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Keßler, Melanie (2007): The AVP Deficit in LAB Mice:: Physiological and Behavioral Effects. Dissertation, LMU München: Faculty of Biology
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Abstract

The increased incidence of psychiatric disorders, such as anxiety disorders and depression, makes a strengthened search of genetic and environmental causal factors essential. Besides clinical studies, the broad preclinical research identifies continuously involved neuronal circuits, proteins, and genes representing new candidates in the progress of pharmacological research and the development of new therapies. In this context, an animal model of extremes in trait anxiety, simulating pathologic anxiety, was generated to investigate the neuronal and genetic basis. Thus, CD1 mice selectively and bi-directionally inbred concerning their anxiety-related behavior form two lines, the high (HAB) and the low (LAB) anxiety-related behavior mice. The two lines display, after 24 generations, robust differences in trait anxiety and, additionally, in depression-like behavior, reflecting the clinical comorbidity of anxiety and depression, both of which are potentially based on a few selected genes in the two lines. The peptide arginine-vasopressin (AVP) is one factor found to be differentially expressed between the two mouse lines. In the present manuscript its involvement in the behavioral phenotype is scrutinized. As the antidiuretic hormone, AVP expressed in the hypothalamic paraventricular nucleus (PVN) and the supraoptic nucleus is well known to regulate peripherally the body water balance. Therefore, the physiological consequence of the differences in Avp expression was analyzed, uncovering signs of central diabetes insipidus in LAB mice, an AVP deficit-related disease in humans. Symptoms also seen in LAB mice are increased daily fluid intake and high amounts of highly diluted urine as a result of the inability to secrete enough AVP in the blood circulation. Besides the antidiuretic function, AVP of the PVN is potentially involved in emotionality-related behaviors and further in the regulation of the hypothalamo-pituitary-adrenocortical axis, the neuroendocrine stress response. Thus, the peripherally observable strong deficit in AVP might also be present in the brain of LAB mice, causing a dysregulation of anxiety-related behavior in these animals. Indeed, the less anxious LAB mice exhibit less releasable AVP in the PVN compared to HAB and “normal” CD1 mice, supporting the role of AVP as a crucial regulatory factor of emotionality Besides the genetic predisposition, environmental factors, especially maternal and social interactions after birth, display a significant parameter in shaping the genetically given behavioral traits in emotionality. Therefore, we tested the maternal rearing behavior of HAB and LAB dams for differences possibly involved in the development of the two phenotypes. As dams of the two lines differ in their nursing style with LAB mothers showing less arched back nursing, a posture associated with the quality of maternal investment, we cross-fostered pups of the two lines to quantify the maternal influence on the anxiety- and stress-related phenotype of HAB and LAB mice. As we found just slight shifts in some parameters still within the range of the HAB and LAB phenotype, the two breeding lines can be defined as mainly genetically distinct, providing a beneficial tool to identify genes responsible for pathologic alterations in human diseases.