A novel arousal-based individual screening reveals susceptibility and resilience to PTSD-like phenotypes in mice

Sebastiano A Torrisi; Gianluca Lavanco; Oriana M Maurel; Walter Gulisano; Samuele Laudani; Federica Geraci; Margherita Grasso; Cristina Barbagallo; Filippo Caraci; Claudio Bucolo; Marco Ragusa; Francesco Papaleo; Patrizia Campolongo; Daniela Puzzo; Filippo Drago; Salvatore Salomone; Gian Marco Leggio

doi:10.1016/j.ynstr.2020.100286

A novel arousal-based individual screening reveals susceptibility and resilience to PTSD-like phenotypes in mice

Neurobiol Stress. 2020 Dec 24:14:100286. doi: 10.1016/j.ynstr.2020.100286. eCollection 2021 May.

Authors

Sebastiano A Torrisi¹, Gianluca Lavanco^{1

2}, Oriana M Maurel^{1

3}, Walter Gulisano¹, Samuele Laudani¹, Federica Geraci¹, Margherita Grasso^{4

5}, Cristina Barbagallo¹, Filippo Caraci^{4

5}, Claudio Bucolo¹, Marco Ragusa^{1

4}, Francesco Papaleo⁶, Patrizia Campolongo^{7

8}, Daniela Puzzo¹, Filippo Drago¹, Salvatore Salomone¹, Gian Marco Leggio¹

Affiliations

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.

Abstract

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.

Keywords: 5-trial SM, 5-trial social memory; AIS, arousal-based individual screening; ASR, acoustic startle reactivity; Amy, amygdala; Animal model; BDNF, brain derived neurotropic factor; BST, basal synaptic transmission; C, control; CORT, corticosterone; DSM-5, Diagnostic and Statistical Manual of Mental Disorders; EPM, elevated plus maze; FDA, Food and Drug Administration; FKBP5, FK506 binding protein 5; FST, forced swim test; Fear conditioning; HIP, hippocampus; HPA, hypothalamic–pituitary–adrenal; HT, hypothalamus; OF, open field; PTSD, post-traumatic stress disorder; Resilience; SGK1, serum/glucocorticoid-regulated kinase 1; SSRIs, selective serotonin reuptake inhibitors; Stress; Susceptibility; TE, trauma-exposed; Z-score; fEPSPs, field excitatory post-synaptic potentials; mPFC, medial prefrontal cortex.