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

For detailed references see...

DFG, intramural funding

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 preclinical project, to promote resilience against stress-related somatic and affective pathologies in male and female mice by repeated subcutaneous (s.c.), intranasal (i.n.) or intragastric (i.g.) administrations of heat-inactivated preparations of immunoregulatory "old friends from mud and soil", including Mycobacterium vaccae NCTC 11659, M. vaccae ATCC 15483typestrain and M. aurum DSM 33539, and to understand the underlying mechanisms.

Background: Epidemiological data provide strong evidence for a steady rise in the incidence of many stress-associated psychosomatic disorders in developed countries since the 1950s.(1-10) Although the underlying mechanism is not clear, decreased immunoregulation, resulting from decreased numbers of regulatory T cells (Tregs),(11, 12) is likely to play a role. Furthermore, as less people in rural compared with urban areas suffer from stress-associated somatic and mental disorders,(13-19) it is likely that a reduced exposure, especially during early life,(20) to microorganisms with which mammals co-evolved (=Old Friends), at least in part accounts for immunoregulatory deficits, increased stress-induced inflammation and disease prevalence in modern industrialized urban areas.

DFG, intramural funding

Reber SO, Langgartner D, Foertsch S, Postolache TT, Brenner LA, Guendel H, et al. (2016): Chronic subordinate colony housing paradigm: A mouse model for mechanisms of PTSD vulnerability, targeted prevention, and treatment—2016 Curt Richter Award Paper. Psychoneuroendocrinology. 74:221-230. For detailed references see ...