The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus
Introduction The incidence and severity of posttraumatic stress disorder (PTSD) is higher in women than men because of environmental and biological factors. Specific mechanisms in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide and its type I receptor) system may confer PTSD ri...
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| Format: | Article |
| Language: | English |
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Cambridge University Press
2022-06-01
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| Series: | European Psychiatry |
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| Online Access: | https://www.cambridge.org/core/product/identifier/S0924933822002139/type/journal_article |
| _version_ | 1827754592288374784 |
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| author | R. Andero |
| author_facet | R. Andero |
| author_sort | R. Andero |
| collection | DOAJ |
| description |
Introduction
The incidence and severity of posttraumatic stress disorder (PTSD) is higher in women than men because of environmental and biological factors. Specific mechanisms in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide and its type I receptor) system may confer PTSD risk in women. Interestingly, while the PACAP (ADCYAP1) - PAC1R (ADCYAP1R1) system is expressed highly in the hypothalamus, no relationship has been described for this pathway in the hypothalamus with fear processing or in PTSD.
Objectives
We studied whether the estrous/menstrual cycle at the moment of trauma predicts PTSD and the involvement of the PACAP neurons in the amygdala and hypothalamus during traumatic stress.
Methods
Mice: DREADDs, immunohistochemistry and behavior. Humans: fear-potentiated startle and questionnaires.
Results
Here, we show that acute stress immobilization (IMO) produces fear extinction impairments in female mice. Also, IMO elicits 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) after fear extinction. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 SNP show impaired fear extinction. In mice, DREADD-mediated inhibition of the MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We ruled out contributions from inherent hormonal states showing that the menstrual or estrous cycle phase at the moment of trauma does not result in a vulnerable phenotype.
Conclusions
Our data suggest that the PACAP-PAC1R hypothalamic system may be a novel candidate to treat and prevent PTSD symptoms including fear dysregulations.
Disclosure
No significant relationships.
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| first_indexed | 2024-03-11T07:52:34Z |
| format | Article |
| id | doaj.art-75112b42460e4207b76c08a594a7c998 |
| institution | Directory Open Access Journal |
| issn | 0924-9338 1778-3585 |
| language | English |
| last_indexed | 2024-03-11T07:52:34Z |
| publishDate | 2022-06-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | European Psychiatry |
| spelling | doaj.art-75112b42460e4207b76c08a594a7c9982023-11-17T05:06:30ZengCambridge University PressEuropean Psychiatry0924-93381778-35852022-06-0165S67S6710.1192/j.eurpsy.2022.213The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamusR. Andero0Universitat Autònoma de Barcelona, Institute Of Neuroscience, Cerdanyola del Vallès, Spain Introduction The incidence and severity of posttraumatic stress disorder (PTSD) is higher in women than men because of environmental and biological factors. Specific mechanisms in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide and its type I receptor) system may confer PTSD risk in women. Interestingly, while the PACAP (ADCYAP1) - PAC1R (ADCYAP1R1) system is expressed highly in the hypothalamus, no relationship has been described for this pathway in the hypothalamus with fear processing or in PTSD. Objectives We studied whether the estrous/menstrual cycle at the moment of trauma predicts PTSD and the involvement of the PACAP neurons in the amygdala and hypothalamus during traumatic stress. Methods Mice: DREADDs, immunohistochemistry and behavior. Humans: fear-potentiated startle and questionnaires. Results Here, we show that acute stress immobilization (IMO) produces fear extinction impairments in female mice. Also, IMO elicits 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) after fear extinction. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 SNP show impaired fear extinction. In mice, DREADD-mediated inhibition of the MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We ruled out contributions from inherent hormonal states showing that the menstrual or estrous cycle phase at the moment of trauma does not result in a vulnerable phenotype. Conclusions Our data suggest that the PACAP-PAC1R hypothalamic system may be a novel candidate to treat and prevent PTSD symptoms including fear dysregulations. Disclosure No significant relationships. https://www.cambridge.org/core/product/identifier/S0924933822002139/type/journal_articletranslationalhumanmouseStress |
| spellingShingle | R. Andero The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus European Psychiatry translational human mouse Stress |
| title | The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus |
| title_full | The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus |
| title_fullStr | The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus |
| title_full_unstemmed | The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus |
| title_short | The role of PACAP/PAC1R in PTSD: effects on fear extinction via the ventromedial hypothalamus |
| title_sort | role of pacap pac1r in ptsd effects on fear extinction via the ventromedial hypothalamus |
| topic | translational human mouse Stress |
| url | https://www.cambridge.org/core/product/identifier/S0924933822002139/type/journal_article |
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