Spuren eines Traumas - Die Entwicklung eines Tiermodells der Posttraumatischen Belastungsstörung
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Philipps-Universität Marburg
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Abstract
This dissertation establishes the first valid animal model of Posttraumatic Stress Disorder (PTSD) which separately measures conditioned and sensitised aspects of trauma-related fear.
A first project constructed a theoretical framework of trauma processing and defined criteria for animal models of PTSD.
The second project aimed at selecting suitable animals for the respective PTSD model. From the literature it was known that the two inbred mouse substrains C57BL/6JOla (BL6JOla) and C57BL/6N (BL6N) differ in the extinction of conditioned fear, with B6JOla mice showing faster extinction than B6N mice. Further it had been shown that B6JOla mice do not express the protein α -synuclein. In several control studies the difference of the two BL/6 substrains in the extinction of fear could be replicated. It could, furthermore, be demonstrated that the diverging extinction behaviour is not based on the acquisition of the tone-footshock-association, on innate emotionality, pain threshold or innate reaction to the tone. Moreover, an involvement of α -synuclein-expression in the expression of extinction could be ruled out. As a consequence of project 2, the two inbred mouse strains B6JOla and B6N were selected as potentially suitable animals for a mouse model of PTSD with different susceptibility to develop trauma-related symptoms.
The third project comprised of the establishment of the animal model of PTSD, with B6N mice as the “vulnerable” and B6JOla as the “resilient” strain. A stress-sensitisation paradigm was used as the experimental approach, consisting of the application of a single unsignalled strong electric footshock and the measurement of conditioned and sensitised fear thereafter. Additional behavioural tests recorded stress-induced anxiety-like and depression-like behavioural alterations as well as changes in the social interaction behaviour of the animals. A range of experiments analysed whether “stress-sensitisation of B6N and B6JOla mice” would meet the criteria outlined in project 1. The model proved face-validity: after shock application the “vulnerable” B6N mice showed a positive dose-response-relationship of shock intensity and contextually conditioned and sensitised fear, persistence of conditioned fear and an increase of sensitised fear with ongoing time after stressor. The highest levels of fear one month after shock were accompanied by reduced exploratory behaviour, reduced feeding in a novel environment, stronger passive stress-coping strategies and a moderately reduced social interaction with partner mice of different ages. Compared to the “vulnerable” B6N strain, less animals of the “resilient” B6JOla strain developed strong conditioned and sensitised fear. Furthermore, the time window of intensive fear reactions was shorter in B6JOla mice, as the animals developed their maximal fear levels later, and returned to low levels of fear earlier than B6N mice. The animal model is characterised by predictive validity, as one month incubated fear in B6N animals with a strong phenotype was ameliorated by chronic treatment with the SSRI fluoxetine.
The fourth project tested the assumption of the underlying conceptual framework, according to which sensitised and conditioned fear after a trauma would result from independent memory processes. To this end the formation of the context-shock-association in the stress-sensitisation paradigm was impaired by the application of an N-Methyl-D-Aspartate- (NMDA) receptor antagonist, bilaterally into the dorsal hippocampus before shock application. After a fear incubation time of four weeks the PTSD-like conditioned and sensitised fear reactions of the animals were analysed. Treated animals showed only half as much conditioned fear in reaction to the shock context, but similar sensitised fear compared to control animals. The result of project 4 provides first evidence for an independence of the non-associative from the associative fear memory after trauma, and therefore for an independence of the PTSD-related symptom hyperarousal from trauma-related memory and flashbacks.
Taken together, the here established animal model provides a new tool to investigate neurobiological pathomechanisms of PTSD, to study factors of vulnerability and resilience and to test potentially preventive or therapeutic substances on both the associative and non-associative traces of fear after trauma.
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Created: 2006Issued: 2006-09-08Updated: 2011-08-10
Faculty
Fachbereich Psychologie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
TraumaExtinktionVulnerabilityExtinctionDesensitisationSensitivierungRisikofaktorenSchutzfaktorenHabituationSensitisationPTBSPTSDResilienceHabituationAnimal modelDesensitivierung
DFG-subjects
AngstPsychisches TraumaKlassische KonditionierungTiermodellFurchtPosttraumatisches StresssyndromStress
DDC-Numbers
150
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Siegmund, Anja (132058189): Spuren eines Traumas - Die Entwicklung eines Tiermodells der Posttraumatischen Belastungsstörung. : Philipps-Universität Marburg 2006-09-08. DOI: https://doi.org/10.17192/z2006.0150.
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This item has been published with the following license: In Copyright