Social hierarchy position in female mice is associated with plasma corticosterone levels and hypothalamic gene expression.

Social hierarchies emerge when animals compete for access to resources such as food, mates or physical space. Wild and laboratory male mice have been shown to develop linear hierarchies, however, less is known regarding whether female mice have sufficient intrasexual competition to establish significant social dominance relationships. In this study, we examined whether groups of outbred CD-1 virgin female mice housed in a large vivaria formed social hierarchies. We show that females use fighting, chasing and mounting behaviors to rapidly establish highly directionally consistent social relationships. Notably, these female hierarchies are less linear, steep and despotic compared to male hierarchies. Female estrus state was not found to have a significant effect on aggressive behavior, though dominant females had elongated estrus cycles (due to increased time in estrus) compared to subordinate females. Plasma estradiol levels were equivalent between dominant and subordinate females. Subordinate females had significantly higher levels of basal corticosterone compared to dominant females. Analyses of gene expression in the ventromedial hypothalamus indicated that subordinate females have elevated ERα, ERß and OTR mRNA compared to dominant females. This study provides a methodological framework for the study of the neuroendocrine basis of female social aggression and dominance in laboratory mice.

Ultrasonic vocalization in female rats: A comparison among three outbred stocks from pups to adults.

Long Evans (LE), Sprague-Dawley (SD) and Wistar (WU) are outbred rat stocks, which differ in terms of brain, physiology, pharmacological reactivity and behavior. Extending our previous work with males from these stocks, we here report the analysis of ultrasonic vocalizations (USV) in females. Identical to our previous studies, we tested them as pups for 40-kHz calls during short-term isolation, as juveniles for appetitive 50-kHz calls during a cage test or when being tickled, and finally as adults for 22-kHz calls in a fear conditioning paradigm. Stock differences were obtained in all four tests, albeit with different patterns: As pups, WU rats emitted more calls and spent more time calling than SD or LE rats. Furthermore, LE rats emitted calls with shorter durations, whereas SD emitted calls with lower peak frequencies and less frequency modulation. Furthermore, stock differences in call sub-types were detected. In the cage test, 50-kHz calls were most frequent in WU and rather few in LE rats. Call durations were longer in WU rats. When being tickled, SD females emitted calls with shorter durations and lower peak frequencies. Also, frequency modulation and call amplitude was higher in LE. Finally, the fear-conditioning test led to partly unexpected results, since many females, especially WU, did not emit 22-kHz calls even during the conditioning phase, but all stocks showed the expected behavioral immobility and responded with audible calls to the aversive shocks. These results are discussed with respect to factors of testing, development, gender, and stock.

Sigma 1 Receptor Antagonists Inhibit Manic-Like Behaviors in Two Congenital Strains of Mice.

Background: Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3ß that accompanies this disease. Methods: In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the "manic" Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors. Results: The activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3ß inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the "bipolar" HINT1-/- mice during pro-depressive episodes. Conclusions: σ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.

Wheat grain consumption and selection by inbred and outbred strains of mice.

Food selection and avoidance are driven primarily by orosensory cues. Previous studies with C57BL/6J mice indicated marked differences in selection and consumption of individual grains of different wheat varieties when presented in binary mixtures. The present study examined the patterns of mouse grain selection across four strains of laboratory mice: two inbred, BALB/c and C57BL/6J, and two outbred, Swiss-Webster and CD1. Four pairs of wheat varieties that were known to vary a priori for consumption preference or seed coat ('bran') color were tested. Two variety pairs were near-isogenic (>98% similar) with contrasting red and white seed coat coloration/pigmentation. All four mice strains exhibited similar preferences between wheat variety pairs, whereas consumption was not highly related to mouse body weight. This result indicates a more generalized phenomenon regarding how mice select and then consume individual wheat grains. The study supported the continued use of C57BL/6J as an effective strain model system to study food perception.

Air puff-induced 22-kHz calls in F344 rats.

Air puff-induced ultrasonic vocalizations in adult rats, termed "22-kHz calls," have been applied as a useful animal model to develop psychoneurological and psychopharmacological studies focusing on human aversive affective disorders. To date, all previous studies on air puff-induced 22-kHz calls have used outbred rats. Furthermore, newly developed gene targeting technologies, which are essential for further advancement of biomedical experiments using air puff-induced 22-kHz calls, have enabled the production of genetically modified rats using inbred rat strains. Therefore, we considered it necessary to assess air puff-induced 22-kHz calls in inbred rats. In this study, we assessed differences in air puff-induced 22-kHz calls between inbred F344 rats and outbred Wistar rats. Male F344 rats displayed similar total (summed) duration of air puff-induced 22 kHz vocalizations to that of male Wistar rats, however, Wistar rats emitted fewer calls of longer duration, while F344 rats emitted higher number of vocalizations of shorter duration. Additionally, female F344 rats emitted fewer air puff-induced 22-kHz calls than did males, thus confirming the existence of a sex difference that was previously reported for outbred Wistar rats. The results of this study could confirm the reliability of air puff stimulus for induction of a similar amount of emissions of 22-kHz calls in different rat strains, enabling the use of air puff-induced 22-kHz calls in inbred F344 rats and derived genetically modified animals in future studies concerning human aversive affective disorders.

Comparative analysis of the behavioral and biomolecular parameters of four mouse strains.

The use of mice as experimental models in pharmacological and biochemical research began over 100 years ago, during which time different mice strains with specific features were developed. Numerous studies demonstrate that the pharmacological efficacy of various compounds significantly varies among different animal strains, a factor which must be considered when analyzing experimental data. The Sabra strain, developed more than 35 years ago, is widely used for research in Israel but has an unclear origin and is not characterized as well as other strains. Comparative analyses of the molecular characteristics of Sabra and other strains should help to understand their characteristics and to enhance the validity of their experimental use. Thus, four mouse strains-outbred ICR and Sabra as well as inbred C57Bl/6J and Balb/c were compared. Animals' weight, blood corticosterone and hippocampal BDNF mRNA levels were measured, and animals' behavior was compared using the EPM, open field, FST, and hot plate tests. We found that although Sabra mice are bigger and heavier than other tested lines, this is not reflected in behavior or in biomolecular features, wherein Sabra mice lay within the diapason of other tested animals. Thus, behavioral tests of anxiety-like behavior and locomotor activity revealed that Sabra mice scored close to the mean of all tested lines. Analysis of blood corticosterone levels did not show significant differences among tested strains. We also found a correlation between general and locomotor activity of the tested strains and their hippocampal BDNF mRNA expression. In summary, we may conclude that Sabra mice have traits similar to the better known lines, and therefore they are good subjects for neuroscience research.

Modeling mania: Further validation for Black Swiss mice as model animals.

The paucity of appropriate animal models for bipolar disorder hinders the research of the disorder and its treatments. Previous work suggests that Black Swiss (BS) mice may be a suitable model animal for behavioral domains of mania including reward-seeking, risk-taking, vigor, aggression and sensitivity to psychostimulants. These behaviors are high in BS mice compared with other strains and are responsive to the mood stabilizers lithium and valproate but not to the antidepressant imipramine. The current study evaluated the etiological validity of this model by assessing brain expression of two proteins implicated in affective disorders, ß-catenin and BDNF, in BS mice versus C57bl/6, A/J and CBA/J mice. Additionally, pharmacological validity was further tested by assessing the effects of risperidone in a behavioral battery of tests. ß-catenin and BDNF expression were evaluated in the frontal cortex and hippocampus of untreated BS, CBA/J, A/J and C57bl/6 mice by western blot. Subchronic 0.1 and 0.3mg/kg doses of risperidone were tested in a battery of behavioral tests for domains of mania. Expression of ß-catenin was found to be lower in the hippocampus of BS mice compared with the other strains. Reduced ß-catenin expression was not observed in the frontal cortex. BDNF expression levels were similar between strains in both the hippocampus and frontal cortex. In the behavioral tests, risperidone ameliorated amphetamine-induced hyperactivity without affecting other tests in the battery. These results offer additional pharmacological and possible etiological validity supporting the utilization of Black Swiss mice as a model for domains of mania.

Omission of the habituation procedure in the acquisition of a working memory task - evidence from Balb/c, C57/BL6J, and CD-1 mice.

Training animals in spatial mazes have always been preceded by prior habituation to the test apparatus and testing conditions with the main goal to reduce fear and anxiety from exposure to the unfamiliar maze environment. This approach makes assumptions about the baseline level of emotionality in animals without actual objective measurements. It also ignores that genetic factors and experimental manipulations can reduce or prolong fear and anxiety from novelty, hence affecting the acquisition of a memory task. In the present study, C57, CD-1 and Balb/c mice were introduced to a working memory task in a radial-arm maze without habituation. Fear-induced anxiety from exposure to the novelty in this maze is demonstrated by a very low number of arm entries. Animals have to climb onto a bridge in order to reach an arm of the maze. In the first session block, Bab/c mice made very few arm entries and made more arm repeats than CD-1 and C57 mice, and CD-1 made few arm entries and made more arm repeats than C57/BL6J mice. In the second session block, all three strains of mice did make 8 arm entries. Balb/c mice seem to perform better than C57 and CD-1 mice as shown by a low number of arm repeats in the second session block, a high number of correct choices before first errors in the third session block, and low number of errors and sessions to criterion. In the present case, a high baseline level of emotionality did not prevent Balb/c mice to perform better than C57 and CD-1 mice.

A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock.

The laboratory rat (Rattus norvegicus) is a key tool for the study of medicine and pharmacology for human health. A large database of phenotypes for integrated fields such as cardiovascular, neuroscience, and exercise physiology exists in the literature. However, the molecular characterization of the genetic loci that give rise to variation in these traits has proven to be difficult. Here we show how one obstacle to progress, the fine-mapping of quantitative trait loci (QTL), can be overcome by using an outbred population of rats. By use of a genetically heterogeneous stock of rats, we map a locus contributing to variation in a fear-related measure (two-way active avoidance in the shuttle box) to a region on chromosome 5 containing nine genes. By establishing a protocol measuring multiple phenotypes including immunology, neuroinflammation, and hematology, as well as cardiovascular, metabolic, and behavioral traits, we establish the rat HS as a new resource for the fine-mapping of QTLs contributing to variation in complex traits of biomedical relevance.