Stress-related disorders, pituitary adenylate cyclase-activating peptide (PACAP)ergic system, and sex differences - PubMed (original) (raw)
Stress-related disorders, pituitary adenylate cyclase-activating peptide (PACAP)ergic system, and sex differences
Teniel S Ramikie et al. Dialogues Clin Neurosci. 2016 Dec.
Abstract
Trauma-related disorders, such as posttraumatic stress disorder (PTSD) are remarkably common and debilitating, and are often characterized by dysregulated threat responses. Across numerous epidemiological studies, females have been found to have an approximately twofold increased risk for PTSD and other stress-related disorders. Understanding the biological mechanisms of this differential risk is of critical importance. Recent data suggest that the pituitary adenylate cyclase-activating polypeptide (PACAP) pathway is a critical regulator of the stress response across species. Moreover, increasing evidence suggests that this pathway is regulated by both stress and estrogen modulation and may provide an important window into understanding mechanisms of sex differences in the stress response. We have recently shown that PACAP and its receptor (PAC1R) are critical mediators of abnormal processes after psychological trauma. Notably, in heavily traumatized human subjects, there appears to be a robust sex-specific association of PACAP blood levels and PAC1R gene variants with fear physiology, PTSD diagnosis, and symptoms, specifically in females. The sex-specific association occurs within a single-nucleotide polymorphism (rs2267735) that resides in a putative estrogen response element involved in PAC1R gene regulation. Complementing these human data, the PAC1R messenger RNA is induced with fear conditioning or estrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1R pathway are regulated by estrogen and are involved in abnormal fear responses underlying PTSD.
Los trastornos relacionados con el trauma, como el trastorno por estrés postraumático (TEPT) en humanos, son extraordinariamente comunes y desgastadores, y a menudo están caracterizados por respuestas desreguladas a la amenaza. En numerosos estudios epidemiológicos se ha encontrado que las mujeres tienen un riesgo aumentado al doble para el TEPT y otros trastornos relacionados con el estrés. La comprensión de los mecanismos biológicos de este riesgo diferencial es de gran importancia. Hay datos recientes que sugieren que, a través de las especies, la vía del polipéptido activador de la adenilato ciclasa hipofisiaria (PAACH) tiene una regulación central en la respuesta de estrés. Sin embargo, hay evidencia creciente que sugiere que esta vía está regulada por el estrés y la modulación estrogénica y puede aportar una ventana importante para la comprensión de los mecanismos de las diferencias por sexo en la respuesta de estrés. Nosotros hemos mostrado recientemente que el PAACH y su receptor (R1PAC) son importantes mediadores de los procesos anormales después del trauma psicológico. Es notable que, específicamente en mujeres víctimas de grandes traumas, al parecer hay una potente asociación específica entre los niveles sanguíneos de PAACH y variantes del gen R1PAC con la fisiología del miedo, y síntomas y diagnóstico de TEPT. La asociación específica con el sexo ocurre con el polimorfismo del nucleótido único (rs2267735) que se encuentra en un elemento de la respuesta putativa de estrógeno involucrada en la regulación del gen R1PAC. Como complemento a estos datos humanos, en modelos de roedores el ARN mensajero del R1PAC está inducido por el condicionamiento al miedo o por el reemplazo de estrógenos. Estos datos sugieren que las perturbaciones en la vía del PACCH-R1PAC están reguladas por estrógenos y participan en las respuestas anormales al miedo del TEPT.
Les troubles liés aux traumatismes, comme les troubles du stress post-traumatique (TSPT) chez les humains, sont extrêmement courants et invalidants et souvent caractérisés par une dérégulation des réponses à la menace. De nombreuses études épidémiologiques indiquent que les femmes ont environ deux fois plus de risque de TSPT et d'autres troubles liés au stress. La compréhension des mécanismes biologiques de ce risque différentiel est d'une importance essentielle. Selon des données récentes, la voie du PACAP (pituitary adenylate cyclase-activating polypeptide) est un régulateur capital de la réponse au stress commun à l'ensemble des espèces. De plus, il existe des preuves croissantes de la régulation de ces voies par la modulation à la fois du stress et des estrogènes et de leur apport d'une ouverture importante dans la compréhension du mécanisme des différences selon le sexe dans la réponse au stress. Nous avons récemment montré que la PACAP et son récepteur (PAC1R) sont des médiateurs essentiels des processus anormaux après un traumatisme psychologique. Il semble y avoir, en particulier chez les humains fortement traumatisés, une importante association des concentrations sanguines de PACAP et des variants du gène PAS1R spécifiques du sexe avec la physiologie de la peur, le diagnostic de TSPT et des symptômes, en particulier chez les femmes. L'association spécifique au sexe est liée à un polymorphisme nucléotidique (rs2267735) localisé dans une séquence d'ADN supposée être un élément de réponse à l'estrogène impliqué dans la régulation du gène PAC1R. Pour compléter ces données humaines, l'ARN messager du PAC1R est induit avec le conditionnement à la peur ou le remplacement des estrogènes dans des modèles murins. Ces données suggèrent que les perturbations dans la voie du PACAP-PAC1R sont régulées par les estrogènes et impliquées dans les réponses anormales à la peur sous-tendant le TSPT.
Keywords: ADCYAP1; ADCYAP1R1; PACAP; PTSD; amygdala; anxiety; estrogen; fear; fear conditioning; genetic; sex difference; threat.
Figures
Figure 1.. The ADCYAP1R1 risk allele (rs2267735) is associated with increased amygdala activation (A) and decreased amygdala-hippocampal connectivity (B) in traumatized women when viewing fearful faces (N=49). Adapted from reference 76: Stevens JS, Almli LM, Fani N, et al. PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus. Proc Natl Acad Sci U S A. 2014;111(8):3158-3163. Copyright© National Academy of Science 2014
Figure 2.. Schematic illustrating the proposed relationship between pituitary adenylate cyclase-activating polypeptide (PACAP)-PAC1 receptor (PAC1R) signaling and fear/stress processes elicited by trauma exposure. (Left) The predominant gonadal hormone in females, estradiol (E,), and trauma both regulate the PACAP-PAC1R system in the female brain to drive normal fear and stress processes. (Right) Females, but not males, with high plasma PACAP38 levels and PAC1R polymorphisms may have altered PACAP-PAC1R signaling, which consequently drives pathological fear and stress processes associated with posttraumatic stress disorder (PTSD). This schematic diagram suggests that the responsiveness of the PACAP-PAC1R system to E, might be important in regulating PACAP-PAC1R activation of fearand stress-dependent pathways and phenotypes that underlie the sex-bias in PTSD prevalence. ERE, estrogen responsive element; E2, estradiol; Trauma, psychological trauma; PACAP, pituitary adenylate cyclase-activating polypeptide
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