Limbic system control of endocrine stress responses

The body's response to a stressor consists of behavioural, autonomic, and endocrine components. This response is generally considered, in the short term at least, to be beneficial to survival. However, long term activation of the stress response, due to chronic exposure to stressors, has been implicated in the development of a number of human diseases e.g. coronary disease, autoimmune disorders and depression. With a view to preventing the detrimental effects of the stress response, the brain pathways regulating the stress response have been the focus of a considerable amount of research. One of the first steps is to determine how the brain regulates the body's response to an acute stressor. With this in mind, the experiments detailed in this thesis were aimed at furthering our knowledge of the brain regions, particularly the limbic structures, regulating one of the body's responses to acute stressors, the activation of the hypothalamic-pituitary-adrenal (HPA) axis. The experiments described in Chapter Two aimed to test the proposal that neurons of the medial prefrontal cortex (mPFC) inhibit the HPA axis response to psychological stressors but not the HPA axis response to physical stressors. It was found that lesions of the infralimbic (IL) and prelimbic (PrL) regions of the mPFC had no effect on the HPA axis response to a psychological stressor (white noise exposure), but significantly increased the HPA axis response to a physical stressor (systemic interleukin-1β  [IL-1β ] administration). However, the mPFC does not project to the apex of the HPA axis, the corticotropin-releasing factor (CRF) cells within the medial parvocellular division of the paraventricular nucleus of the hypothalamus (mPVN). Therefore, we attempted to determine the brain pathways that might mediate the control exerted by the mPFC over the HPA axis response to IL-1β administration. It was found that mPFC lesions reduced the amount of IL-1β -induced neuronal activity in the ventral aspect of the bed nucleus of the stria terminalis (vBNST). The results of Chapter Two led us to investigate whether neurons of the vBNST regulate the HPA axis response to IL-1β administration. The experiments detailed in Chapter Three found that lesions encompassing both the dorsal and ventral aspects of the BNST increased baseline HPA axis activity but reduced the activity of this axis seen after systemic IL-1β administration. However, similar lesions had no effect on the HPA axis response to a psychological stressor (restraint). Since BNST lesions only altered the HPA axis response seen after IL-1β administration, the retrograde tracer cholera toxin subunit-b (CTb) was used to determine whether PVN-projecting BNST neurons are activated after exposure to this physical stressor. The results of this study demonstrate that a substantial proportion of neurons in the vBNST that are activated after IL-1β administration also project to the PVN. In Chapter Four, to follow on from the results presented in Chapters Two and Three, the retrograde tracer CTb was used to determine whether any of the BNSTprojecting neurons of the mPFC are activated by systemic IL-1β administration. When CTb was iontophoretically deposited into the BNST it was found that none of the BNST-projecting neurons in the mPFC were activated after IL-1β administration, suggesting that mPFC control over the vBNST might involve a polysynaptic pathway. Since neurons of the central amygdala (CeA) may influence the HPA axis response to IL-1β administration via the vBNST, we also determined whether BNST-projecting neurons of the CeA were activated after IL-1β  administration. Analysis revealed that only a very small proportion of the CeA neurons activated after IL-1β administration project directly to the BNST. However, the nature of the separation between the IL-1β activated neurons and the BNST-projecting neurons of the CeA has led us to suggest a pathway of disinhibition that would allow the vBNST to act as a relay between the CeA and the HPA axis. Chapter Five of this thesis examined the effect of BNST lesions on the level of activity seen in catecholamine cell bodies of the ventrolateral medulla (VLM) and nucleus tractus solitarius (NTS) after IL-1β administration or restraint. Lesions encompassing both the dorsal and ventral aspects of the BNST reduced the number of activated catecholamine cells seen in the VLM and NTS after IL-1β administration. However, similar lesions of the BNST had no effect on the number of activated catecholamine cells seen in these brainstem regions after restraint. Further to these results, retrograde tracing experiments revealed that none of VLM- or NTS-projecting neurons in the BNST were activated after IL-1β administration. Therefore, it appears that the BNST might regulate the IL-1β -induced activity of catecholamine neurons of the VLM and NTS via an indirect projection. It is well known that glucocorticoids, the end product of the HPA axis, feed back to inhibit the HPA axis. However, it has been suggested that the brain pathways regulating the HPA axis response to a psychological stressor are susceptible to glucocorticoid-mediated feedback inhibition, while those regulating the HPA axis response to a physical stressor are not. The experiments detailed in Chapter Six were designed to test this proposal. It was found that corticosterone administered 1 h before IL-1β administration did not alter the HPA axis response to this physical stressor. Also, the administration of corticosterone 1 h before the onset of either white noise or airpuff also had no effect on the HPA axis responses to these two psychological stressors. Therefore, it appears that, at least in the time frame investigated, the brain pathways regulating the HPA axis response to physical and psychological stressors can both display insensitivity to glucocorticoid-mediated feedback inhibition. The failure of glucocorticoids to inhibit the HPA axis response to stressor exposure raises interesting questions about the nature of negative-feedback inhibition. In the final experimental chapter, Chapter Seven, the effects of systemic apomorphine (APO), an agonist of both D1 and D2 dopamine receptor subtypes, on the HPA axis response and neuronal activity seen after either a physical or psychological stressor were examined. It was found that, while the administration of APO alone had no effect on the activity of the HPA axis, administration of APO potentiated the HPA axis response to IL-1β administration. In contrast, administration of APO did not affect the HPA axis response to white noise exposure. Analysis of the neuronal activity seen in response to IL-1β administration showed that APO, while having no affect on the amount of neuronal activity seen in a number of limbic structures, increased the amount of catecholamine cell activity seen in the NTS after this stressor. These results suggest that APO may potentiate the HPA axis response to a physical stressor via brainstem catecholamine neurons of the NTS; a result of particular relevance given the impending use of systemic APO, clinically, as a treatment for erectile dysfunction. Overall, the experiments presented in this thesis have contributed to our knowledge of how the HPA axis response to an acute stressor exposure is regulated. Since over-activation of the HPA axis has been implicated in the aetiology of a number of human diseases, there is considerable interest in the development of pharmacological therapies to regulate the HPA axis response to stressor exposure. The results presented in this thesis may have important implications for the development of these therapies.

Topic: Stress Responses and Cortisol
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences