European journal of pharmacology · 2026
Heart-brain axis dysregulation in PTSD mice: Vagal-mediated insular cortex hyperactivity and its reversal by propranolol.
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Niu Jingwen, Xia Wei, Li Haipeng, Xia Ran, Wang Jingji, Zhang Junjie, Yang Shaojie, Zhu Guoqi, Chen Lixia
Аннотация
BACKGROUND: While abnormal brain connectivity is central to PTSD, sympathetically-driven cardiac dysfunction also occurs. Given the established role of cardiac modulation of brain function and its implication in psychiatric disorders, this study aims to delineate the role of the heart-brain connection in the mechanisms underlying PTSD.
METHODS: A single prolonged stress (SPS)-induced male C57BL/6J mouse model of PTSD was employed. Anxiety- and fear-like behaviors were assessed using behavioral tests. Cardiac function and insular cortex excitability were measured via ECG, in vivo electrophysiology, and immunofluorescence. Chronic isoproterenol (ISO) mimicked sympathetic cardiac overactivation. Left cervical vagotomy tested the cardiac-to-insular pathway. Propranolol's therapeutic effect was evaluated.
RESULTS: Both SPS and chronic ISO treatment significantly increased heart rate and induced prominent PTSD-like behaviors in mice. Electrophysiological and immunofluorescence analyses revealed markedly enhanced neuronal excitability in the insular cortex following SPS and ISO, as evidenced by increased c-Fos-positive neurons, elevated local field potential power spectral density, and altered frequency band distribution. Vagotomy blocked ISO-induced tachycardia and behavioral effects, identifying the vagus nerve as the critical signaling conduit. Furthermore, propranolol effectively reduced heart rate, suppressed excessive neuronal activation and abnormal oscillatory activity in the insular cortex, and significantly alleviated PTSD-like behaviors in SPS mice.
CONCLUSION: This study highlights the critical role of heart-insular cortex functional interaction in PTSD pathogenesis, mediated by vagal transmission of sympathetically driven cardiac signals leading to insular cortex hyperactivity and behavioral abnormalities. Propranolol targets this pathway, showing therapeutic potential and providing novel insights into PTSD heart-brain mechanisms.
METHODS: A single prolonged stress (SPS)-induced male C57BL/6J mouse model of PTSD was employed. Anxiety- and fear-like behaviors were assessed using behavioral tests. Cardiac function and insular cortex excitability were measured via ECG, in vivo electrophysiology, and immunofluorescence. Chronic isoproterenol (ISO) mimicked sympathetic cardiac overactivation. Left cervical vagotomy tested the cardiac-to-insular pathway. Propranolol's therapeutic effect was evaluated.
RESULTS: Both SPS and chronic ISO treatment significantly increased heart rate and induced prominent PTSD-like behaviors in mice. Electrophysiological and immunofluorescence analyses revealed markedly enhanced neuronal excitability in the insular cortex following SPS and ISO, as evidenced by increased c-Fos-positive neurons, elevated local field potential power spectral density, and altered frequency band distribution. Vagotomy blocked ISO-induced tachycardia and behavioral effects, identifying the vagus nerve as the critical signaling conduit. Furthermore, propranolol effectively reduced heart rate, suppressed excessive neuronal activation and abnormal oscillatory activity in the insular cortex, and significantly alleviated PTSD-like behaviors in SPS mice.
CONCLUSION: This study highlights the critical role of heart-insular cortex functional interaction in PTSD pathogenesis, mediated by vagal transmission of sympathetically driven cardiac signals leading to insular cortex hyperactivity and behavioral abnormalities. Propranolol targets this pathway, showing therapeutic potential and providing novel insights into PTSD heart-brain mechanisms.