Quality and chronicity of stressors differentially affect psychoneuroendocrine and immune system cross-talk in mouse models

Stress physiology overlaps to a great extent in humans and mice, thus preclinical models can guide and refine hypothesis-driven clinical research questions. The brain is a primary mediator and target of stress resiliency and vulnerability because it determines what is threatening and regulates behavioural and physiological responses to a given stressor. A growing body of evidence suggests that the sustained activation of the HPA axis, and the consequent suppressed activity of the immune system mediated by glucocorticoid hormones, may increase the susceptibility to disease. The connection between central stress response pathways and peripheral targets involves a number of neurochemical and/or inflammatory factors that ultimately affect neuronal functioning and/or survival as well as adaptive physiological responses that allow fighting against external challenges. In this regard Brain-Derived Neurotrophic Factor (BDNF) represents a crucial factor for the integration of neural, immune, endocrine and metabolic responses to stressful challenges. However, the quality and quantity of stress, and the mechanisms leading to increased susceptibility to disease, are still a matter of intense investigation. The general objective of the work presented in this thesis was to characterise how quality and timing of stressors differentially impact on behavioural, neuroendocrine and immune profile in animal models. To this aim both central (BDNF levels) and peripheral (CORT, cytokines, splenic apoptosis, leptin and adiponectin levels) responses, as well as endophenotype of depression, were analyzed in mouse models. In particular, in Chapter 2, we report about the impact of social deprivation on anxiety and depressive-like behaviours, promoting a disrupted emotional state, while in Chapter 3 we identify a specific neuroendocrine-immune profile associated to specific changes in central mediators, describing the relevance of the nature and length of stress exposure. Both these studies relied on the assessment of BDNF as the principal mediator in the orchestration of brain and peripheral responses. Chapter 4 describes research in which both psychophysical and social stressors promote disease in a transgenic mouse model of breast cancer, through a specific neuroendocrine-immune-leptin axis. Analyses of the effects of stressful events in wild type and transgenic mice – described in Chapter 2, 3 and 4 - highlight the importance of individual responses to environmental stimuli in defining the outcome of disease. Results are discussed considering that stressful life events are related to a range of physical and emotional health problems and reduced quality of life, social support being a crucial protective factor in disease susceptibility.