A novel arousal-based individual screening reveals susceptibility and resilience to PTSD-like phenotypes in mice
Neurobiology of Stress. 2021-05-01; 14: 100286
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Torrisi SA(1), Lavanco G(1)(2), Maurel OM(1)(3), Gulisano W(1), Laudani S(1), Geraci F(1), Grasso M(4)(5), Barbagallo C(1), Caraci F(4)(5), Bucolo C(1), Ragusa M(1)(4), Papaleo F(6), Campolongo P(7)(8), Puzzo D(1), Drago F(1), Salomone S(1), Leggio GM(1).
(1)Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
(2)INSERM, U1215 Neurocentre Magendie and University of Bordeaux, Bordeaux, France.
(3)Research Group « Neuronal Plasticity », Max Planck Institute of Psychiatry, Munich, Germany.
(4)Oasi Research Institute-IRCCS, Troina, Italy.
(5)Department of Drug Sciences, University of Catania, Catania, Italy.
(6)Genetics of Cognition Laboratory, Neuroscience area, Istituto Italiano di
Tecnologia, Genova, Italy.
(7)Department of Physiology and Pharmacology « Vittorio Erspamer », Sapienza
University of Rome, Rome, Italy.
(8)Neurobiology of Behavior Laboratory, Santa Lucia Foundation, Rome, Italy.
Translational animal models for studying post-traumatic stress disorder (PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of PTSD-like phenotypes triggered after exposure to a single traumatic event, trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent PTSD-like phenotypes including exaggerated fear reactivity and avoidance of trauma-related cue (up to 75 days post-trauma), increased avoidance-like behavior and social/cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by PTSD-related genes as well as dysfunction of hypothalamic-pituitary-adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with paroxetine ameliorated the PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of PTSD. It might shed light on the unclear PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder.
© 2020 The Authors.