Neuroendocrine and cellular mechanisms in stress resilience: From hormonal influence in the CNS to mitochondrial dysfunction and oxidative stress

Abstract Recent advancements in neuroendocrinology challenge the long‐held belief that hormonal effects are confined to perivascular tissues and do not extend to the central nervous system (CNS). This paradigm shift, propelled by groundbreaking research, reveals that synthetic hormones, notably in anti‐inflammatory medications, significantly influence steroid psychosis, behavioural, and cognitive impairments, as well as neuropeptide functions. A seminal development in this field occurred in 1968 with McEven's proposal that rodent brains are responsive to glucocorticoids, fundamentally altering the understanding of how anxiety impacts CNS functionality and leading to the identification of glucocorticosteroids and mineralocorticoids as distinct corticotropic receptors. This paper focuses on the intricate roles of the neuroendocrine, immunological, and CNS in fostering stress resilience, underscored by recent animal model studies. These studies highlight active, compensatory, and passive strategies for resilience, supporting the concept that anxiety and depression are systemic disorders involving dysregulation across both peripheral and central systems. Resilience is conceptualized as a multifaceted process that enhances psychological adaptability to stress through adaptive mechanisms within the immunological system, brain, hypothalamo–pituitary–adrenal axis, and ANS Axis. Furthermore, the paper explores oxidative stress, particularly its origin from the production of reactive oxygen species (ROS) in mitochondria. The mitochondria's role extends beyond ATP production, encompassing lipid, heme, purine, and steroidogenesis synthesis. ROS‐induced damage to biomolecules can lead to significant mitochondrial dysfunction and cell apoptosis, emphasizing the critical nature of mitochondrial health in overall cellular function and stress resilience. This comprehensive synthesis of neuroendocrinological and cellular biological research offers new insights into the systemic complexity of stress‐related disorders and the imperative for multidisciplinary approaches in their study and treatment.