Nk3R blockade has sex-divergent effects on memory in mice

Altres ajuts: National Alliance for Research on Schizophrenia and Depression: 22434 ; Fundación Alicia KoplowitzMemory consolidation is a process required for the formation of long-term memories. The G-protein-coupled receptor (GPCR) neurokinin-3-receptor (Nk3R) and its interactions with sex hormones seem important for the modulation of fear memory consolidation: Nk3R antagonism in male mice impairs fear memory, but enhances it in females. However, the involvement of the Nk3R as a modulator of other memories in both sexes remains unexplored. We use the novel object recognition paradigm to test the effect of a systemic blockade of Nk3R during memory consolidation. Further, we assess the expression of estrogen receptor α, estrogen receptor β, and androgen receptor and heterodimerization with Nk3R in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) of mice. Nk3R systemic antagonism elicited decreased memory consolidation in males while it enhanced it in females during proestrus. Nk3R analysis in the different subregions of the mPFC and the DH showed a higher expression in males than females. Moreover, females presented upregulation of the androgen receptor in the CA1 and the estrogen receptor beta in the cingulate cortex, CA1, and dentate gyrus. Overall, males presented an upregulation of the estrogen receptor alpha. We also explored the heterodimerization of GCPR membrane sex hormone receptors with the Nk3R. We found a higher percentage of Nk3R-membrane G-protein estrogen receptors heterodimers in the prelimbic cortex of the mPFC in females, suggesting an interaction of estradiol with Nk3R in memory consolidation. However, males presented a higher percentage of Nk3R-membrane G-protein androgen receptors heterodimers compared to females, pointing to an interaction of testosterone with Nk3R in memory consolidation. These data propose novel ideas on functional interactions between Nk3R, sex hormones, estrogen receptors, and androgen receptors in memory consolidation

La modelación biofísica y agroclimática: Asimilación y aplicación de la plataforma BioMA en Cuba para evaluar los impactos del cambio climático y opciones de adaptación

Este informe resume el trabajo realizado para hacer la transferencia de la plataforma BioMA a Cuba y sus primeras aplicaciones para evaluar los impactos del cambio climático y de opciones de adaptación del agro-manejo. Estos trabajos fueron conducidos en el contexto del proyecto BASAL Proyecto Bases Ambientales para la Sostenibilidad Alimentaria Local (BASAL), un proyecto de cooperación de Cuba con la Unión Europea, que pretende reducir las vulnerabilidades relacionadas con el cambio climático en el sector agrícola a nivel local y nacional.JRC.D.5-Food Securit

A crowdsourcing database for the copy-number variation of the Spanish population

Background: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants. Results: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/. Conclusion: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database

Macrocircuitry and microcircuitry of the Tac2 pathway in fear conditioning

Els trastorns basats en la por són condicions altament incapacitants i els tractaments actuals no tenen èxit en molts casos. Les dones presenten gairebé tres vegades més prevalença vital d'aquests trastorns que els homes. Investigacions recents han demostrat que les neurones taquiquinina 2 (Tac2) de l'amígdala centromedial (CeM) són crucials per a la regulació del condicionament de la por (FC) en ratolins mascles. Aquí, hem trobat que l'administració sistèmica d'un antagonista del receptor de neuroquinina-3 (Nk3R) (osanetant) després de l'adquisició de la por provocada va alterar la consolidació de la memòria d'una manera oposada al sexe. A més, aquesta manipulació farmacològica va alterar l'augment normal de la testosterona a FC en ratolins mascles. Curiosament, les dones només van mostrar alteracions de consolidació de la memòria quan el fàrmac es va administrar en l'etapa de proestro del cicle estral (estradiol i progesterona alts). Concordantment, el silenciament quimiogenètic de les neurones CeM-Tac2 després de la FC va imitar les alteracions de consolidació de la memòria observades després de l'administració sistèmica d'osanetant. A més, vam utilitzar el nou paradigma de reconeixement d'objectes per provar l'efecte d'un bloqueig sistèmic de Nk3R durant la consolidació de la memòria. A més, avaluem l'expressió del receptor d'estrògens alfa, el receptor d'estrògens beta i el receptor d'andrògens i l'heterodimerització amb Nk3R a l'escorça prefrontal medial (mPFC) i l'hipocamp dorsal (DH) dels ratolins. L'antagonisme sistèmic Nk3R va provocar una disminució de la consolidació de la memòria en els homes mentre que la va millorar en les dones durant el proestro. L'anàlisi de Nk3R a les diferents subregions del mPFC i el DH va mostrar una expressió més alta en homes que en dones. A més, les dones van presentar una regulació positiva del receptor d'andrògens al CA1 i del receptor d'estrògens beta a l'escorça cingulada, CA1 i Dentate Gyrus. En general, els homes van presentar una regulació positiva del receptor d'estrògens alfa. També vam explorar l'heterodimerització dels receptors d'hormones sexuals de membrana GCPR amb el Nk3R. Hem trobat un percentatge més alt d'heterodímers dels receptors d'estrògens de proteïna G de membrana Nk3R tant en mPFC com en DH en dones que suggereix una interacció d'estradiol amb Nk3R en la consolidació de la memòria. No obstant això, els homes van presentar un percentatge més elevat d'heterodímers dels receptors d'andrògens de proteïna G de membrana Nk3R a l'escorça cingulada i prelímbica apuntant a la interacció de la testosterona amb Nk3R en la consolidació de la memòria. Aquestes dades proposen idees noves sobre les interaccions funcionals entre NK3R, hormones sexuals, receptors d'estrògens i receptors d'andrògens en la consolidació de la memòria que poden ser rellevants per a individus sans i pacients psiquiàtrics.Los trastornos basados en el miedo son condiciones altamente incapacitantes y los tratamientos actuales no tienen éxito en muchos casos. Las mujeres presentan casi tres veces más prevalencia de vida de estos trastornos que los hombres. Investigaciones recientes han demostrado que las neuronas de taquiquinina 2 (Tac2) de la amígdala centromedial (CeM) son cruciales para la regulación del condicionamiento del miedo (FC) en ratones macho. Aquí, hemos encontrado que la administración sistémica de un antagonista del receptor de neuroquinina-3 (Nk3R) (osanetant) después de la adquisición del miedo estimulado alteró la consolidación de la memoria de una manera opuesta al sexo. Además, esta manipulación farmacológica alteró el aumento normal de testosterona a FC en ratones macho. Curiosamente, las hembras solo exhibieron alteraciones en la consolidación de la memoria cuando la droga se administró en la etapa de proestro del ciclo estral (estradiol y progesterona altos). En concordancia, el silenciamiento quimiogenético de las neuronas CeM-Tac2 después de FC imitó las alteraciones de consolidación de la memoria observadas después de la administración sistémica de osanetant. Además, utilizamos el nuevo paradigma de reconocimiento de objetos para probar el efecto de un bloqueo sistémico de Nk3R durante la consolidación de la memoria. Además, evaluamos la expresión del receptor de estrógeno alfa, el receptor de estrógeno beta y el receptor de andrógeno y la heterodimerización con Nk3R en la corteza prefrontal medial (mPFC) y el hipocampo dorsal (DH) de ratones. El antagonismo sistémico de Nk3R provocó una disminución de la consolidación de la memoria en los machos, mientras que la mejoró en las hembras durante el proestro. El análisis de Nk3R en las diferentes subregiones de mPFC y DH mostró una mayor expresión en machos que en hembras. Además, las hembras presentaron regulación positiva del receptor de andrógenos en CA1 y del receptor de estrógenos beta en la corteza cingulada, CA1 y Dentado Gyrus. En general, los hombres presentaron una regulación positiva del receptor de estrógeno alfa. También exploramos la heterodimerización de los receptores de hormonas sexuales de membrana GCPR con el Nk3R. Encontramos un mayor porcentaje de heterodímeros de receptores de estrógeno de proteína G de membrana Nk3R tanto en mPFC como en DH en mujeres, lo que sugiere una interacción de estradiol con Nk3R en la consolidación de la memoria. Sin embargo, los hombres presentaron un mayor porcentaje de heterodímeros de receptores de andrógenos de proteína G de membrana Nk3R en la corteza cingulada y prelímbica, lo que apunta a la interacción de la testosterona con Nk3R en la consolidación de la memoria. Estos datos proponen ideas novedosas sobre interacciones funcionales entre NK3R, hormonas sexuales, receptores de estrógenos y receptores de andrógenos en la consolidación de la memoria que pueden ser relevantes para individuos sanos y pacientes psiquiátricos.Fear-based disorders are highly disabling conditions and current treatments are not successful in many cases. Women present almost three times more life prevalence of these disorders than men. Recent research has shown that centromedial amygdala (CeM) tachykinin 2 (Tac2) neurons are crucial for the regulation of fear conditioning (FC) in male mice. Here, we have found that systemic administration of a Neurokinin-3-Receptor (Nk3R) antagonist (osanetant) after cued-fear acquisition altered memory consolidation in a sex-opposite manner. Further, this pharmacological manipulation altered the normal rise in testosterone to FC in male mice. Interestingly, females only exhibited memory consolidation alterations when the drug was given in the proestrus stage of the estrous cycle (high estradiol and progesterone). Concordantly, chemogenetic silencing of CeM-Tac2 neurons after FC mimicked the memory consolidation alterations observed after systemic osanetant administration. Moreover, we used the novel object recognition paradigm to test the effect of a systemic blockade of Nk3R during memory consolidation. Further, we assess the expression of Estrogen Receptor Alpha, Estrogen Receptor Beta and Androgen Receptor and heterodimerization with Nk3R in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) of mice. Nk3R systemic antagonism elicited decreased memory consolidation in males while it enhanced it in females during proestrus. Nk3R analysis in the different subregions of the mPFC and the DH showed a higher expression in males than females. Moreover, females presented upregulation of the Androgen receptor in the CA1 and the Estrogen receptor beta in the cingulate cortex, CA1, and Dentate Gyrus. Overall, males presented an upregulation of the Estrogen receptor alpha. We also explored the heterodimerization of GCPR membrane sex hormones receptors with the Nk3R. We found a higher percentage of Nk3R-membrane G-Protein Estrogen Receptors heterodimers in both mPFC and DH in females suggesting an interaction of estradiol with Nk3R in memory consolidation. However, males presented a higher percentage of Nk3R- membrane G-Protein Androgen Receptors heterodimers in the Cingulate and Prelimbic Cortex pointing at the interaction of testosterone with Nk3R in memory consolidation. These data propose novel ideas on functional interactions between NK3R, sex hormones, Estrogen receptors, and Androgen receptors in memory consolidation which may be relevant for healthy individuals and psychiatric patients

Effects of Tac2 pathway blockade on fear memory consolidation, circulating steroids expression, and mRNA and protein expression in the Central Amygdala

This dataset includes the source data related to the submission of the article "Sex differences in fear memory consolidation via Tac2 signaling in mice" to Nature Communications. It includes fear memory consolidation affections after the administration of a Neurokinin 3 Receptor antagonist including behavioral and molecular data related to sex-steroids and amygdalar mRNA and protein expression

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Altres ajuts: Fundación Koplovitz; NIH: P50 MH115874, F32MH125634, K08 DK118201; VA Merit and Department of Defense; Instituto de la Mujer: 235/09Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction

Sex differences in fear memory consolidation via Tac2 signaling in mice

Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impair fear memory in male mice. Surprisingly, we demonstrate here the opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3β/β-Catenin signaling both mediate the opposite-sex differential Tac2 pathway regulation of fear memory.We would also like to thank Noemí Haro for help with estradiol determination. Procedural images were created with BioRender.com. RA was supported by a NARSAD Young Investigator Grant #22434, Ramón y Cajal program RYC2014-15784, RETOS-MICINN SAF2016-76565-R FEDER funds, and ERANET-Neuron JTC 2019 ISCIII AC19/00077. CAS is supported by Ministerio de Ciencia e Inovación (MICINN) grant SAF2016-80027-R, PID2019-106615RB-100, and ISCIII (CIBERNED CB06/05/0042). RN was supported by MICINNgrant SAF2017-83430 and was a recipient of an ICREA Academia Award (Generalitat de Catalunya, 2015-2019). AF 2018 FI_B00030 and CMS 2017 FI_B00326 were recipients of Generalitat de Catalunya predoctoral fellowship. ERV was supported by BES-2017-080870 FPI-2017 fellowship from MINECO. LPC was supported by an FJC2018-037958-I (MCIyU). PM received support from FPU16/05416 (MCECD). OP was supported by the Spanish Health National System CPII16/00027

Sex differences in fear memory consolidation via Tac2 signaling in mice

Altres ajuts: NARSAD Young Investigator Grant #22434; FJC2018-037958-I (MCIyU)Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impair fear memory in male mice. Surprisingly, we demonstrate here the opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3β/β-Catenin signaling both mediate the opposite-sex differential Tac2 pathway regulation of fear memory. The Tachykinin 2 (Tac2) pathway in the central amygdala is sufficient and necessary for modulating fear memory consolidation. The authors show that silencing Tac2 neurons in the amygdala of male mice reduces fear expression, while fear expression in female mice is increased when manipulations are made during proestrus

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.We thank Drs. Javier Carrasco, Núria Barba, Mar Castillo, Roser Nadal, Antonio Armario, Laura Perez-Caballero and Ignacio Marín Blasco at the Institute of Neurosciences, UAB. RA was supported by a NARSAD Young Investigator Grant #22434, Ramón y Cajal program RYC2014-15784, RETOS-MINECO SAF2016-76565-R FEDER funds and PID2020-112705RB-I00 FEDER funds, ERANET-Neuron JTC 2019 ISCIII AC19/00077 and Fundación Koplowitz. A.F. received the predoctoral fellowship 2018 FI_B00030 from Generalitat de Catalunya. E.R.V. was supported by the BES-2017-080870 FPI-2017 fellowship from MINECO. Á.F. was supported by FJCI-2016-29888 contract from MICINN. L.L.G.E. was a recipient of a grant from the Women’s Institute of Spain (235/09). O.P. was supported by the Spanish Health National System CPII16/00027. K.J.R. and E.L.N. were supported by NIH P50 MH115874. E.L.N. was supported by NIH F32MH125634. R.A.R. and P.D. are supported by NIH K08 DK118201. S.N. received funding from VA Merit and Department of Defense