Personalized resilience: how individual variability in brain–immune responses to stress influences the development of anxiety disorders

Nadine PeixotoRosalina Fonseca^*

• Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Stress exposure has increased significantly, contributing to higher rates of anxiety, depression, and post-traumatic stress disorder. However, individual responses to stress vary greatly, underscoring the concept of stress resilience. The acute stress response activates the amygdala, hippocampus, and prefrontal cortex, stimulating the HPA axis and triggering cortisol release, which typically restores balance through negative feedback mechanisms. In contrast, chronic stress or exposure to severe stressors leads to sustained HPA axis activation, amygdala hyperreactivity, and immune dysfunction, all of which promote the development of anxiety disorders. This review explores potential central and peripheral biomarkers of resilience, emphasizing the interplay between immune responses, the HPA axis, and the endocannabinoid signaling system. We discuss whether amygdala reactivity could serve as a predictor of stress vulnerability, along with cortisol levels and sleep disturbances, as these are often hallmarks of stress-related disorders. Furthermore, we suggest that pro-inflammatory cytokines such as TNF-α and IL-6—key indicators of stress-induced inflammation—may serve as predictors of anxiety-related vulnerability. Furthermore, we discuss the potential role of the endocannabinoid system as an integrative hub for stress responses. Given its capacity to coordinate central and peripheral mechanisms—from neuroimmune to metabolic processes—we examine how genetic and functional variations in CB1R and FAAH may influence individual resilience, highlighting their potential as biomarkers of stress susceptibility. Clinically is of utmost relevance the identification of reliable and reproducible biomarkers for advancing diagnostic precision and developing personalized therapeutic interventions for stress-related disorders.