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Bunck, Mirjam (2008): Behavioral phenotyping, gene expression profiles, and cognitive aspects in a mouse model of trait anxiety. Dissertation, LMU München: Faculty of Biology
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Abstract

Anxiety reflects a fundamental emotion, essential for survival. However, if it occurs unpredictably and exaggerated for a long period of time, it becomes pathological, confining a normal course of life. Anxiety disorders are among the most disabling psychiatric diseases, with increasing incidence. They are complex and occur as a combination of both, inherited and stress-related phenomena, whose origin and underlying mechanisms are still poorly understood. Besides clinical studies, extensive preclinical research is strongly focusing on the genetic, environmental, and developmental underpinnings of both, “physiological” and “pathological” anxiety. Thus, in the year 2000, two mouse lines were generated by bi-directional selective inbreeding, reflecting extremes in trait anxiety. These phenotypic extremes, independent of gender, display either high (HAB) or low (LAB) anxiety-related behavior as measured in the elevated plus-maze test and a variety of other paradigms. Since anxiety is not considered as a single entity, but covers multiple facets, the studies presented in this thesis address behavioral, neuroendocrine, genetic, developmental as well as cognitive aspects in this mouse model of trait anxiety. Comprehensive phenotyping confirmed the phenotypic divergence of the mouse lines. Although selection pressure was only exerted on anxiety-related behavior, the mouse lines exhibited comorbid depression-like and altered explorative behavior. Moreover, expression profiling of genes well described in the regulation of emotionality at the level of the hypothalamo-pituitary-adrenocortical axis and synaptic neurotransmission, as well as pharmacological intervention, highlighted arginine-vasopressin (AVP), corticotropin-releasing hormone (CRH), and synaptotagmin 4 (Syt4) as potential mediators contributing to the observed behavioral differences. AVP has been identified to be under-expressed in several brain regions of LAB mice associated with their non-anxious and non-depression-like behaviors. In addition, several genetic polymorphisms have been identified that are likely to play a critical role in the AVP under-expression of these animals. In contrast, the highly anxious HAB animals revealed a CRH over-expression in various brain areas. The significance of CRH over-expression in mediating the HAB-specific phenotype was pharmacologically validated via CRH receptor 1 antagonist administration. Synaptic release, indicated by Syt4 expression, was found to be altered in both inbred mouse lines in opposite directions, indicating a dysregulation in both extremes of trait anxiety. Furthermore, glyoxalase1 (Glx1), a cellular detoxification enzyme, has been identified to be differently expressed already at early postnatal developmental stages in association with the phenotypic divergence. Thus, Glx1 might act as a biomarker suitable for the early prediction of pathological anxiety. As anxiety disorders have often been described to be accompanied by alterations in cognitive abilities, this coherency was also addressed in the HAB/LAB model. Indeed, HAB mice showed a superior ability in a social learning paradigm and displayed delayed extinction in a classical fear-conditioning study, the latter being similarly observed in patients suffering from posttraumatic stress disorder. Taken together, the HAB/LAB mouse model covers many clinical core symptoms of anxiety disorders at different levels, including behavioral emotionality, gene expression, and cognitive alterations. Therefore, it provides a valuable and promising tool to elucidate the neurobiological basis of the continuum from vital to pathological anxiety.