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AuthorNold, Verenadc.contributor.author
Date of accession2022-10-04T09:41:06Zdc.date.accessioned
Available in OPARU since2022-10-04T09:41:06Zdc.date.available
Year of creation2021dc.date.created
Date of first publication2022-10-04dc.date.issued
AbstractThe body constantly needs to adjust physiologic processes according to current environmental influences. Such influences could be the cycle of day and night or the appearance of a challenging situation. Glucocorticoids play a central role in these adjustments. A sudden increase in glucocorticoid levels in the morning is an integral part of the circadian rhythm and human awakening response, while an on demand secretion of glucocorticoids is typical for the stress response. Even though the rise in glucocorticoids is rather unspecific, the Psycho-Immune-Neuro-Energy (PINE) network responds with a variety of nuanced reactions that are modulated by context, timing, and dose. This flexibility is essential for health and well-being since it allows adaptation to the present situation and thus resolving the associated stress. Persisting stress due to maladaptation is thought to cause wear and tear in the long run. Resistance to glucocorticoid signalling and decreased glucocorticoid dynamics are commonly observed symptoms in a variety of disorders that have been associated with chronic stress. Moreover, co-morbid symptoms often reflect alterations in several components of the PINE network. Maintaining or restoring the flexibility of the PINE network to respond to glucocorticoids could therefore be a preventive or curative measure against stress-associated disorders and co-morbid symptoms. To this end, a better understanding of the multiple interactions between the components of the PINE network and the influence of internal and external modulators of glucocorticoid signalling is required. The goal of this thesis was to study components of the PINE network through encounters with different stress paradigms with the aim to better resolve early changes indicating a critical transition in the stress response system towards disorder. While stress models do not lead to a (psychiatric) pathology per se, finding biomarkers of a type of prodromal phase, where adaptive or maladaptive responses to stress can be observed, might be possible. In study I, the effects of social isolation during adolescence combined with unpredictable chronic mild stress during early adulthood on the PINE network were investigated in male Wistar Kyoto rats. An activation of the immune system in terms of blood cellular composition was observed, but with no resulting changes in cytokine levels. In the hippocampus, a brain region responsible for memory formation, improved mitochondrial respiration and increased mitochondrial density were observed. An elevated metabolism of tryptophan was demonstrated by measuring plasma and cerebrospinal fluid (CSF) levels of tryptophan catabolites (TRYCATs). The observed changes indicated lower neurostimulation via TRYCATs. In the pre-frontal cortex (PFC), a brain region responsible for decision-making, and in the hippocampus, a reduced expression of genes related to neuronal activity was measured. In total, the observed changes in the PINE network in response to the applied mild stressors indicated adaption to the situation. However, the putatively reduced activity of the central nervous system (CNS) and the observed lethargy of the animals could lead to decreased responsivity and adaptive capacity on long-term. Rats that were exposed to unpredictable chronic mild stress for a prolonged time showed depressive-like behaviours in the sucrose-preference and forced-swim tests. Given that the PINE network is strongly regulated by glucocorticoids, studies II and IV investigated a single nucleotide polymorphism (SNP) in FKBP5, a gene encoding for an inhibitor of glucocorticoid receptor (GR) maturation. The genetic variant rs1360780 with thymidine instead of cytosine was shown to be stronger induced upon stress and is associated with an elevated risk to develop psychiatric, inflammatory, and metabolic disorders. These negative effects pre-dominantly occur in combination with aversive experiences during childhood. To study causal relationships between the risk and resilience variants of FKBP5, environmental influences, and well-being, Fkbp5 -humanized mice were generated and characterized within the scope of this thesis. Within study II, repeated separation from mothers and peers before weaning was used to induce early life adversity (ELA) in Fkbp5 -humanized mice and the e ects on social-, anxiety-, and activity-behaviour were analysed in adulthood. Males were less active than females and displayed lower levels of glucocorticoids. Female carriers of the resiliency-associated CG-allele responded to ELA with increased activity, while carriers of the AT-allele had a lower responsivity to novel environments irrespective of early life conditioning. In parallel to the behavioural diffrences, CG-allele carrying females had pronounced diurnal rhythms of glucocorticoids while female AT-allele carriers had a disrupted circadian rhythm, including elevated nadir glucocorticoid levels and no signi cant rise towards awakening. On a molecular level, AT- vs. CG-allele carriers showed lower expression of genes related to circadian entrainment in the hypothalamus, a brain region integrating nervous and endocrine signalling. The comparison between mice with undisturbed development and those exposed to ELA revealed that ELA in addition led to a lower expression of these genes and genes related to dopaminergic and endocannabinoid signalling in the hippocampus. Moreover, lower expression of genes related to synaptic communication in both brain regions but higher expression of genes related to mitochondrial energy production and metabolism was seen in AT- vs. CG-allele carriers. Viewed together the data suggests that changed communication within the brain could, via attenuated circadian entrainment, manifest in altered alertness and activity states that hinder AT- vs. CG-allele carriers to respond and adjust to novel situations. ELA may push AT-allele carriers further in that direction by modulating gene expression, but the functional differences in glucocorticoid rhythmicity and behaviour were already elicited by the genetic predisposition of carrying the AT-allele alone. To further define the role of energy production and consumption in discriminating AT- and CG-allele carriers with or without ELA is an interesting task for future research. Since the levels of TRYCATs have an impact on brain activity and are influenced by stress, the applicability of TRYCAT profiles as biomarkers for lifetime stress and decreased cognitive abilities was assessed. This was done in serum samples of healthy elderly humans at risk to develop neuro-cognitive disorders that were enrolled in study III. The levels of 3-hydroxy-kynurenine (3-HK), the precursor of the neuroactive quinolinic acid (QUIN), positively correlated with the number of stressful life events while QUIN negatively correlated with executive functions. To test whether physical and cognitive training would result in changes of the TRYCAT profiles, a 10-week intervention period was carried out and serum TRYCATs were assessed afterwards. After physical training, the levels of 3-HK decreased on trend level while after cognitive training the levels of 3-HK and of the anti-excitatory kynurenic acid (KYNA) decreased. However, no training-related effects on cognition were observed. Together, the findings could indicate that changes in cognition occur on a long-term basis while molecular changes manifest rather short-term. Whether TRYCAT profiling can be used as biomarker to monitor treatment success needs to be further investigated. In study IV, the acute transcriptional response of primary murine brain cells to glucocorticoids in the context of both human SNP versions, as well as putative reasons for cell-type dependent reactivity were determined. Baseline expression levels of Fkbp5 and Nr3c1, the gene encoding for the GR, suggested that neurons would rather be irresponsive to glucocorticoids since they expressed high amounts of Fkbp5 and low amounts of Nr3c1. In contrast, microglia and astrocytes expressed more Nr3c1 and less Fkbp5 than neurons, with microglia expressing more Fkbp5 than astrocytes. As to be expected from these findings, the transcriptional differences between the studied CNS cell types indicated that astrocytes responded the most to stimulation with glucocorticoids, followed by microglia and neurons. Moreover, the AT-allele was associated with a stronger induction of Fkbp5 than the CG-allele. While the acute induction of other glucocorticoid-responsive genes was not further influenced by the Fkbp5 genotype, potential effects on repeated or chronic stimulation with glucocorticoids require further investigation. Since astrocytes maintain the cerebral energy household, the findings of this study suggest that regulation of metabolism is a crucial part of the cerebral response to glucocorticoids. Furthermore, Fkbp5 -genotype dependent reactivity of astrocytes might contribute to differences in stress coping of rs1360780 SNP carriers, making astrocytes an interesting target for further research. This dissertation showed that internal and external factors comprising genetic make-up, lifetime experiences, and the current physiology influence the functioning of the PINE network, responsiveness to novel situations, and the presumably associated stress. These factors interact with each other, as well as with timing and dose, and can give rise to different coping strategies ranging from reduced receptiveness to increased activity. Dependent on the context, these strategies may be more or less effective in relieving stress. Thus, gene × environment interactions shape the individual resilience or vulnerability to stress-associated disorders. Although different models and stressors were used to investigate the effects of different factors influencing the PINE network, parallels in terms of increased metabolic readiness in the brain, decreased cognitive activity, and altered circadian rhythmicity were seen in the stress- and genetically-burdened groups. The matching of ndings across studies suggests that negative effects of stressors converge on similar pathways and could explain why multiple hits on these pathways can accumulate and synergise in worsening the outcome of the a ected individual. Moreover, the preservation of these critical pathways across species indicates that the used animal models are valid to study aspects of human pathomechanisms including altered glucocorticoid regulation exerting an impact on metabolism, CNS functioning, and the immune system. Taking actions against putatively negative effects of the repeatedly observed changes in the prodromal stage by optimizing resource allocation, establishing active and resting phases, and promoting exibility in the mental and behavioural repertoire could represent central treatment goals. Personalization of preventive or curative attempts that account for individual risk and resilience factor interactions by tackling alterations in the PINE network from several angles appears desirable to maintain or improve quality of life. This strategy may boost the effectiveness of existing treatments and help patients that are currently considered to be treatment-resistant. The results of this thesis imply promotion of physical activity and regulation of Fkbp5 and glucocorticoid dynamics, especially in astrocytes, to be promising treatment modalities. More research to enable stratification of patients or persons at risk into permissive treatment groups and to monitor and improve treatment effectiveness through optimal timing and contextualization of the interventions is needed.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
Has partKüster OC, Laptinskaya D, Fissler P, Schnack C, Zügel M, Nold V, Thurm F, Pleiner S, Karabatsiakis A, von Einem B, Weydt P, Liesener A, Borta A, Woll A, Hengerer B, Kolassa IT, von Arnim CAF Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway. Journal of Alzheimer's Disease. 2017; 59(3): 1097-1111. DOI: 10.3233/JAD-170447dc.relation.haspart
Has partNold V, Sweatman C, Karabatsiakis A, Böck C, Bretschneider T, Lawless N, Fundel-Clemens K, Kolassa IT, Allers KA Activation of the kynurenine pathway and mitochondrial respiration to face allostatic load in a double-hit model of stress Psychoneuroendocrinology Apr 23;107:148-159. DOI:10.1016/j.psyneuen. 2019.04.006.dc.relation.haspart
Has partNold V, Allers KA Consequences of Chronic Stress on the PINE Network Intech Open 2021 ISBN: 978-1-83969-138-6. DOI: 10.5772/intechopen.97149dc.relation.haspart
Has partNold V, Portenhauser M, Del Prete D, Koros E, Blasius A, Peleh T, Hengerer B, Kolassa IT, Slezak M, Allers KA Impact of Fkbp5 × Early Life Adversity × Sex in Humanized Mice on Multidimensional Stress Responses and Circadian Rhythmicity Molecular Psychiatry 2022 (epub ahead of print). DOI: 10.1038/s41380-022-01549-zdc.relation.haspart
Has partNold V, Richter N, Hengerer B, Kolassa IT, Allers KA, Astrocytes as Mediators of Fkbp5 Polymorphism-Associated Risk for Pathology - First Insights from Novel Humanized Mouse Strains, European Journal of Neurosience Oct 2020; 53(2):402-415. DOI: 10.1111/ejn.14999dc.relation.haspart
LicenseLizenz Adc.rights
Link to license texthttps://oparu.uni-ulm.de/xmlui/licenseA_v1dc.rights.uri
KeywordFK-506-binding proteindc.subject
KeywordAnimal modeldc.subject
KeywordBehaviourdc.subject
KeywordPsycho-immune-neuro-energy networkdc.subject
KeywordKynurenine pathwaydc.subject
KeywordBiomarkersdc.subject
KeywordCognitiondc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHMitochondriadc.subject.mesh
MeSHModels, Animaldc.subject.mesh
MeSHKynureninedc.subject.mesh
MeSHTacrolimus binding proteinsdc.subject.mesh
TitleConsequences of stress on the psycho-immune-neuro-energy network : On the search for novel biomarkers and protective factorsdc.title
Resource typeDissertationdc.type
Date of acceptance2022-05-23dcterms.dateAccepted
RefereeKolassa, Iris-Tatjanadc.contributor.referee
RefereeHarkin, Andrewdc.contributor.referee
RefereeTuckermann, Jandc.contributor.referee
DOIhttp://dx.doi.org/10.18725/OPARU-44944dc.identifier.doi
PPN1818230429dc.identifier.ppn
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-45020-8dc.identifier.urn
GNDStressdc.subject.gnd
GNDGen FKBP5dc.subject.gnd
GNDTiermodelldc.subject.gnd
GNDAnpassungdc.subject.gnd
FacultyFakultät für Ingenieurwissenschaften, Informatik und Psychologieuulm.affiliationGeneral
InstitutionInstitut für Psychologie und Pädagogikuulm.affiliationSpecific
InstitutionInstitut für Molekulare Endokrinologie der Tiereuulm.affiliationSpecific
Grantor of degreeFakultät für Ingenieurwissenschaften, Informatik und Psychologieuulm.thesisGrantor
DCMI TypeTextuulm.typeDCMI
CategoryPublikationenuulm.category
Bibliographyuulmuulm.bibliographie


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