What can we learn on rodent fearfulness/anxiety from the genetically heterogeneous NIH-HS rat stock?

The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M520/N, F344/N, ACI/N, BN/SsN and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced “depressive” symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis- and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.

Relationships of open-field behaviour with anxiety in the elevated zero-maze test:Focus on freezing and grooming

The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants accumulated along many outbreeding generations. In the present study, 90 NIH-HS male rats were tested for anxiety/fearfulness in the elevated zero-maze and in the open-field test in order to investigate the associations among defensive responses from both tests and, in particular, those among open- field self-grooming and freezing. These associations were evaluated by means of a correlational-factorial approach and an analysis of differences between sub- groups displaying extreme scores in representative variables. The final factor analysis revealed a first factor with high loadings of all variables from the zero-maze (“Maze timidity/conflict” factor), and a second (independent) factor dominated by open-field crossings (-0.74), rearings (-0.62) and freezing (0.65), with lower loadings of open-field grooming (-0.39) and stretched attend postures, as well as of entries and time (loadings of -0.32 to -0.25) in the open sections of the zero-maze (“Open Behavior inhibition/ desinhibition” factor), suggesting that open-field self-grooming is a response associated to activity, in the present study, rather than to inhibition. Furthermore, the finding that grooming in the OF loaded negatively in a second factor supports a relationship between grooming and dearousal. Present results, thus, are in accordance with the usefulness of these tests for the purposes they are commonly employed and add new evidence supporting their concurrent validity, as indicated by the relationships observed among measures from both tests.