Review
Of mice and rats: Key species variations in the sexual differentiation of brain and behavior

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Abstract

Mice and rats are important mammalian models in biomedical research. In contrast to other biomedical fields, work on sexual differentiation of brain and behavior has traditionally utilized comparative animal models. As mice are gaining in popularity, it is essential to acknowledge the differences between these two rodents. Here we review neural and behavioral sexual dimorphisms in rats and mice, which highlight species differences and experimental gaps in the literature, that are needed for direct species comparisons. Moving forward, investigators must answer fundamental questions about their chosen organism, and attend to both species and strain differences as they select the optimal animal models for their research questions.

Introduction

One distinct advantage of a comparative approach to neuroendocrine research is that information obtained from different model organisms can be used to determine general rules that may apply across many vertebrates. In behavioral neuroendocrinology, the goal is to establish both structural similarities and differences in the brain, and to relate these to function. Researchers have used a broad arsenal of species, but when it comes to rodents, the rat has been the traditional animal of choice. Laboratory rats display a variety of well-characterized behaviors and are practical to work with; they are docile, breed readily, have relatively large brains, enough blood for multiple hormone assays, and are easily maintained. Nonetheless, work with mice is on the rise for a number of reasons, particularly the availability of genetic models and tools.

Where there is commonality, it is helpful to discuss research results from rats and mice (often referred to as “rodents”) together. Work done previously on rats is useful to guide and inform mouse studies. However, data from rats may not always generalize to mice. For example, the role of gonadal steroid hormones in the regulation of mounting behavior seems to differ between rats and mice, as well as between inbred mouse strains [38]. Additionally, the role of androgen versus estrogen receptors in brain sexual differentiation also varies between species. There are now enough critical data on sexual differentiation in the mouse that it is useful to compare this body of work with rat studies.

A few caveats need to be made as we describe and interpret the data within this review. First, sex differences are often examined in gonad-intact adult animals. This is not a problem if the goal is to identify sex differences per se and not to study the development of these differences. However, data from animals of different sexes, tested with different levels of gonadal hormones in circulation cannot be used to address questions on sexual differentiation. Second, hundreds of inbred rat and mouse strains exist and there are neural and behavioral differences between and within strains [135]. It is clear that similar studies conducted in different rat or mouse strains may have different outcomes, and we need to be cautious about general conclusions based on only one or two strains. Strain differences can be used to the experimenters’ advantage when examining genetic factors that influence behavior. In addition, for specific behaviors, some strains are more useful than others. For example, in mice, DBA/2 is an aggressive strain while C57BL/6 is not [116]. If expression of a gene is hypothesized to reduce resident-intruder aggression, it might be best to knock it down in a relatively unaggressive strain, such as C57BL/6. However, if the gene is predicted to increase aggression, the more aggressive DBA/2 strain might be a better choice. Therefore, the conclusion that a gene does or does not affect a particular behavior might vary depending on the inbred strain employed.

Another source of variation is that individual investigators working with mice often do their own colony maintenance using different breeding protocols. Consequently, a C57BL/6J mouse in one investigator’s lab may be genetically different from a C57BL/6J purchased from Jackson Laboratories [61]. Additionally, different commercial breeding houses produce their own lineages of rats and mice that, while derived from the same ancestral strains (i.e. C57BL/6), have been maintained in closed colonies for multiple generations. Gene mutations and changes in copy numbers between lineages have been observed [61] and may affect brain and behavior [206]. Due to the early development of inbred strains of mice and their current widespread use in molecular genetics, there is substantially more information concerning strain differences in mice than rats on numerous, specific levels [36], [91], [128]. Even so, both strain and species differences will be considered in this review.

Finally, much of the mouse data has been generated with gene-disrupted, over-expressing, or knockout (KO) models. If we are concerned with the developmental process of sexual differentiation, and are examining endpoints at or shortly after birth, the fact that the targeted genes are not functional (or over expressing) during development helps in determining the developmental function of the knocked out gene. Alternatively, if we are assessing developmental effects on adult behaviors, and these behaviors require adult expression of the same gene that has been disrupted, we cannot learn much about the developmental role of the gene. A related issue pertinent to work done with knockout and transgenic mice, is that newly generated models are often tested before they are completely backcrossed (at least 10 generations) into a more uniform genetic background. Many reports of phenotypic effects of gene knockouts have been based on work done in mice from mixed genetic backgrounds. Once a disrupted gene is moved into a more uniform background, previously reported differences might be diminished, amplified, or no longer exist because of allelic changes in behavior modifying genes. These issues may make it difficult for laboratories to replicate each other’s work, or even lead to failures to replicate within a lab as the KO mouse is bred into a pure background.

While keeping these confounding factors in mind, this review will first consider sexual differentiation of neuroanatomical markers in the hypothalamus that provide examples of how sex differences in mice differ from rats. Next we will discuss sexual differentiation of three behaviors: partner preference, masculine sexual behavior, and female sexual behavior. Certainly there are many more sexually dimorphic behaviors in rodents (and other animals); however, the paucity of mouse data prevents comparing mice with rats for many behavioral tasks. We have selected these three particular behaviors, because there are a sufficient number of mouse studies from which to draw information.

Section snippets

Sex and species differences in neuroanatomical markers in the hypothalamus

A major contributing factor in sexual differentiation of the rodent brain is the gonadal secretion of testosterone during a specific critical period in male development. In certain tissues, including the brain, testosterone is converted to estradiol by the enzyme aromatase. Brain sexual dimorphisms and concordant sex differences in physiology and behavior arise primarily due to these critical period influences. The neonatal critical period for development of rat brain begins before birth ending

Sex and species differences in partner preference behavior

The hypothalamus is one of the major brain areas responsible for sex-specific behaviors, but inputs from the olfactory system to the hypothalamus are also very important to the display of these behaviors. Many of the sex differences within the olfactory system of rats and mice have been presumed to be the same, therefore there are gaps in the literature that make direct comparisons of rats and mice difficult. Nonetheless, species differences in olfactory regulated behaviors, including partner

Masculine sexual behavior

Not surprisingly, much of the social behavior that rodents engage in is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for young. All these behaviors are sexually dimorphic, but the sexual differentiation of copulatory behavior is the best characterized of all rodent social behaviors. This is likely due to several factors, including that the behaviors are stereotyped, stable, and quantifiable. In a landmark study of sexual differentiation,

Female sex behavior: receptivity and lordosis

Similar to male sexual behavior, female sexual behavior has been extensively studied to the point where striking differences between rats and mice have been revealed. To gauge receptivity in female rodents when mounted by a male, the most frequently used measure is the stereotypical lordosis reflex [21], [166]. Sexually experienced female rats and mice in the estrus phase of their reproductive cycle assume the lordosis posture if mounted by a male [131]. Diestrus and OVX females with low levels

Concluding summary

Studies of sexually dimorphic brain regions and behaviors may be more advanced in rats, but work in mice has been progressing. Findings with KO mice of mixed genetic background, when compared directly to discoveries in rats, can create some confusion. This review highlights some of the apparent species differences as well as similarities. The gonadal steroid modulation and developmental progression of the calbindin-ir sub-region of the POA, and the role and distribution of the ERβ in the AVPV

Acknowledgments

The authors’ work is supported by R01 MH61376 (ST) and R01 MH057759 (EFR). PJB is supported by T32 GM08715 and KHC is supported by T32 HD007323.

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    These authors contributed equally to this manuscript.

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