The pituitary adenylate cyclase-activating polypeptide system as a sex-specific modulator of hippocampal response to threat stimuli

Daniel Porta-Casteràs; Marta Cano; Trevor Steward; Raül Andero; Narcís Cardoner

doi:10.1016/j.ynstr.2022.100448

The pituitary adenylate cyclase-activating polypeptide system as a sex-specific modulator of hippocampal response to threat stimuli

Neurobiol Stress. 2022 Apr 14:18:100448. doi: 10.1016/j.ynstr.2022.100448. eCollection 2022 May.

Authors

Daniel Porta-Casteràs^{1

2

3}, Marta Cano^{1

3

4

5}, Trevor Steward^{6

7}, Raül Andero^{1

4

5

8

9}, Narcís Cardoner^{1

2

3

5}

Affiliations

¹ Mental Health Department, Unitat de Neurociència Traslacional, Parc Tauli University Hospital, Institut d'Investigació i Innovació Sanitària Parc Taulí (I3PT), Barcelona, Spain.
² Department of Psychiatry and Forensic Medicine, School of Medicine Bellaterra, Universitat Autònoma de Barcelona, Barcelona, Spain.
³ Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
⁴ Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁵ CIBERSAM, Carlos III Health Institute, Madrid, Spain.
⁶ Melbourne School of Psychological Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia.
⁷ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia.
⁸ Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁹ ICREA, Barcelona, Spain.

Abstract

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor gene polymorphism has been postulated as a potential sex-specific diagnostic biomarker of trauma-related disorders. However, no research to date has evaluated whether the PACAPergic system may act as a vulnerability/resilience neuromechanism to trauma-induced psychopathology in healthy participants without heightened risk to experience traumatic events.

Methods: Here, we compared the amygdala and hippocampus response to fearful faces in participants with at-risk genotype versus non-risk participants from the Human Connectome Project (n = 991; 53.4% female).

Results: Increased hippocampal response to fearful faces in the female risk group emerged in sex by genetic risk interaction.

Conclusions: Our findings revealed the first sex-specific neurogenetic vulnerability factor to trauma-related disorders, and emphasize the importance of prevention-based strategies to ameliorate neuropsychiatric pathophysiology.

Keywords: Hippocampus; PACAP; PTSD; Threat; Women; fMRI.