Brain pathways mediating hypothalamic-pituitary-adrenal axis responses to emotional stressors

Abstract

Hypothalamic-pituitary-adrenal (HPA) axis activation is a key element of the stress response, regardless of the stressor involved. While the precise identities of the brain pathways that control this response remain unclear, there is considerable evidence that amygdala cells and medullary catecholamine cells are involved. However, recent work suggests that their contribution may vary with the type of stressor. The primary aims of the studies described in this thesis were: firstly, to identify whether physical and emotional stressors elicit distinctive patterns of neuronal activation amongst amygdala and medullary catecholamine cell populations; secondly, to determine in detail the amygdala and catecholamine pathways that might contribute to the activation of the HPA axis by emotional stressors; thirdly, to determine whether the activities of these pathways are modified by the gonadal steroid oestrogen.To address the first aim, patterns of stress-induced amygdala and medullary catecholamine cell activation were mapped on the basis of immunolabelling for Fos expression in adult male rats. Emotional (restraint and noise) and physical (haemorrhage or immune challenge) stressors elicited very distinct patterns of activity. In the amygdala, emotional stressors mainly activated medial amygdala cells whereas physical stressors mainly activated central amygdala cells. In the brainstem, emotional stressors consistently recruited a more caudal population of brainstem noradrenaline cells than did physical stressors.To evaluate the role of the amygdala in the generation of HPA axis responses to an emotional stressor, neurochemical lesion and retrograde tracing experiments were performed. Ibotenic acid lesions of the medial amygdala reduced putative CRF cell responses to restraint but central amygdala lesions had no effect. Experiments involving a combination of Fos immunolabelling and retrograde tracing showed that the medialnamygdala is likely to influence HPA axis function via a direct projection to the CRF cells located in the paraventricular nucleus (PVN).To investigate whether brainstem catecholamine cells do regulate HPA axis responses to an emotional stressor, restraint-induced Fos expression was examined in male rats prepared with either: (i) PVN-directed injections of a retrograde tracer; (ii) 6- hydroxydopamine lesions of PVN catecholamine terminals; or (iii) ibotenic acid lesions of medullary catecholamine cell groups. Retrograde tracing experiments revealed that most stressor-responsive, PVN-projecting medullary cells were catecholaminergic. However, destruction of PVN catecholamine terminals did not alter HPA axis responses to restraint, even though animals with lesions corresponding to medullary catecholamine cell groups showed suppressed HPA axis responses. It was concluded that medullary neurons influence HPA axis responses to emotional stressors via a multisynaptic pathway. Because medullary catecholamine cells project to the amygdala and medullary lesions suppressed medial amygdala cell responses to restraint, we further suggest that it is medullary catecholamine cells that influence HPA axis responses to emotional stressors and that they achieve this via an input to the medial amygdala.n n n n