A comparative analysis of neurohumoral regulation and hormonal dynamics in post-traumatic stress disorder (PTSD) between human and mouse models

Post-traumatic stress disorder (PTSD) is a multifaceted psychiatric condition arising from exposure to traumatic events, affecting millions globally, particularly among veterans, survivors of violence, and individuals impacted by natural disasters. It manifests through persistent symptoms such as intrusive memories, hyperarousal, emotional dysregulation, and cognitive impairments. This review examines the neurobiological mechanisms underlying PTSD, focusing on the critical roles of neurohumoral regulation and hormonal dynamics, particularly the hypothalamic-pituitary-adrenal (HPA) axis. Dysregulation of the HPA axis, characterized by paradoxical cortisol dynamics that transition from hyperactivity in acute stress phases to hypoactivity in chronic stages, is a hallmark of PTSD. This hormonal imbalance influences the neural pathways associated with fear responses, emotional regulation, and stress recovery. Additionally, the review highlights the complex interplay between the HPA axis and other hormonal systems, such as the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes, and neuropeptides like oxytocin and vasopressin. These interactions contribute to the disorder’s heterogeneity and individualized responses to trauma. Animal studies, particularly those using mouse models, have provided critical insights into genetic, physiological, and methodological factors influencing PTSD development. However, notable differences in glucocorticoid dynamics, receptor sensitivity, and stress recovery between humans and mice underscore the challenges of directly extrapolating findings across species. Furthermore, the review explores sex-specific vulnerabilities, with women being disproportionately affected due to the modulatory effects of estrogen, progesterone, and testosterone on stress resilience and emotional processing. Neurochemical dysregulation, particularly involving serotonin, dopamine, and gamma-aminobutyric acid (GABA), further compounds the complexity of PTSD, influencing mood regulation and behavioral responses to trauma. This comprehensive analysis underscores the need for a multidimensional approach to understanding PTSD, integrating hormonal, genetic, and neurochemical perspectives. Such an approach is vital for developing targeted therapeutic interventions that address the dynamic and individualized nature of the disorder.