Abstract
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.
Highlights
About three decades ago Hansen and Spuhler raised the issue that most commonly used outbred laboratory rat stocks could have a rather narrow genetic ancestry [1]
It is unlikely that the passive coping style of NIH-HS rats in the forced swimming test, as well as in the shuttle box avoidance task, can be accounted for by any motor problem or by any general activity deficit, as in separate experiments we have found that NIH-HS rats show higher swimming speed and better efficiency in several learning tasks than those seen in RHA-I and RLA-I rats
We have demonstrated that the NIH-HS rat colony exhibits a behavioural “defensive” profile indicating that these animals are rather fearful and anxious, presenting a predominantly passive/reactive coping style as well as a “depressive” and stress-prone hormone profile
Summary
About three decades ago Hansen and Spuhler raised the issue that most commonly used outbred laboratory rat stocks could have a rather narrow genetic ancestry [1]. (1) In measures of novel-cage (i.e. open-field-like) activity, novelty-induced self-grooming responses, “latency to the first entry into an open section”, spontaneous “exploratory crossings between compartments” (during the period of familiarization to the shuttle box), “number of entries into open sections” and “time spent in open sections” of the “elevated zero-maze” (ZM) test of anxiety, the mean values of the NHS-HS rat stock resemble more the scores of RLA-I rats (as an example see Table 1(a)) which, in turn, are more anxious/fearful than the RHA-I strain according to those behavioural parameters (see [8,9,10,11,28,29]). (4) The levels of context-conditioned freezing (i.e. classically conditioned fear) displayed by NIH-HS rats during the initial stages of the shuttle box training session (when no rat has still made any avoidance response) are more similar to the freezing levels shown by the high anxious RLA-I rats All the above mentioned studies on the anxiety/fearfulness (i.e. defensive response) profiles of NIH-HS rats have led to the conclusion that the genetically heterogeneous rat stock displays relatively elevated anxiety/fear responses, as shown by unlearned and learned anxiety tests and tasks, while they show intermediate fear-potentiated startle responses (falling in between the low startle scores of RHA-I—low anxious/ fearful rats and the high startle responses of RLA-I— high anxious/fearful rats)
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