Project 3

Chronic psychosocial stress and HPA axis function

Exposure to acute stressful stimuli leads to the activation of both the sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis and, consequently, to the systemic release of catecholamines and glucocorticoids (GCs). These stress hormones, in turn, trigger physiological alterations enabling an organism to adjust to the new situation and to show an adequate behavioural response. However, if the stress systems are activated over a prolonged period of time, chronically-elevated levels of plasma GC can promote development of somatic and affective disorders. Thus, it is adaptive for an individual to habituate possibly fast to prolonged and non-life-threatening homotypic stressors, but to stay responsive to novel and possibly dangerous challenges.

Interestingly, mice exposed to 19 days of chronic subordinate colony housing (CSC) seem to exactly implement this principle at the level of the adrenal glands. CSC mice show unaffected basal morning corticosterone (CORT) levels despite a pronounced increase in adrenal mass (Reber et al., 2007 PNEC), likely mediated by an attenuation of adrenal corticotrophin (ACTH) responsiveness. The latter was indicated by a reduction of adrenal in vitro CORT secretion in response to various concentrations of ACTH (Reber et al., 2007 PNEC; Uschold-Schmidt et al., 2012 PNEC; Reber et al., 2016 PNAS; Langgartner et al., 2016 BBI). However, in contrast to the in vitro situation, CSC mice show an even more pronounced CORT response to an acute heterotypic stressor exposure (elevated platform, EPF; Uschold-Schmidt et al., 2012 PNEC) compared with respectively treated SHC mice. This is in line with recent data showing an increased availability and mobilization capacity of the CORT precursor molecule cholesterol in CSC compared with SHC mice, possibly contributing to their increased in vivo CORT response during acute heterotypic stressor exposure (Füchsl et al., 2013 Stress). Together, these data clearly argue against a breakdown of adrenal functioning during CSC, but support the hypothesis that a reduction of adrenal ACTH responsiveness during times of chronic stress prevents prolonged hypercorticism and, thus, is adaptive and beneficial. Of note, CSC mice do not develop any signs of depressive-like behaviour (Slattery et al., 2012 PNEC), which can be induced by chronically treating rodents with CORT.

The value and clinical relevance of this project has recently been acknowledged with the "Ernst and Berta Scharrer Prize (German Society of Endocrinology: 'This price awards outstanding original studies in the field of neuroendocrinology.').

Unravelling the underlying mechanisms might help to preventively or therapeutically facilitate stress resilience. We are currently investigating whether i) an additional factor present during heterotypic stressor exposure, and not during in vitro stimulation, rescues adrenal ACTH sensitivity, or itself acts as CORT secretagogue in chronically stressed CSC mice, ii) what this factor might be, and iii) whether or not these HPA axis changes depend on the coping strategy during CSC exposure.

Funding: University intern budget; previously funded by the DFG grant RE-2911/5-1