Limbic brain pathways that suppress hormonal stress response

When humans are exposed to frequent or prolonged periods of psychological stress, their chances of developing a psychiatric or physical illness are significantly increased. One of the causes of this effect is believed to be an enhanced adrenocortical hormone secretion that accompanies the stress response. This secretion is controlled by the hypothalamic-pituitary-adrenal (HPA) axis and excessive HPA axis activity has been linked to disorders such as immunosuppression, depression and hypertension. There are two obvious strategies that one could take to reduce HPA responses in situations where individuals are at risk due to unavoidable exposure to high levels of stress. The first is to map the pathways that stimulate HPA responses to stress and develop drugs that block their activity. The second and perhaps more exciting alternative is to develop drugs that target stress-protective mechanisms and maximise their activity. Recent research suggests that one such mechanism may reside in distinct limbic areas such as lateral septum (LS) and that it operates by limiting the HPA axis response to stress. Therefore, the aim of the proposed project is manifold. Firstly, to investigate whether the LS possesses a mechanism that selectively limits the HPA axis response to psychological stress. Secondly, to investigate whether this mechanism operates directly by activation of GABAergic projections from the LS to the hypothalamic paraventricular nucleus or indirectly by suppressing the activity of amygdala and brainstem catecholamine neurons that normally drive the HPA axis response to psychological stress. Thirdly, to investigate the possible involvement of septal neurotrophic factors such as BDNF in this HPA-inhibitory mechanism and fourthly, to investigate whether this HPA inhibitory mechanism operates by a glucocorticoid mediated feedback mechanism and further whether it is under the control of a described serotonergic input to the LS. The ultimate aim of the present project is to learn how the activity of this protective mechanism can be pharmacologically enhanced to provide improved protection from the deleterious effects of exaggerated psychological stress exposures, which are an important and growing problem in our modern world.

It is generally accepted that stress influences many biological functions and is causally involved in various physiological and mental dysfunctions. One of the major goals of the present research project was to identify brain mechanisms that regulate stress and anxiety responses and to determine brain regions that detect and trigger many of the behavioural, autonomic and endocrine responses elicited by stress exposure. The main focus in our project was to form a better understanding of the complex control systems regulating the hypothalamic-pituitary-adrenal (HPA) axis, the main hormonal stress system. Therefore, we were able to identify a stress inhibitory pathway localised within the limbic septal area especially the lateral part of the septum (LS) that suppress neuroendocrine stress responses. In addition to HPA axis regulation we found that this area modulates stress coping behavior in the forced swim test, a widely used test to assess antidepressant properties of drugs. Ablation of this region was associated with an increase of passive coping (behavioural despair) and a reduction of active coping behaviours. Thus, our data strengthen the suggestion that the LS belongs to a behavioural inhibition system responsible for promoting the expression of relevant active behavioural responses in aversive and stressful situations. Next we examined whether this septal area is involved in the glucocorticoid-mediated negative feedback mechanism, as a high density of glucocorticoid receptors was found in the LS. However, we found that this HPA inhibitory mechanism of the LS is not mediated via septal corticosteroid receptors as intraseptal glucocorticoid and mineralocorticoid receptor blockade failed to change HPA axis activity. In a further series of experiments we investigated the neurochemical mechanisms regulating stress and anxiety responses in the LS. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we were able to observe a stress-induced release of the putatively anxiogenic neuropeptide substance P in the LS. Furthermore, our data show that blockade of septal substance P-receptors (via administration of a selective NK1 antagonist) reduces passive and increases active coping strategies in the forced swim test indicating an antidepressant-like effect. In addition, there is also some evidence that the septal serotonergic system plays a crucial role in mediating behavioral and physiological stress responses. Therefore, we investigated whether pharmacological manipulation of the serotonergic system in the LS affects basal HPA axis activity or HPA axis responses to psychological stress. Interestingly, our data indicate a critical role of septal 5-HT1A receptors in mediating stress-preventing actions of the LS as activation of septal 5-HT1A receptors inhibits neuroendocrine and facilitates behavioral stress responses. Taken together, our results show that the LS plays an important role in promoting a HPA-axis inhibitory mechanism and active coping strategies during stress exposure. Thus, these data provide some evidence about the neuronal mechanisms that might be activated to protect the organism from the excessive secretion of stress hormones.