Sexual differentiation of the brain : investigating the role of Sry using animal models

Recent findings have challenged the dogma that gonadal hormones are the sole factor mediating sexual differentiation of the mammalian brain, and have highlighted the importance of sex-linked genes in this process, either independently, or in combination with, gonadal hormones. Using two rodent models, this thesis investigated the roles of the Y-linked (male-specific) gene Sry and other sex chromosome-linked genes on emotional behaviour. Using an established murine ‘four core genotype’ (FCG) model an attempt was made to dissociate, ‘Sry-dependent effects’ (due to direct effects of Sry brain expression, or to downstream hormonal factors) and effects due to ‘sex chromosome complement’ (i.e. sex-linked genes other than Sry). The mouse work was augmented by the development of a novel rat Sry antisense ‘knockdown’ model permitting investigation of the behavioural effects of direct manipulation of Sry expressed in discrete brain areas.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Sexual differentiation of the brain: investigating the role of Sry using animal models

Recent findings have challenged the dogma that gonadal hormones are the sole factor mediating sexual differentiation of the mammalian brain, and have highlighted the importance of sex-linked genes in this process, either independently, or in combination with, gonadal hormones. Using two rodent models, this thesis investigated the roles of the Y-linked (male-specific) gene Sry and other sex chromosome-linked genes on emotional behaviour. Using an established murine ‘four core genotype’ (FCG) model an attempt was made to dissociate, ‘Sry-dependent effects’ (due to direct effects of Sry brain expression, or to downstream hormonal factors) and effects due to ‘sex chromosome complement’ (i.e. sex-linked genes other than Sry). The mouse work was augmented by the development of a novel rat Sry antisense ‘knockdown’ model permitting investigation of the behavioural effects of direct manipulation of Sry expressed in discrete brain areas

The role of imprinted genes in mediating susceptibility to neuropsychiatric disorders

Imprinted genes, which are thought to comprise < 1% of the mammalian genome, are defined by their parent-of-origin specific monoallelic expression arising as a consequence of differential epigenetic marking of alleles in the paternal and maternal germlines. Such genes are highly represented in the brain and placental transcriptomes, and have been shown to exert significant influence on fundamental developmental processes in these organs. Converging evidence from work in man and animal models has shown that imprinted genes can influence a variety of brain and behavioral endophenotypes. In this article, we review the current evidence that imprinted gene dysfunction is associated with vulnerability to several common psychiatric disorders. We also discuss how studying imprinted gene (dys)function may provide mechanistic insights into two important areas in modern psychiatry: first, how environmental factors (especially in utero) interact with genetic liability via epigenetic mechanisms to predispose to later mental illness, and second, the molecular underpinnings of sex-specific vulnerability to psychiatric disorders

The Role of the Y Chromosome in Brain Function

In mammals, sex differences are evident in many aspects of brain development, brain function and behaviour. Ultimately, such differences must arise from the differential sex chromosome complements in males and females: males inherit a single X chromosome and a Y chromosome, whilst females inherit two X chromosomes. One possible mechanism for sexual differentiation of the brain is via male-limited expression of genes on the small Y chromosome. Many Y-linked genes have been implicated in the development of the testes, and therefore could theoretically contribute to sexual differentiation of the brain indirectly, through influencing gonadal hormone production. Alternatively, Y-linked genes that are expressed in the brain could directly influence neural masculinisation. The present paper reviews evidence from human genetic studies and animal models for Y-linked effects (both direct and indirect) on neurodevelopment, brain function and behaviour. Besides enhancing our knowledge of the mechanisms underlying mammalian neural sexual differentiation, studies geared towards understanding the role of the Y chromosome in brain function will help to elucidate the molecular basis of sex-biased neuropsychiatric disorders, allowing for more selective sex-specific therapies

Dissociable effects of Sry and sex chromosome complement on activity, feeding and anxiety-related behaviours in mice.

Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine 'four core genotype' (FCG) model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression) and direct effects of sex-linked genes other than Sry ('sex chromosome complement' effects) to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry) exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry); in two behavioural tests (the elevated plus and zero mazes) XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water) consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i) the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii) dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions

Anxiety-related and activity measures in the elevated zero maze.

<p>Gonadally female mice spent significantly less time than gonadally male mice on the aversive open quadrants of the elevated zero maze irrespective of karyotype (<b>A</b>, *p=0.05), and made fewer entries into these zones (<b>B</b>, *p<0.05).</p

Anxiety-related and activity measures in the open field test.

<p>All four experimental groups from the FCG cross spent an equal amount of time in the aversive central portion of the arena (<b>A</b>), made equal numbers of entries into this area (<b>B</b>), and showed equal latencies in making the first entry into this zone (<b>C</b>). There was a significant interaction between SRY DEPENDENCE and SEX CHROMOSOME COMPLEMENT on activity within the open field, consistent with gonadally female mice with an XX karyotype being more active than gonadally female mice with an XY karyotype, and gonadally male mice with an XY karyotype being more active than gonadally male mice with an XX karyotype (<b>D</b>).</p

Measures of activity, shelter time and food consumption over a 24hr continuous monitoring period.

<p>Gonadally female mice were more active than gonadally male mice irrespective of karyotype, as indexed by horizontal activity (<b>A</b>) but there was no difference between the four experimental groups on a second measure of activity, number of running wheel revolutions (<b>B</b>). All four groups spent equal amounts of time in the shelter (<b>C</b>). Gonadally male mice, and mice with an XY karyotype, consumed more food per unit bodyweight than gonadally female mice (*p<0.05) and mice with an XX karyotype (<b>D</b>).</p