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: intramural funding; previously funded by the DFG grant RE-2911/5-1

Literature: Reber et al., 2007 Endocrinology; Uschold-Schmidt et al., 2012, PNEC; Füchsl et al., 2013 PLOSOne, Stress; Uschold-Schmidt et al., 2013 J Endocrinol; Bartlang et al., 2014 Chronobiol Int; Füchsl et al., 2014 Endocrinology; Langgartner et al., 2015 Front in Psychiatry; Füchsl et al., 2016 PLOSOne; Koch et al., 2016 J Endocrinol; Langgartner et al., 2017 Stress; Langgartner et al., 2020 PNEC.

Although a strong association between psychiatric and somatic disorders is generally accepted, little is known regarding the interrelation between mental and skeletal health. While depressive disorders were shown to be strongly associated with osteoporosis and increased fracture risk, evidence from post-traumatic stress disorder (PTSD) patients is less consistent. Given that the CSC paradigm induces a behavioural, physiological and immunological phenotype closely related to what is known from PTSD patients, we hold a stress model in hand allowing us to investigate the possible mechanisms underlying disturbance of bone metaolism in PTSD patients.

Therefore, in collaboration with the group of Prof. Anita Ignatius (Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm), here mainly with Dr. Melanie Haffner-Luntzer, we are investigating in male mice whether and how chronic psychosocial stress induced by the chronic subordinate colony housing (CSC) model influences bone metabolism and fracture healing. Besides typical physiological stress consequences, like increased adrenal weight, decreased thymus weight and increased anxiety-related behaviour, our findings indicate a disturbed long bone development as well as compromized fracture healing in chronically stressed compared to unstressed control mice, which are both likely to be at least in part mediated by disturbance of endochondral ossification processes (Förtsch et al., 2017 DMM; Haffner-Luntzer et al., 2019 PNAS). These findings offer possibilities for clinical translation in patients suffering from PTSD and fracture.

The value and clinical relevance of this interdisciplinary project has been acknowledged with the "ORS Travel Award 2018" from the "Deutsche Gesellschaft für Orthopädie und Unfallchirurgie  (DGOU, Germany Scoiety for Orthopaedics and Trauma)" and the "ISFR Award 2019" from the "Orthopaedic Research Society (ORS) for Dr. Melanie Haffner-Luntzer (Institute of Orthopedic Research and Biomechanics, Prof. A. Ignatius, University Medical Center Ulm).

Funding: German Research Foundation, Project B06 within the CRC 1149, INST 40/599-1, PIs  Prof. Dr. Stefan Reber Ulm and Dr. Melanie Haffner-Luntzer;  Gender Equality Funding of Dr. Melanie Haffner-Luntzer provided by the DFG-funded CRC1149; University intern budget of SOR; previously funded by the Innovation fond of the medical faculty of the Ulm University.

Literature: Foertsch et al., 2017 Disease Models & Mechanisms; Haffner-Luntzer, Foertsch et al., 2019 PNAS; Tschaffon et al., 2022 Endocrine. 

The postpartum period represents a time with high risk for women to develop mood and anxiety disorders, such as postpartum anxiety (PPA) and postpartum depression (PPD). PPA and PPD, often comorbid, lead to impaired maternal-infant attachment during the critical stages of early brain development and increase the risk of the offspring developing long-term behavioural and emotional problems, including increased vulnerability to mental illness. Although, both the physiological and immunological adaptations that occur throughout the peripartum period and risk factors for PPA and PPD, including stress during pregnancy, are well-known, the mechanisms underlying postpartum mood and anxiety disorders remain elusive. Numerous hypotheses have been postulated to underlie these disorders, such as disruption of ongoing peripartum-associated brain plasticity. Another, less explored hypothesis is that constant immune activation and chronic low grade inflammation in the mother might underlie post-partum mood disorders as well as an increased risk for the offspring to develop somatic and affective disorders later in life, especially when facing chronic severe life stressors (=second hit). Intriguingly, chronic stress interferes with hippocampal neurogenesis and leads to chronic low-grade inflammation. Importantly, and consistent with the above detailed role of immune activation in the development of mood disorders, we have recently shown that immunoregulation induced by repeated preimmunization (s.c.) with a heat-killed preparation of Mycobacterium vaccae (National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, was able to prevent stress-induced anxiety, spontaneous colitis, and aggravation of dextran sulfate sodium (DSS)-induced colitis, a murine model of inflammatory bowel disease. Therefore, in this proposal we aim to determine in collaboration with Prof. Dr. David Slattery (Laboratory for Translational Psychiatry, Frankfurt University Medical Center, Goethe University, Frankfurt, Germany) whether M. vaccae given prior to mating can protect the dam from the detrimental effects of pregnancy stress on behaviour, HPA axis, inflammatory responses and hippocampal neurogenesis. Further, we will determine whether this can also protect the offspring from the effects of prenatal stress and/or subsequent exposure to
chronic psychosocial stress in adulthood. Taken together, this project will determine whether immunoregulatory approaches can protect both the mother and her offspring from consequences of subsequent chronic stress during pregnancy.

Funding: German Research Foundation, RE 2911/23-1; PIs S.O. Reber (Ulm) and D.A. Slattery (SL141/6-1, Laboratory for Translational Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe University Frankfurt)

Literature: Reber et al., 2016 PNAS; Lowry et al., 2016 Cur Environmental Health Rep; Amoroso et al., 2019, 2020 BBI; Amoroso et al., 2021 Int J Mol Sci.