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Forschungsarbeit

Daytime-dependent effects of chronic / intermittent stressor exposure on behaviour, physiology, immunology, and the internal clock

by Manuela Bartlang (02.04.2012)

The word stress is used by almost everybody during everyday life (e.g. someone is stressed out, stressful relationship, etc.). The “father of stress”, Hans Seyle, defined the term stress as a “non-specific response of the body to any physical demand”, which in turn he called “stressors” (Selye 1975). Stressors can be classified according to the following categories: Quality (positive vs. negative), type (physiological vs. psychological), and duration (acute vs. chronic). Acute stress (minutes to hours) leads to vital adaptive responses that help an individual cope with the situation.

However, since the demands on individuals in today’s highly-demanding and challenging society can be continuous, stress perception, mostly of psychosocial nature, also escalates. This chronic stress can result in several somatic illnesses, like cardiovascular diseases and cancer, as well as in affective disorders such as depression and anxiety disorders (Reber 2011). Moreover, as psychosocial stress is probably the most potent and naturalistic type of challenge (Koolhaas et al. 1997), stress researchers have incorporated this fact into animal models. One such model is social defeat (SD), which involves an animal being defeated by a larger, dominant conspecific. Furthermore, stress is one of the factors that decreases the cortisol awakening response (CAR) via a concomitant 75% increase of basal plasma cortisol during the dark phase. The CAR is partly controlled by the endogenous clock and the reduced response indicates that the circadian clock is affected by stress exposure (Meerlo et al. 1997).

This finding indicates that circadian/endogenous rhythms, such as for instance cortisol and body temperature rhythms, are influenced by stress exposure. The term “circadian rhythms” describes internal rhythms with a periodicity of approximately 24 hours generated by endogenous clocks that rhythmically express clock genes (e.g. Per1, Per2) and are synchronized with the environment. All organisms possess these endogenous clocks and, thereby, can adapt to the daily rhythm of changes in light intensity and temperature. Acute disruptions of the circadian system are a common experience in today’s society, e.g. in form of jet lags, and are associated with symptoms of fatigue, disorientation, and insomnia, but do not normally have profound consequences on health. In contrast, chronic disruptions are believed to have significant adverse health consequences on peripheral organs, particularly in the development or aggravation of cardiovascular diseases (Martino et al. 2008). Besides somatic disorders, mental illnesses, including major depression, are also thought to arise from disturbed circadian rhythms. In mammals, the central circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which acts as the “master clock”, whereas peripheral components are present in virtually all organs and function as “slave clocks” (Takahashi et al. 2008; Fig. A).

The SCN is entrained to the environment by external cues with the 24 hour light-dark cycle representing the strongest Zeitgeber (Fig. A). In order to prepare humans/animals for the onset of activity, the SCN activates the hypothalamus-pituitary-adrenal (HPA) axis, part of the neuroendocrine system and critically involved in stress reactions (Fig. B). This activation of the HPA axis results in a diurnal rhythm of circulating glucocorticoids (GC) in the body, which exhibit their peak in the early morning in day-active species (i.e. humans) or in the early evening in nocturnal animals (i.e. rats and mice). The SCN belongs to the rare areas that do not express GC receptors, which means that the “master clock”, unlike peripheral clocks, maintains its intrinsic rhythm independent of stress-induced GC secretion. Therefore, the SCN can reset the peripheral clocks to their original phase after termination of stress exposure. While this applies for acute stressful situations (Balsalobre 2002), it is presently unknown if this is also true under chronic stress situations.

As it was shown that restraint stress during the active phase seems to be more severe than during the inactive phase (Perez-Cruz et al. 2009), my studies at the University of Regensburg under the supervision of Prof. Inga Neumann and Prof. Charlotte Förster (University of Würzburg) aimed to elucidate (a) whether the circadian clock modulates stress severity in a daytime-dependent manner and (b) whether psychosocial stress affects the circadian clock in dependence of the time of stress exposure. Therefore, male mice were exposed to psychosocial stress in the form of 19 daily SD either during their inactive phase (i.e. in the morning) or during their active phase (i.e. in the evening). After the end of the stress paradigm, we investigated peripheral physiological effects and central protein PER2 expression in the SCN in addition to behavioural and immunological effects. Independent of the time of stress exposure, alterations in behaviour, physiology, and immunology were observed following SD. Interestingly, it also transpired that the daytime of stress exposure had pronounced and, for some parameters, even opposite effects on a variety of investigated parameters. In general, peripheral and central physiology was more affected following SD applied during the light, meaning inactive phase of the animals, indicated by a marked reduction of body weight gain during the 19 days of SD and increased adrenal gland weight after termination of SD. Furthermore, the area containing PER2 positive neurons in the SCN was expanded in the anterior-posterior direction following SD during the inactive phase.

In contrast, a reduction in activity during the active phase, an aggravation of chemically-induced colitis and a behavioural phenotype typing towards depression was observed following SD during the dark, meaning active phase of the animals. One can conclude that mice exposed to SD in their inactive phase show a more active coping style and no signs of depressive-like behavior. Therefore, it is possible that the physiological changes seen following SD during the light phase are adaptive and beneficial, and a lack of physiological adaptation is maladaptive and may result in affective and somatic disorders. Currently, this hypothesis is under investigation, as I am continuing this work as a PhD student in the same laboratory.

Interaction between the circadian system (A) and the stress system (B)

A: The mammalian circadian timing system is composed of a hypothalamic pacemaker, the SCN, an alignment of SCN-generated circadian physiology outputs, and molecular clocks in the cells of peripheral tissues (Levi et al. 2009).[Bildunterschrift / Subline]: A: The mammalian circadian timing system is composed of a hypothalamic pacemaker, the SCN, an alignment of SCN-generated circadian physiology outputs, and molecular clocks in the cells of peripheral tissues (Levi et al. 2009).
B: Functional anatomy of HPA axis; the SCN signals to the paraventricular nucleus in the hypothalamus in a rhythmic fashion, thereby finally inducing the secretion of GC from the adrenal cortex in a daily fashion (adapted from Turnbull and Rivier 1999).[Bildunterschrift / Subline]: B: Functional anatomy of HPA axis; the SCN signals to the paraventricular nucleus in the hypothalamus in a rhythmic fashion, thereby finally inducing the secretion of GC from the adrenal cortex in a daily fashion (adapted from Turnbull and Rivier 1999).

Stationen
  • seit 01/2011
  • Doktorarbeit am Arbeitskreis von Prof. Dr. Charlotte Förster (Universität Würzburg) in Zusammenarbeit mit dem Arbeitskreis von Prof. Dr. Inga Neumann (Universität Regensburg), Förderung durch die Deutsche Forschungsgemeinschaft
  • 10/2009 bis 07/2010
  • Master-/Diplomarbeit am Arbeitskreis von Prof. Dr. Inga Neumann
  • 07.12.2010
  • Diplom-Biologin Univ.
  • 11.10.2010
  • Master of Science
  • 06.08.2009
  • Bachelor of Science
  • 09/2008 bis 07/2010
  • Masterstudium “Experimental and Clinical Neurosciences” (gefördert durch das Elitenetzwerk Bayern) an der Universität Regensburg
  • 10/2004 bis 12/2010
  • Studium der Biologie (Diplom) an der Universität Regensburg

Auslandserfahrung
  • 04/2009 bis 06/2009
  • Forschungsaufenthalt am Karolinska Institut, Stockholm (Schweden); Kooperationsprojekt mit der Arbeitsgruppe „Circadian Rhythm“, Abteilung Neurologie
  • Master of Science

Preise und Auszeichnungen
  • 09/2009
  • Eröffnungsvortrag für den Elitestudiengang „Experimental and Clinical Neurosciences“ 2009-2011
  • 12/2009
  • MLP-Stipendium