Das Potential kognitiv-technischer Systeme wird zunehmend in der Medizin erkannt und genutzt. Kognitiv-technische Systeme interagieren autonom und unterstützen ihre Nutzer durch intelligentes Wahrnehmen, Erkennen und Handeln. Die Erforschung und Entwicklung kognitiv-medizintechnischer Systeme, als hilfreiche und unterstützende Assistenten und Experten, zielt auf eine Optimierung patientenspezifischer Diagnosen und individueller Therapien in unterschiedlichen Fachdisziplinen der Medizin. Innerhalb dieses Projekts, gefördert durch das Margarete-von-Wrangell Habilitationsprogramm, werden einzelne Komponente für ein automatisiertes intelligentes medizintechnisches System für die nicht-invasive kardiovaskuläre Prävention konzipiert und entwickelt. Dabei wird der Zusammenhang zwischen emotionalem Stress und kardiovaskulären Risiken untersucht. Kognitiv-technische Systeme, die stresshafte Emotionen automatisch verarbeiten, frühzeitig erkennen und intelligent interpretieren, sind besonders in der Medizin eine wertvolle diagnostische Unterstützung für die Risikoanalyse und zielen auf eine Verbesserung der Versorgungsqualität der Patienten. Die Verarbeitung, Erkennung und Interpretation der emotionalen und stresshaften Zustände ist dabei sensorgestützt und basiert auf die Verarbeitung und Analyse von Biosignalen sowie, je nach Kontext, auf die multimodale Sensorfusionierung und Datenanalyse. Dabei kommen Methoden des Maschinellen Lernens zum Einsatz.

2015 - 2022

Margarete von Wrangell Habilitationsprogramm, MWK Baden-Württemberg

Inflammatory disorders, such as Crohn's Disease (CD) and Ulcerative Colitis (UC) represent a major health concern, particularly in Western societies, with a life-time prevalence of approximately 0.1%. In addition to limiting quality of life due to abdominal cramps and pain, diarrhea, bloody stools, ulceration, fever, tiredness and other socially-unacceptable symptoms, inflammatory bowel disorders (IBD) are further linked to an increased risk for developing inflammation-related colorectal cancer (CRC).

The pathogenesis of IBD is still not completely understood. It is generally accepted that IBD has a complex and multi-factorial etiology, involving genetic and environmental factors, which are in turn associated with a dysregulation of the mucosal immune system. One environmental factor that is often discussed in this context during the last decades is the perceived level of life stress. Interestingly, available data suggest IBD to be rather associated with hypocortisolism than hypercortisolism.

In line with this hypothesis, we could already show that 19 days of chronic subordinate colony housing (CSC) not only result in basal evening hypocorticism but also reliably induce spontaneous colonic inflammation (Reber et al., 2007 PNEC; Reber et al., 2008 Stress; Reber et al., 2011 BBI; Reber, 2012 PNEC; Reber, 2016 PNAS; Fig. 5). The latter is causally mediated by a pronounced rise in CORT during the initial phase of CSC, preceding later development of hypocorticism and GC resistance, as well as by an increased bacterial translocation as consequence of disturbed colonic barrier functions. CSC-induced colitis is indicated by an increased histological damage score (Fig. 5), which is first detectable after 14 d of CSC, and increased numbers of colonic macrophages, dendritic and Th cells, and cytokine secretion from isolated lamina propria mononuclear and mesenteric lymph node cells, the latter lasting at least until day 8 following CSC termination. In addition, CSC mice show a pronounced reduction in the percentage of Treg cells in peripheral lymphoid organs (Schmidt et al., 2010 BBI), likely contributing to an overall increased inflammatory state and, consequently, to spontaneous colitis development.

Intriguingly, we just recently could show that CSC results in a pronounced expansion of enterohepatic helicobacter species (EHS) in the intestinal microbiome (Reber et al., 2016 PNAS) and that CSC-induced colitis does not develop under specific-pathogen-free (SPF) conditions (Langgartner et al., 2016 BBI), suggesting that translocation of certain pathobionts instead of commensal gut bacteria is critically required for development of stress-induced intestinal pathologies. Of note, stress-protective effects of M.vaccae pre-immunization were not mediated by preventing the colitogenic shift in the intestinal microbiome following CSC, but by inducing intestinal Treg cells, which in turn prevented that the colitogenic microbiome translates into colonic inflammation and tissue damage. Importantly, our data further indicate that CSC-induced HPA axis changes (i.e. hypocorticism) is not critically involved in CSC-induced colitis development (Reber et al., 2016 PNAS; Langgartner et al., 2016 BBI).

The value and clinical relevance of this interdisciplinary project has been acknowledged with the "Ismar-Boas Preis 2007" for excellent work in the field of gastroenterology from the "Deutsche Gesellschaft für Visceralchirurgie (DGVS)".

Currently we are investigating whether i) CSC-induced spontaneous colitis is causally involved in the increased anxiety state detected following CSC exposure and ii) colitis severity depends on the coping strategy of an individual shown during CSC exposure.

Reber et al., 2006, 2007 Endocrinology; Reber et al., 2008 Stress; Reber et al., 2011 BBI; Langgartner et al., 2017 BBI; Peterlik et al., 2017 BBI; Armacki et al., 2018 JCI; Langgartner et al., 2018 Front Beh Neurosci.

intramural funding; previously funded by the DFG grant RE-2911/2-1

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.

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.

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

Chronic stress, in particular chronic psychosocial stress, is a risk factor in the etiology of various psychopathologies including general and social anxiety-related disorders. However, despite substantial research efforts in the last decades, the etiology of such stress-associated disorders remains poorly understood. As we previously have shown that CSC exposure increases both general- and social anxiety-related behavior (Slattery et al., 2012 PNEC), we have an animal model in hands allowing us to investigate in detail the underlying mechanisms. Thereby we focus the autonomic nervous system by using telemetry (Fig. 6 right panel), as well as on the assessment of neuro-inflammatory processes by Taqman PCR and immunohistochemistry. Interestingly, while the CSC-induced increase in general anxiety was long-lasting and still detectable 10 days following termination of CSC, social deficits were only transient, suggesting different neuronal mechanisms to be involved in these behavioral stress consequences. As accumulating evidence supports the idea that the sensory, in particular the visual, contact to a rodent conspecific during/following stressor exposure is able to induce a stress response in the observer animal, we also consider different sensory contact modalities to the stressor (last dominant mouse during CSC) following termination of the physical stressor exposure (Fig. 6 left and middle panel).

University intern Budget

Chronic psychosocial stress is a major burden of modern life and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Given that many of these disorders, including posttraumatic stress disorder (PTSD), are further associated with decreases in regulatory T cells (Treg), it is likely that a failure of immunoregulation promotes an over-reacting of the inflammatory stress responses and, thus, predisposes an individual to develop stress-related disorders in general, and PTSD in particular. Importantly, adverse consequences of psychological stress/traumatization during adulthood on mental health vary strongly between individuals, with some individuals being more resilient than others. Given the above detailed link between an over-reacting inflammatory stress/trauma response and the development of stress-associated disorders including PTSD, all genetic and environmental factors facilitating an adult’s immune (re-) activity are, therefore, likely to increase their stress/trauma vulnerability. In line with the hypothesis that one such factor is early life adversity, psychosocial stress has been shown repeatedly to activate peripheral inflammatory pathways, and to do so more robustly in people with histories of early life abuse and/or neglect who are also at significantly heightened risk for PTSD development in response to trauma exposure in adult life. Importantly, we have further shown in male mice 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. As own unpublished preliminary mouse data presented in this grant proposal further indicate that early life adversity (=first hit) has negative behavioral consequences and increases the vulnerability to chronic stress during adulthood (=second hit) in a sex dependent manner and that these negative stress effects can be ameliorated/prevented by repeated s.c. M. vaccae administrations, we in the current proposal will investigate the detailed mechanisms (Treg counts and functionality, brain microglia activation and IL-4 signaling, peripheral and central parasympathetic anti-inflammatory reflex activity, role of intestinal microbiome) underlying both the negative stress consequences and the protective effects of M. vaccae. Together, these studies may help to develop novel therapeutic approaches, specifically the use of biological immunomodulators with immunoregulatory potential, to attenuate or prevent long-term adverse consequences of multiple psychosocial stressors occurring at different phases of life.

Veenema, Reber et al., 2008 Endocrinology; 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.

German Research Foundation, RE 2911/21-1

It is the major aim of this Project, in collaboration with the labs of Prof. Dr. Christopher Lowry (University of Colorado, Boulder, USA) and Prof. Dr. Steffen Stenger (Department of Medical Microbiology and Hygiene, Ulm University Medical Center, Ulm, Germany) to promote resilience against stress-related somatic and affective pathologies by treating mice either prior to or following/during stress/psychosocial trauma exposure with a heat-killed preparation of immunoregulatory "old friends from mud and soil", including Mycobacterium vaccae NCTC 11659, M. vaccae ATCC15483^typestrain, and to combine this with various ex vivo and in vitro approaches to reveal the underlying mechanisms.

Major findings so far:

-Preparations of M. vaccae , regardless of their administration route, have stressprotective properties in male mice.

-Preparations of various rapid growing mycobacteria (RGM) promote immunoregulation in vitro.

-Preparations of M. vaccae promote active stress coping in male mice. 

-Preparations of M. vaccae have anxiolytic effects, and prevent development of spontaneous and aggravation of chemically-induced colitis in male mice.

-Effects of M. vaccae on anxiety and colitis in male mice, but not on "stress coping", were mediated via Treg cell induction.

Office of Naval Research Global, N00014-17-S-B001; Grant12274897 (M. vaccae) & intramural funding (other RGMs)

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.