF PEPTIDERGIC SYSTEMS RELATED TO SOCIAL BEHAVIOR. INTERACTION RELAXIN3-OXITOCIN (Q3145267)
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Project Q3145267 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | DEVELOPMENT OF PEPTIDERGIC SYSTEMS RELATED TO SOCIAL BEHAVIOR. INTERACTION RELAXIN3-OXITOCIN |
Project Q3145267 in Spain |
Statements
72,600.0 Euro
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145,200.0 Euro
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50.0 percent
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1 January 2019
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31 December 2022
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UNIVERSIDAD JAUME I
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12040
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EN LAS PRIMERAS ETAPAS DE VIDA POSTNATAL SE CONFIGURAN LAS REDES NEURONALES QUE SOPORTAN LAS FUNCIONES NEUROLOGICAS Y EL COMPORTAMIENTO ADULTO. ALTERACIONES EN DICHA CONFIGURACION PRODUCEN DISFUNCIONES QUE SE TRADUCEN EN SINDROMES DE ENFERMEDADES MENTALES COMO EL AUTISMO Y LA ESQUIZOFRENIA. LOS COMPORTAMIENTOS EMOCIONALES Y SOCIALES DEPENDEN FUNDAMENTALMENTE DE TRES ESTRUCTURAS CEREBRALES: LA CORTEZA PREFRONTAL, EL HIPOCAMPO Y LA AMIGDALA. LAS TRES EN EL ADULTO ESTAN INERVADAS POR SISTEMAS PEPTIDERGICOS QUE MODULAN SU ACTIVIDAD. EXISTE UNA ABUNDANTE LITERATURA SOBRE EL PAPEL DE LA OXITOCINA EN ESTOS CIRCUITOS Y SU POSIBLE IMPLICACION EN EL TRATAMIENTO DEL AUTISMO, SIN EMBARGO, ES POCO LO QUE SE HA ESTUDIADO SOBRE OTRO PEPTIDO, RLN3, QUE INERVA LAS MISMAS DIANAS QUE OXITOCINA Y CUYO RECEPTOR, RXFP3 SE EXPRESA EN LAS MISMAS NEURONAS QUE EL RECEPTOR DE OXITOCINA. NUESTROS DATOS PREVIOS TAMBIEN INDICAN QUE EL SISTEMA RLN3-RXFP3 INTERVIENE EN EL RECONOCIMIENTO SOCIAL. LA HIPOTESIS GENERAL ES QUE EL DESARROLLO DEL SISTEMA NI/RLN3/RXFP3 SUBYACE A LA EVOLUCION POSTNATAL DE LOS COMPORTAMIENTOS EMOCIONAL Y SOCIAL Y LA ACCION DE ESTOS SISTEMAS EN EL ADULTO INTERFIERE EN LOS MECANISMOS MOLECULARES QUE ACTIVAN LOS MECANISMOS DE MEMORIA EMOCIONAL Y SOCIAL EN HIPOCAMPO AMIGDALA Y CORTEZA PREFRONTAL. ESTA HIPOTESIS SERA TESTADA EN RATA Y RATON MEDIANTE EL DESARROLLO DE 4 OBJETIVOS. 1) DETERMINAR EL PATRON DE EXPRESION DE RLN3 Y RXFP3 DURANTE EL DESARROLLO JUNTO A LA EMERGENCIA DE LA CONDUCTA SOCIAL. UN ESTUDIO DESCRIPTIVO DE LA EXPRESION DEL RECEPTOR RXFP3 Y LA APARICION DE FIBRAS RLN3 ENTRE LOS DIAS POSTNATALES P10 Y P20. 2) DETERMINAR SI LA MANIPULACION EXPERIMENTAL DEL ENTORNO (ESTRES TEMPRANO) ES CAPAZ DE ALTERAR EL DESARROLLO NORMAL Y LA PLASTICIDAD DE LA INERVACION DE NI SOBRE EL SEPTUM, HIPOCAMPO Y / O AMIGDALA. 3) DETERMINAR SI LA ACTIVACION/INACTIVACION OPTOGENETICA DE LAS NEURONAS DEL NI MEDIANTE UNA SECUENCIA CON UN PROMOTOR ESPECIFICO DE RLN3 ES CAPAZ DE ALTERAR LA CONDUCTA DE RECONOCIMIENTO SOCIAL EN EL ADULTO. YA SE TIENE LA SECUENCIA ESPECIFICA DEL PROMOTOR Y SE PRETENDE INSERTARLA CON CHR2 PARA ACTIVACION OPTOGENETICA DURANTE LOS PARADIGMAS DEL LABERINTO DE 3 HABITACIONES Y CONDICIONAMIENTO A CONTEXTO. 4) DETERMINAR SI LA VIA DE SEÑALIZACION IN VIVO DEL SISTEMA RLN3/RXFP3 INHIBE LA SINTESIS DE CAMP QUE ES ACTIVADA POR LA SEÑALIZACION A TRAVES DEL RECEPTOR DE OXITOCINA. PARA ELLO, SE IMPLANTARAN CANULAS EN EL VENTRICULO LATERAL PARA LA INFUSION DE OXITOCINA Y EN AMIGDALA PARA LA INFUSION DE AGONISTAS DE RXFP3. A CONTINUACION SE MEDIRA LA SINTESIS DE CAMP. SE PRETENDE CONOCER SI LA ACTIVACION DE RXFP3 ES CAPAZ DE INHIBIR EL INCREMENTO PRODUCIDO POR OXITOCINA EN AMIGDALA. CON ESTOS OBJETIVOS SE DETERMINARA SI EL SISTEMA NI-RLN3-RXFP3 PARTICIPA EN LA GENERACION DE LOS CIRCUITOS QUE MODULAN LA CONDUCTA SOCIAL Y SI INTERFIERE EN EL ADULTO CON LOS MECANISMOS MODULADOS POR OXITOCINA EN LA FORMACION DE MEMORIAS SOCIALES. (Spanish)
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NEURONAL NETWORKS THAT SUPPORT NEUROLOGICAL FUNCTIONS AND BEHAVIOUR IN ADULT ANIMALS AND HUMANS ARE ESTABLISHED IN THE EARLY STAGES OF POSTNATAL LIFE. ALTERATIONS IN THE FINAL MATURE CONFIGURATION OF THESE NETWORKS CAN PRODUCE DYSFUNCTIONS THAT RESULT IN MENTAL ILLNESSES SUCH AS AUTISM AND SCHIZOPHRENIA. EMOTIONAL AND SOCIAL BEHAVIOURS ARE CLOSELY ASSOCIATED WITH THREE BRAIN STRUCTURES, THE PREFRONTAL CORTEX, HIPPOCAMPUS AND AMYGDALA, WHICH ARE INNERVATED BY MULTIPLE PEPTIDE SYSTEMS THAT MODULATE THEIR ACTIVITY. THERE IS SUBSTANTIAL EVIDENCE FOR A ROLE FOR OXYTOCIN IN EMOTIONAL AND SOCIAL CIRCUITS AND THE POSSIBILITY FOR OXYTOCIN-BASED TREATMENT OF AUTISM. IN CONTRAST, THERE IS VERY LITTLE INFORMATION ON A SIMILAR POTENTIAL ROLE OF ANOTHER PEPTIDE, RELAXIN-3 (RLN3), WHICH IS PRESENT IN NEURONS THAT INNERVATE SIMILAR TARGETS TO OXYTOCIN NEURONS AND WHICH ACTS VIA A G-PROTEIN-COUPLED-RECEPTOR, RXFP3, EXPRESSED BY OXYTOCIN RECEPTOR-POSITIVE NEURONS IN THE AMYGDALA, AS WELL AS MULTIPLE OTHER BRAIN AREAS. OUR RECENT STUDIES ALSO INDICATE THAT THE RELAXIN-3-RXFP3 SYSTEM PLAYS A ROLE IN SOCIAL RECOGNITION AND SOCIAL ANXIETY. THEREFORE, WE HYPOTHESIZE THAT THE DEVELOPMENT OF THE RLN3/RXFP3 SYSTEM SUBSERVES THE POSTNATAL EVOLUTION OF EMOTIONAL AND SOCIAL BEHAVIOURS AND THE ACTION OF THIS SYSTEM IN THE ADULT MODULATES SPECIFIC MOLECULAR MECHANISMS THAT ACTIVATE PROCESSES OF EMOTIONAL AND SOCIAL MEMORY IN AMYGDALA, HIPPOCAMPUS AND PREFRONTAL CORTEX. THIS HYPOTHESIS WILL BE TESTED IN RAT AND MOUSE BY PURSUING FOUR GOALS. 1. DETERMINE THE EXPRESSION LEVELS OF RLN3 AND RXFP3 AND THE INNERVATION PATTERNS DURING PRE AND POSTNATAL DEVELOPMENT, IN PARALLEL WITH THE EMERGENCE OF SOCIAL BEHAVIOUR. THIS WILL PRIMARILY BE A DESCRIPTION OF THE EXPRESSION OF RXFP3 MRNA AND THE APPEARANCE OF RELAXIN-3 FIBRES ACROSS POSTNATAL DAYS (P) 10 TO 20; 2. TO DETERMINE IF EXPERIMENTAL MANIPULATION OF THE TARGET ENVIRONMENT (EARLY LIFE STRESS) IS ABLE TO DISRUPT NORMAL DEVELOPMENT AND PLASTICITY OF THE NI INNERVATION OF THE SEPTUM, HIPPOCAMPUS AND/OR AMYGDALA; 3. DETERMINE IF OPTOGENETIC ACTIVATION/INACTIVATION OF RELAXIN-3 NEURONS IN THE NUCLEUS INCERTUS (NI) EXPRESSING CHANNELRHODOPSIN OR HALORHODOPSIN IS CAPABLE OF ALTERING SOCIAL RECOGNITION BEHAVIOUR IN ADULTS. WE WILL USE A SPECIFIC RELAXIN-3 PROMOTER SEQUENCE (FROM PROF ANDREW GUNDLACH, AUSTRALIA) AND WILL USE IT TO INSERT CHR2 OR HALOR INTO NI NEURONS AND ASSESS HOW OPTOGENETIC ACTIVATION OR INHIBITION OF THESE NEURONS ALTERS MOUSE/RAT PERFORMANCE IN THE 3-CHAMBER PARADIGM AND/OR CONTEXTUAL CONDITIONING; 4. DETERMINE WHETHER RXFP3 ACTIVATION IN VIVO COMPETES WITH, OR FACILITATES, CELLULAR RESPONSES AND SIGNALLING PRODUCED VIA THE OXYTOCIN RECEPTOR. CANNULAE WILL BE IMPLANTED IN THE LATERAL VENTRICLE AND THE AMYGDALA FOR THE INFUSION OF OXYTOCIN, RXFP3 AGONISTS AND COMBINATIONS, FOLLOWED BY ANALYSIS OF THE LEVELS OF CAMP WITHIN THE INFUSED AREAS. PRIMARILY WE WILL DETERMINE IF ACTIVATION OF RXFP3 IS ABLE TO MODULATE OXYTOCIN ACTION IN THE DIFFERENT REGIONS OF THE AMYGDALA. OUR EXPERIMENTS SHOULD ESTABLISH WHETHER THE NI-RLN3-RXFP3 SYSTEM PARTICIPATES IN THE DEVELOPMENT OF CIRCUITS THAT CONTROL SOCIAL BEHAVIOUR AND CAN INTERFERE WITH/MODIFY OXYTOCIN SIGNALLING DURING DEVELOPMENT AND IN THE FORMATION OF SOCIAL BEHAVIOUR AND MEMORY IN ADULT RODENTS. (English)
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Castellón de la Plana/Castelló de la Plana
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Identifiers
RTI2018-095698-B-I00
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