| Summary: | The hypothalamo-pituitary-adrenal (HPA) axis is the main regulator of stress in mammals, and prolongation of the stress response can lead to manifestation of metabolic and psychiatric disorders. Leptin is an adipokine known to act at the hypothalamus to regulate body fat stores, appetite and energy expenditure, but the role of leptin on the HPA response to stress is still not well understood. Psychological stress, specifically loneliness in humans - referred to as social isolation (SI) in social mammals - can also alter HPA functioning. The work described in this thesis investigates the effects of leptin and SI on the HPA response to acute stress. My studies suggest that leptin does not influence basal HPA activity, or influence the HPA response to acute endotoxin challenge in rats. They also show that SI does not affect basal HPA activity, but that short term chronic SI does cause hyperactivity of the HPA in response to acute restraint stress, and that the stress axis is hyper-sensitised at the level of the hypothalamus and the adrenal gland after this period of SI. My work suggests that this HPA hyperactivity may be the result of an overactive CRH feed-forward mechanism. I have also shown that short term intermittent SI and long term chronic SI both cause hypoactivity of the HPA axis response to acute restraint stress, with the former regulated by an unknown mechanism and the latter possibly regulated by an overactive glucocorticoid feedback mechanism. In summary, these studies have highlighted the complex differential activation of the HPA axis in response to different types of stressors; both immunological and psychological. I have also demonstrated the different effects of novel SI paradigms on HPA response to acute stress, and how such psychological stress can impair the functioning of a key system in the body that may be involved in metabolic and psychiatric disease.
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