Behavioral phenotyping, gene expression profiles, and cognitive aspects in a mouse model of trait anxiety

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.