Genetic, hormonal, and metabolomic influences on social behavior and sex preference of XXY mice

Abstract

Lee PW, Swerdloff RS. Genetic, hormonal, and metabolomic influences on social behavior and sex preference of XXY mice. Am J Physiol Endocrinol Metab 299: E446-E455, 2010. First published June 22, 2010; doi:10.1152/ajpendo.00085.2010.-XXY men (Klinefelter syndrome) are testosterone deficient, socially isolated, exhibit impaired gender identity, and may experience more homosexual behaviors. Here, we characterize social behaviors in a validated XXY mouse model to understand mechanisms. Sociability and gender preference were assessed by three-chambered choice tasks before and after castration and after testosterone replacement. Metabolomic activities of brain and blood were quantified through fractional synthesis rates of palmitate and ribose (GC-MS). XXY mice exhibit greater sociability than XY littermates, particularly for male mice. The differences in sociability disappear after matching androgen exposure. Intact XXY, compared with XY, mice prefer male mice odors when the alternatives are ovariectomized female mice odors, but they prefer estrous over male mice odors, suggesting that preference for male mice may be due to social, not sexual, cues. Castration followed by testosterone treatment essentially remove these preferences. Fractional synthesis rates of palmitate are higher in the hypothalamus, amygdala, and hippocampus of XXY compared with XY mice but not with ribose in these brain regions or palmitate in blood. Androgen ablation in XY mice increases fractional synthesis rates of fatty acids in the brain to levels indistinguishable from those in XXY mice. We conclude that intact XXY mice exhibit increased sociability, differences in gender preference for mice and their odors are due to social rather than sexual cues and, these differences are mostly related to androgen deficiency rather than genetics. Specific metabolic changes in brain lipids, which are also regulated by androgens, are observed in brain regions that are involved in these behaviors.aneuploidy; Klinefelter syndrome; testosterone; X-inactivation; brain lipids KLINEFELTER SYNDROME (KS) was first described in 1942 and its chromosomal etiology identified in 1959 (11, 16). It is the most frequent sex chromosome aneuploidy in human males, with an incidence of 1 in 500 male conceptions and 1 in 800 -1,000 live male births (3,22,34). KS patients are males with an extra X chromosome (XXY), and the syndrome is typified by reproductive dysfunction such as androgen deficiency and associated sexual dysfunction, small testicular size, gynecomastia, delayed onset of puberty, infertility, and tall stature as well as nonreproductive characteristics, including dyslexia, slowed learning, and social isolation (17,40,42). KS males also exhibit higher rates of attention deficit hyperactivity disorder (AD/HD) and psychiatric diseases such as schizophrenia and depression. These clinical and behavioral features of KS could be explained as genetic and/or hormonal (testosterone deficiency). Others have also suggested that KS is a useful model to dissect the genetic ba...

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies

“…Our finding of altered amygdalar structure in XXY mice relative to XY littermates is notable in light of the known importance of amygdalar circuitry in appetitive conditioning and social behavior (Fernando et al 2013; Felix-Ortiz and Tye 2014), and documented abnormalities in both these domains amongst XXY mice (Lue et al 2005; Liu et al 2010). However, the most pronounced anatomical alterations detected by our study impact non-amygdala structures such as the lateral septum, BNST and hypothalamus—indicating the need for broader behavioral characterization of XXY mice, especially through tests of fear conditioning, stress reactivity, aggression and defensive behavior (Koolhaas et al 1998; Risold and Swanson 1997; Calandreau et al 2007).…”

“…XO mice have been studied as a potential model for Turner syndrome (TS, 45, X karyotype)—with an emphasis on X haploinsufficiency effects on gene expression (Lopes et al 2010), somatic growth (Burgoyne et al 2002), fertility (Burgoyne and Baker 1985) and behavior (Lynn and Davies 2007). XXY mice have primarily been studied as a model for the cognitive-behavioral alterations and evolving postnatal gonadal dysfunction seen in Klinefelter syndrome (KS, 47, XXY karyotype) (Liu et al 2010; Lue et al 2005). …”

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice

“…Adult male XXY mice which are true aneuploids (from a different cross than the one used here) showed more social interest in a social preference task as compared to XY males (Liu et al, 2010), and adult 1X and XO females both spent less time in the open arms of an EPM compared to 2X females (Isles et al, 2004). Genetic sex also affects the expression of genes involved in anxiety and depressive behaviors (Seney et al, 2013).…”

Mouse model systems to study sex chromosome genes and behavior: Relevance to humans

“…While different from the findings in juvenile FCG mice that XXF are less social in certain contexts, these data are consistent with previous findings in adult Y* mice. Adult 2XM mice spend more time than 1XM investigating a novel mouse than a novel object (Liu et al , 2010). Taken together with the FCG data, these results suggest a role for both Y and X chromosome genes in the development of social behaviors.…”