The AVP Deficit in LAB Mice:

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.