Genetics of Sex Differences in Brain & Behavior

YFRNE 451 No.
of Pages 20, Model 5G

21 October 2010
Frontiers in Neuroendocrinology xxx (2010) xxx–xxx

1
Contents lists available at ScienceDirect
Frontiers in Neuroendocrinology
journal homepage: www.elsevier.com/locate/yfrne
2 Review
3 The genetics of sex differences in brain and behavior

4 Tuck C. Ngun 1, Negar Ghahramani 1, Francisco J. Sánchez, Sven Bocklandt, Eric Vilain ⇑
5 David Geffen School of Medicine at UCLA, Gonda Center, Room 5506, 695 Charles Young Drive South, Los Angeles, CA 90095-7088, United States
6
a r t i c l e i n f o a b s t r a c t
8
2 2
9 Article history: Biological differences between men and women contribute to many sex-specific illnesses and disorders. 23
10 Available online xxxx Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone 24
secretions. However, emerging research has shown that some differences are mediated by mechanisms 25
11 Keywords: other than the action of these hormone secretions and in particular by products of genes located on the X 26
12 Sexual differentiation and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct 27
13 Brain anatomy genetic effects in behavioral and brain sex differences. We highlight the ‘four core genotypes’ model and sex 28
14 Sex differences
differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss 29
15 Sexual orientation
16 Gender identity
novel research being done on unique populations including people attracted to the same sex and people 30
17 Sex chromosomes with a cross-gender identity. As science continues to advance our understanding of biological sex differ- 31
18 SRY ences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biol- 32
19 Dopamine ogy and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for 33
20 Behavior both men and women. 34
21
! 2010 Elsevier Inc. All rights reserved. 35
36
37
38 1. Introduction non-gonadal cells and result in sex differences in the functions of 62
those cells. First, we will highlight some sex differences at the biolog- 63
39 Men and women are different in many ways. These differences ical level and at the psychological level. Then, we will review the ‘clas- 64
40 include both biological phenotypes [e.g. 191] and psychological sic’ view that dominated the field of sex differences—that most sex 65
41 traits [e.g. 200]. Some of these differences are influenced by envi- differences, especially those concerned with reproductive physiology 66
42 ronmental factors [1,340]. Yet, there are fundamental differences and behavior, were due to the action of hormones produced by the go- 67
43 between the sexes that are rooted in biology. nads. Next, we will present the emerging view that ‘direct genetic ef- 68
44 Of particular interest are sex differences that have been identified fects’ play an important role as well. Finally, we will discuss novel 69
45 in the brain. Although the brains of men and women are highly sim- approaches to studying sex differences by focusing on unique groups 70
46 ilar, they show consistent differences that have important implica- of individuals: people with sex-chromosome variations (e.g., Klinefel- 71
47 tions for each sex. That is, brain sex differences uniquely affect ter’s Syndrome and Turner Syndrome), people with genetic mutations 72
48 biochemical processes, may contribute to the susceptibility to spe- in the sexual development pathway, people with an atypical sexual- 73
49 cific diseases, and may influence specific behaviors. Such biological orientation, and people who experience a cross-gender identity. 74
50 differences should never be used to justify discrimination or sexism.
51 However, we believe that a thorough understanding of these differ- 2. Biological sex differences 75
52 ences can inform researchers and clinicians so that they can better
53 address important issues. Two examples include how genetic sex There are many biological differences between males and fe- 76
54 can lead to differences between the sexes in the etiology and the pro- males that are beyond the obvious differences at a gross, macro le- 77
55 gression of disease and how differences in neural development may vel (e.g., height, weight, and external genitalia). Specifically, there 78
56 result in differences in cognition and behavior. are several important physiological differences that have critical 79
57 In this paper, we will review sex differences in brain and behavior implications including the susceptibility to different diseases and 80
58 that are not due to the action of hormones secreted by the gonads— the ability to metabolize different medications. In this section we 81
59 which has been the dominant mechanism associated with such will highlight some sex differences in neuroanatomy and 82
60 differences—but from what we term ‘direct genetic effects.’ These neurochemistry. 83
61 are effects that arise from the expression of X and Y genes within
2.1. Neuroanatomy 84
Q1 ⇑ Corresponding author. Fax: +1 (310) 794 5446.
E-mail address: evilain@ucla.edu (E. Vilain). The two sexes have similar but not identical brains. Most brain 85
1
These authors contributed equally to this work. studies have focused on gross manifestations of these differences— 86
0091-3022/$ - see front matter ! 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.yfrne.2010.10.001
Please cite this article in press as: T.C. Ngun et al., The genetics of sex differences in brain and behavior, Front. Neuroendocrinol. (2010), doi:10.1016/
j.yfrne.2010.10.001
YFRNE 451 No. of Pages 20, Model 5G
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2 T.C. Ngun et al. / Frontiers in Neuroendocrinology xxx (2010) xxx–xxx
Table 1
Selected neuroanatomical sex differences in the rat.
Structure/region Known roles Sex difference Basis of difference

Sexually dimorphic The POA is implicated in the regulation of male copulatory 2.6 times larger in males [118] Perinatal aromatized androgen decreases
nucleus of the behavior [225]. Lesions of the SDN alone slow acquisition neuronal apoptotic rates in males [317]
preoptic area of this behavior. Potential human equivalent is INAH-3 [4]
(SDN-POA)
Anteroventral Involved in regulating the luteinizing hormone surge in 2.2 times larger in females with a Degeneration of cells in this region is greater
periventricular females [317] and male copulatory behavior [262] higher cell density [45] in males [308] due to prenatal action of
nucleus (AVPV) androgen
Bed nucleus of stria Plays a role in the control of male sexual behavior [100], The principal nucleus (BNSTp) is The larger volume in males is due to
terminalis release of gonadotropin [32], and modulation of stress larger in volume in males [85] sexually different apoptotic rates caused by
(BNST) [329,134] testosterone [109]
Corpus callosum Conducts information between the two halves of the Larger in neonatal males [351] Organizational effects of testosterone lead
cortex [304] to masculinization while feminization
appears to be dependent on estrogens
[106,105]
Arcuate nucleus Helps regulate the estrus cycle [203], appetite and body Neurokin-B neurons innervate Dihydrotestosterone is responsible for the
(ARC) weight [217] capillary vessels in the masculine projection pattern [67]
ventromedial ARC in post-pubertal
males only [66]
Amygdala Strongly associated with emotion, decision-making and Adult males have a larger medial Treatment of females with estradiol
Pavlovian conditioning [288] nucleus than adult females [221] masculinizes this nucleus [221]
The posterodorsal aspect of the Activational effects of circulating androgens
medial amygdala is 65% larger in accounts for the larger region in males [73]
males [148]
Cerebral cortex Connected to a wide range of processes from memory [20] Right posterior cortex is thicker Gonadal hormones play a role in
to language [33] to emotional processing [237] than left but only in males [90] maintaining the sex difference (ovariectomy
masculinizes the cortex of females) [90]
Ventromedial Involved in the control of lordosis, mounting, and Females have less synapses in the Organizational effects of aromatized
hypothalamic norepinephrine release [102]. High concentrations of ventrolateral VMN compared to testosterone appear to be crucial in
nucleus (VMN) steroid receptor mRNA have been observed in the males [211] establishing the masculine trait [253]
ventrolateral VMN [297]
Substantia nigra Made up almost entirely of dopaminergic neurons. Females have 20% fewer A genetic component has been
pars compacta Dopamine is involved in control of motor activity [123] dopaminergic neurons [86] demonstrated in mice [60]
*Note: This table highlights some prominent sex differences in the rat brain but it is by no means exhaustive. Conflicting evidence concerning the examples reported here
(particularly in the SDN-POA) exist, and the interpretation of the data is often more complicated than this summary implies.
87 namely the size of specific regions or nuclei. Yet, there is mounting nology continue to advance, we will eventually know how to make 119
88 evidence of sex differences at a finer level including differences in sense of the mounting evidence of sex differences in the brain. For 120
89 synaptic patterns [120,66] and neuronal density [117,211,338]. It now, it is reasonable to suspect that such differences may help ac- 121
90 is beyond the scope of this article to provide a comprehensive re- count for observed sex differences in behavior, neurological dis- 122
91 view of all known neuoranatomical differences. We have provided eases, and cognitive abilities. 123
92 notable sex differences in the rat brain in Table 1. There are also
93 excellent resources for those who are interested in delving deeper 2.2. Neurochemistry 124
94 into this topic [146,98,28].
95 We have chosen to focus on neuroanatomical differences in the Males and females exhibit different patterns of transmitting, 125
96 rat because the biological significance and origins of these differ- regulating, and processing biomolecules. Table 2 presents some 126
97 ences are much clearer than in humans. Neuroanatomical differ- of the neurochemical sex differences that have been identified. 127
98 ences in humans are also well-studied although ethical reasons As a specific example, we focus below on the monoaminergic 128
99 preclude the experimental manipulations that have led to the find- system, which has been implicated in several neurological 129
100 ings detailed in Table 1. This significantly limits the conclusions diseases and mental disorders that differentially affect men and 130
101 that can be drawn from any observations made in humans. women. 131
102 Although these neuroanatomical differences are intriguing, Monoamines are a class of small-molecule neurotransmitters 132
103 most are limited because the practical or functional significance that are involved in the control of a variety of processes including 133
104 of these findings are unknown. Discovering the significance of reproduction and sexual behavior [183,170], respiration [112], and 134
105 these differences is often difficult, even in rodents. de Vries and stress responses [163]. Monoamines have also been implicated in 135
106 Sodersten have eloquently outlined the challenges facing research- numerous mental disorders, including ones that differentially af- 136
107 ers who want to understand the link between sex differences in fect men and women [283,303]. Likewise, sex differences in the 137
108 structure and behavior [82]. A highly relevant case study high- monoaminergic systems in the rat are well-documented. Reisert 138
109 lighted in their review concerns the sexually dimorphic nucleus and Pilgrim provided a comprehensive review of arguments for 139
110 of the preoptic area (SDN-POA). The preoptic area (POA) has been the genetic bases of these differences [259]. 140
111 implicated in the regulation of male copulatory behavior [225], Monoamines are subdivided into two groups—catecholamines 141
112 but the link (if any) between the sex difference in SDN-POA size and indolamines—based on their molecular structure. The main 142
113 and behavior remains elusive. Masculinizing the size of the SDN- catecholamines are dopamine (DA), norepinephrine (NE) and epi- 143
114 POA in female rats does not result in a corresponding masculiniza- nephrine, which are synthesized from the amino acid tyrosine. 144
115 tion and defeminization of behavior [159]. Instead, the SDN-POA Fig. 1 highlights some of the known sex differences of the dopami- 145
116 may be related to inhibition of female sexual behaviors nergic system. Regulation of dopamine can potentially control the 146
117 [252,141], which might not have been an obvious hypothesis given levels of the other two catecholamines as they are derived from 147
118 what was known about the POA previously. As science and tech- dopamine. 148
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Table 2
Selected neurochemical sex differences in the brain.
Neurochemical Known roles Species Selected sex differences

system/
pathway
Catecholamines Involved in the control of a variety of processes including Rat Male have higher norepinephrine (NE) levels in the amygdala and
(also see reproduction and sexual behavior [183,170], respiration [112], and hypothalamus at day 25. Direction of this sex difference is reversed
Fig. 1) stress responses [163] at day 300 [296]
In response to chronic physical stress, dopamine (DA) activity is
upregulated only in males whereas NE activity is increased only in
females [201]
Human Women appear to be more dependent than men on NE for long-
term emotional memory formation [323]
Serotonin Modulates a wide variety of processes including mood, aggression, Rat Sex differences in the serotonergic system are found at multiple
perception, reward, and attention [39] and levels [234,333,348,305,220]. See Fig. 2 for an illustration of some of
human these differences
Aromatase Plays a key role in sexual differentiation of the brain by converting Rat Aromatase activity is higher in males than females in many regions
testosterone to 17b-estradiol [231] including the anterior hypothalamus, BNST and POA [269]
Only males experience spikes in the expression of brain-specific and
total aromatase during embryonic development and shortly after
[71]
Vasopressin VP in the central nervous system (CNS) has been linked to learning, Rat The number of vasopressin-positive cells is two to three times
(VP) memory and motor behavior [263]. It has also been connected to higher in males than in females [81]
the control of social behaviors such as pair-bonding, parenting and Vasopressin-positive projections are also two to three times denser
aggression [151] in males [81]
Intrahypothalamic release of VP due to an increase of plasma
osmolality is higher in females [239]
Human Some studies have found that plasma VP concentrations are higher
in men than in women [263]
Cholinergic The cholinergic system helps regulate the sleep-wake cycle and Rat Levels of acetylcholine (ACh) are higher in females, regardless of
system modulates synaptic plasticity implicated in memory, learning, and estrous cycle, than in males [153]. The maximal level of Ach in
development [77,165]. Sex differences are found at many points in females was found at proestrus
the cholinergic system (reviewed in Rhodes and Rubin [263]) The binding affinity of muscarinic Ach receptors is lower in females
than in males [18]. Estrogens appear to modulate the binding
activity of these receptors [96]
Human Men are more sensitive to cholinergic stimulation than women
[273]
Opioid system Opioids are a class of chemical for which receptors are found Rat Generally, l and j class opioids seem more effective in males than
throughout the CNS [346,206]. Opioids exert an analgesic effect and and females although in some cases the effectiveness is equal [76]. In a
also play a role in stress response and reproduction [315] mouse minority of cases, they are more effective in females
Human l-opioids appear more effective in women than in men [76]
l-opioids show significantly higher binding potential in women in
the amygdala, thalamus and the cerebellum [352]. The sex
difference in the first two regions is reversed after menopause
149 Catecholamines are released by the adrenal glands usually in re- form better on specific visuospatial aspects (e.g., mental rotation) 173
150 sponse to stress, which affects males and females differently. For compared to women; and women perform better on specific verbal 174
151 instance, chronic physical stress impairs memory in male rats only tasks (e.g., verbal fluency) compared to men [155]. Furthermore, 175
152 [201]. The sexes also show differing neurochemical responses: there is a large sex difference in sexual interests and behaviors, 176
153 Dopamine activity is upregulated in males only whereas norepi- such as interest in casual sex, interest in multiple sex partners, 177
154 nephrine is upregulated in females only (Fig. 1A). Sex differences and interest in visual-sexual stimuli (e.g., pornography) 178
155 have also been found in the regulation and modification of dopa- [198,281]. Other examples are summarized in Table 3. 179
156 mine (see Fig. 1B and C). Specifically, the enzyme tyrosine hydrox- Some contend that these differences are due to social systems 180
157 ylase (TH), which is involved in dopamine synthesis [193], is and gender socialization [cf. 310,53,238]. Nevertheless, biological 181
158 regulated by Sry—the male sex determination gene—which is not traits likely contribute to many sex differences. Thus, a thorough 182
159 present in females. Additionally, levels of norepinehrine in the understanding of the main determinants involved in expression 183
160 amygdala differ between the sexes as a result of age. Thus, it is of such sex differences can help us better explain the relationship 184
161 likely that brain catecholaminergic responses to stress might also between brain, behavior, and environment. In addition, it allows us 185
162 differ between the sexes. to determine how one’s sex potentially influences the risk of devel- 186
163 Another monoamine is serotonin, which is an indolamine. Un- oping disorders that manifest and progress differently in men and 187
164 like catecholamines, serotonin is derived from the amino acid tryp- women. Such knowledge can better inform the treatment of these 188
165 tophan. The serotonergic system shows sex differences (Fig. 2), diseases. Tables 3 and 4 illustrate several factors (e.g. hormones 189
166 though many of these differences remain unlinked to behavioral and genes) that may be causally linked to expression of sex differ- 190
167 differences between men and women. Nevertheless, differences ences in behavior and disease, respectively. 191
168 in this system likely have consequences given the link between
169 serotonin and numerous mental disorders [48,275]. 4. The classical view on sex differences 192
170 3. Psychological and behavioral sex differences Researchers have examined what contributes to the differences 193
we see between males and females. Certainly for humans, social 194
171 In addition to biological differences, men and women differ in environments influence some of these differences. For instance, so- 195
172 many psychological and behavioral aspects. For instance, men per- cial stratifications (e.g., social class and the distribution of social 196
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Fig. 1. The catecholaminergic pathway is sexually differentiated. TH: Tyrosine hydroxylase, L-DOPA: L-dihydroxyphenylalanine, NE: norepinephrine. (A) Chronic physical
stress results in sexually dimorphic responses. Dopamine (DA) activity is upregulated exclusively in males (light blue arrow) while norepinephrine activity is upregulated
exclusively in females (yellow arrow) [201]. Only males experience impaired memory. (B) Control of TH expression differs between the sexes. SRY, the testis determining
gene, which is not found in females, directly regulates TH expression in males [86,219]. 17b-estradiol increases TH expression only in males (light blue arrows) [257].
Aromatase activity is more responsive to dihydrotestosterone (DHT) in males than in females (dark blue arrow) [270]. (C) Male rats have higher NE levels than female ones in
the amygdala (A) and hypothalamus (HT) early in life [296]. When the rats reach day 300, the direction of this difference is reversed.
Fig. 2. Serotonin (5-HT) is sexually differentiated on multiple levels. In addition to the differences illustrated above, some of the loci that influence 5-HT levels in the blood
are also sexually dimorphic [333]. Refs.: 1 – [348], 2 – [305], 3 – [234], 4 – [220].
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Table 3
Sex differences in behavioral traits in humans.
Trait Sex bias Evidence for the role of hormones Evidence for the role of genetic factors Other factors affecting sex differences in
behavior
Cognition Men do better at spatial tasks [326] and Prenatal hormone effects shown from No reliable evidence for the effect of sex-chromosome genes proven Greater brain asymmetry in men for both
mathematical problem solving [34]. Women do studies of CAH, Turner’s and Androgen from studies of Turner’s and XX males [131] verbal and non-verbal tasks [137,179]
T.C. Ngun et al. / Frontiers in Neuroendocrinology xxx (2010) xxx–xxx

better on verbal fluency, articulation, and verbal Insensitivity Syndromes [130]
memory tests [28]
Play behavior–movement There are sex differences in choice of Testosterone influences juvenile play [17] Genetics sex seems to affect play behavior more
toys, gender of the play partner, social than prenatal hormone exposure [17]
play [147] and movement [5,78,248]
Parents and other socializing agents (i.e. peers,
community, and child’s own cognitive processes)
[28]
Prenatal androgen levels affect play behavior and Developmental experience [129], visual information [316] affect
movement [235,38] movement organization
Language Women perform better on episodic memory Estrogen influences word and Single nucleotide polymorphisms in the gene, brain derived Greater degrees of left hemispheric
[144] and verbal fluency tasks, men are better at declarative memory abilities in women neurotrophic factor (BDNF) affecting BDNF secretion rates, partly lateralization of brain for language in males and
visuospatial processing [178,195,292] [291,246,205,298,240,294,228,341,280] accounting for greater dependence of females on declarative memory the bilateral language processing in females
and the sex differences observed in language-related tasks [95] [171]
Greater dependence of females on declarative Testosterone influences word memory Faster development of hippocampal brain
memory and males on procedural memory in men [101] regions in girls, activation of certain brain
[320,139] regions such as hippocampus and
parahippocampal gyrus [245,29]
Prenatal testosterone levels relate to
language processing in girls [122]
Aggression Foul language, imitation of aggressive models, Estradiol and progesterone influencing Association between serotonin transporter gene polymorphisms and Low self-control, high impulsivity and negative
violence and physical aggression more common the serotonergic system [336,274] greater impulsivity in males but not females [207] emotionality [187]
in males [40]
Weak association between testosterone Polymorphisms in monoamine oxidase-A (MAOA) gene associated Sex-specific disparities in the neural circuitry of
and aggression in both sexes [8,49] with antisocial personality disorder and aggression in males [62] impulse control and emotion regulation, as well
as serotonergic systems [233]
High testosterone levels leading to Larger orbitofrontal cortexes in women [125]
increased verbal aggression and
impulsivity in women [61,325]
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197 power) and social rules (e.g., customs and traditions) may affect The life sciences have elucidated many factors that contribute 202
198 the ability for people to access educational resources or to engage to sex differences. In this section, we briefly review the classical 203
199 in certain behaviors [156,339]. However, social factors alone do not view that gonadal hormones contribute to most, if not all, sex 204
200 contribute to all differences seen between males and females— differences after gonadal differentiation. We will then present 205
201 especially regarding biological differences [72]. some findings that have challenged this view. 206
Table 4
Sex differences in neurological disease.
Disease Sex bias Evidence for the role of hormones Evidence for the role of genetics Other factors affecting sex
differences in disease
Alzheimer’s Women demonstrate higher AD Gonadal hormones implicated in APOE allele type [172,75] (i.e. less Greater degeneration in areas of
disease prevalence at older ages [7,110] gender-related cognitive deficits of and slower rate of amyloid plaque orbitofrontal cortex, middle and
(AD) AD but the interaction is complex formation in men due to APOE e2 posterior cingulate cortex,
[30] [164] hypothalamus, and mammillary
bodies in men, and anterior
thalamic in women [58]
Parkinson’s Overrepresented in males [79,321] Most women manifest PD after Linkage to X chromosome markers Environmental factors [87]
disease menopause [31] in 362 families, and to Xq28 in 443
(PD) discordant sibling pairs [208,241]
Age at onset is later in women Estrogen affecting BDNF secretion Val66met polymorphism in BDNF Anatomical and structural
[318] [108] in women [152] differences in dopaminergic
systems among males and females
[28]
Pathological symptoms of PD differ Early life estrogen decline seems to
among males and females be more important [35,210,258]
[19,104,267]
Autism There is a high male to female ratio Gonadal hormones affecting Single nucleotide polymorphisms Alterations in oxytocin or arginine
in the prevalence of autism [222] oxytocin (OT) and arginine in the OT receptor in the Chinese vasopressin activity, and
vasopressin (AVP) receptors Han [343] and American Caucasian differential processing of the
[83,330] population [161], SNPs in the oxytocin precursor [184,181,140]
vasopressin receptor (V1aR) gene
[347,331]
X-chromosome has effects on
cognition and social aspects
[209,322]
Addiction Drug addiction more frequent in Estradiol levels correlate with drug Genes encoded on sex Neuroanatomical differences in
men [28] induced reinforcing behavior chromosomes can affect sex- motivation systems among males
whereas progesterone levels are related differences in addiction and females [28]
negatively associated with (the four core genotype mice)
addiction [334,169,168] [256]
Higher relapse rates, faster Sex-related alterations in the
progression of compulsive drug cortico-limbic-striatal system that
abuse and dependence have in mediates reward processing [266]
women [51,185]
Depression Women are twice as likely as men Low estrogen levels in female rats Heritability rates estimated to be Maladaptive coping, pessimism,
to develop depression during mediated by influences on 70% [173] dependency, low self-esteem,
reproductive years [177] neurotransmitter levels [175] victimization, sexual abuse,
comorbid anxiety disorder more
common in depressed women
[121]
Low testosterone levels associate Polymorphisms in serotonin gene, Early life events increase
with risk for depression in young estrogen receptor 1 (ESR1) depression rates in adult women
and middle aged-men [70,285] polymorphism in the presence of [176]
Val/Val genotype of the Val158Met
polymorphism in the Catechol-O-
methyl transferase (COMT) gene,
longer CA repeats of human
estrogen receptor 2 (ESR2), short
CAG repeats in androgen receptor
gene [63]
Anxiety The rate of anxiety disorders is States of anxiety and panic have The Val158 allele of COMT is Animal studies indicate females
disorders higher in females [283]. The high been reported to be affected by the associated with panic disorder in undergo less neurobiological
co morbidity of these disorders menstrual cycle and pregnancy, Caucasian women but not men changes in response to stress
with major depression helps implicating a role for estrogen and [136]. In Asians, Met158 is compared to males [6]. It is
account for the sex difference in progesterone [283] associated with panic disorder in speculated that this indicates
depression [52] women but not men [136] increased adaptability in males and
hence lower prevalence of affective
illness [6]
Pregnancy and lactation seem to 5HTTLPR is a polymorphism
alter brain neurochemical system associated with anxiety in humans.
that affect anxiety and fear [6] The orthologous polymorphism in
rhesus macaques interacts with
early adversity in a sexually
dimorphic manner [27]
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Table 4 (continued)
Disease Sex bias Evidence for the role of hormones Evidence for the role of genetics Other factors affecting sex
differences in disease
Schizophrenia More common in men than in This disease is not common before Eight ultra-rare variants in eight Anatomical and structural brain
women [160] adolescence and puberty [88] distinct miRNA genes in 4% of differences among males and
analyzed males with schizophrenia females [115]
[103]
Age at onset is later in women, Male schizophrenics have higher Relatives of females with Higher cortical levels in males as
another smaller peak of onset levels of luteinizing hormone (LH) schizophrenia demonstrate higher compared to females according to
during peri- and post-menopause and testosterone than healthy levels of the psychotic forms some studies [115]
[160,254] subjects, and female whereas relatives of schizophrenic
schizophrenics higher levels of LH men express lower rates of
and lower levels of estrogen [186] psychosis suggesting the presence
of genetic heterogeneity [116]
Pathological symptoms of Higher rate of CAG repeat Higher sensitivity of the dopamine
schizophrenia differ among males expansions among families of system in men as compared to
and females (males experience female patients and not male women (normal males produce
more negative symptoms, greater patients [224] more striatal dopamine in
decrease in emotion expression response to an amphetamine
and recognition, greater paranoid challenge as compared to females)
delusions in women) [115] [227]
Lower chances of full recovery, and
a poorer prognosis in men
[160,254]
Anatomical brain differences
between male and female patients
207 4.1. The role of gonadal hormones from the expression of X and Y genes within non-gonadal cells that 247
result in sex differences in the functions of those cells or target 248
208 Sexual development in mammals can be divided into two cells. Such direct genetic actions are wide-ranging and can include 249
209 main components: sex determination and sex differentiation effects of locally produced hormones or other non-hormonal mes- 250
210 [324]. ‘Sex determination’ is the process by which the bipotential senger molecules. For example, sex differences arising in the brain 251
211 gonad develops into either a testis or an ovary, which depends from differential paracrine secretion of neurosteroids would be 252
212 exclusively on genetics. ‘Sex differentiation’ is the development considered a direct genetic effect. The commonality among these 253
213 of other internal reproductive structures, the external genitalia, actions is that they are not dependent on mediation by hormones 254
214 and non-gonadal sex differences. Unlike sex determination, sex secreted by the gonads. In many cases, the identity of the messen- 255
215 differentiation is driven by gonadal hormones. It was widely be- ger molecules have yet to be identified. This review will now focus 256
216 lieved that sex differences that emerged after sex determination on examples in which sex differences in behaviors are unlikely to 257
217 were largely due to the actions of gonadal hormones. Examples be influenced by only the action of gonadal hormonal secretions 258
218 of this pervasive view include writings from Lillie in 1939 and may in fact be due to direct genetic effects. 259
219 (‘‘[T]he mechanism of sex differentiation is taken over by extra-
220 cellular agents, the male and female hormones.” [197]), Jost in 4.2. Exceptions to the classical view 260
221 1970 (‘‘The developmental analysis of the body sex characteristics
222 reveals a hormonal control.” [167]), Morris et al. in 2004 (‘‘[A] The idea that factors other than the gonadal hormone milieu 261
223 single factor—the steroid hormone testosterone—accounts for could account for sex differences first gained credence from re- 262
224 most, and perhaps all, of the known sex differences. . .” [225]) search performed on the zebra finch. In zebra finches, males exhi- 263
225 and Zhao et al. in 2010 (‘‘[T]he sexual phenotype of individuals bit courtship behaviors that are unique to their sex. Specifically, 264
226 is dependent on the gonad. . .” [349]). We will use the term they possess the ability to sing a distinct courtship song. This 265
227 ‘classical view’ to refer to this hypothesis. male-specific ability has been attributed to several brain regions 266
228 The classical view was based on decades of compelling re- that are larger in males compared to females [10,236]. Given the 267
229 search demonstrating the organizational and activation effects hypothesis that such differences must have been the result of 268
230 of gonadal hormones in vertebrates [196,12]. ‘Organizational ef- sex-specific hormones, several researchers unsuccessfully at- 269
231 fects’ refer to the permanent, irreversible changes during develop- tempted to alter the courtship behavior of finches by manipulating 270
232 ment that organize the body in either a male- or female-typical hormone levels [244]. For example, it was shown that castrated 271
233 pattern. For instance, the neonatal surge of testosterone in male male zebra finches were not significantly different from intact 272
234 rodents leads to life-long changes in the synaptic pattern of the male zebra finches in terms of song development [9]. Furthermore, 273
235 ventrolateral ventromedial hypothalamic nucleus [253]. ‘Activa- female zebra finches that developed testes continued to develop 274
236 tional effects’ refer to the short-term changes that occur in the feminine song circuitry and did not exhibit masculine song behav- 275
237 body depending on the presence or absence of specific hormones. ior [328,327]. 276
238 An example of this is the requirement for the presence of both Several other experimental manipulations led researchers to 277
239 estrogen and progesterone to induce or ‘‘activate” lordosis in question the role of hormones. For instance, Jacobs et al. treated fe- 278
240 female rats [251]. male zebra finches with estrogen at the beginning of hatching gi- 279
241 Recently, it was found that gonadal hormones might not be the ven that estrogen induces male sexual differentiation in the 280
242 sole contributor to male- and female-typical development. Genes zebra finch neural song system [126]. Interestingly, estrogen treat- 281
243 encoded on the sex chromosomes that directly act on the brain ment was not able to cause full masculinization of the neural cir- 282
244 to influence neural developmental and sex-specific behaviors have cuitry of the zebra finch song system (the song circuitry was still 283
245 been identified—an example of what we describe as direct genetic smaller compared to control males) [162,299] and supraphysiolog- 284
246 effects [113,84]. When we use this term, we refer to effects arising ical doses of estrogen were required for full masculinization [13]. 285
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286 Similarly, it was shown that inhibiting the action of estrogen by 5. An expanded view on sex differences 352
287 using aromatase blockers in males did not completely prevent
288 the male differentiation pathway [10,91,150,11,16]. In light of scientific findings, such as with the zebra finch and 353
289 The discovery of a rare type of zebra finch provided further sup- the tammar wallaby presented above, the field of sex differences 354
290 port for a new hypothesis regarding sexual differentiation: The has now come to encompass studies that examine gonadal hor- 355
291 bilateral gynandromorphic finch has male-typical phenotypes on mone as well as genetic origins of these differences. One of the 356
292 one half of the body (e.g., plumage, testis, and song circuitry) and most significant challenges in studying the establishment of sex 357
293 female-typical phenotypes on the other half of the body. Each half differences in animal models has been the difficulty in separating 358
294 of such finches is either entirely genetically male or genetically fe- gonadal sex from chromosomal sex. These two parameters almost 359
295 male. Thus, each side contains the sex-specific genes necessary for always correlate in an animal. 360
296 the development of the corresponding sex-specific traits. In this In the following section, we highlight the ‘four core genotypes’ 361
297 model, while the gonadal hormonal actions in producing sex differ- model, which has proven to be a powerful tool in teasing out the 362
298 ences in the brain cannot be completely ruled out (both sides of the effects of gonadal versus chromosomal sex and enabling research- 363
299 neural song system were larger than that of normal females), their ers to overcome this confound. We then discuss in-depth sexual 364
300 influences cannot fully explain the differences observed between differentiation and sex differences in the midbrain dopaminergic 365
301 the left and right sides of the brain. Given this explanation, the system, focusing specifically on the role of Sry. We discuss the 366
302 most reasonable theory is that endogenous genetic differences in implications that these differences may have on the development 367
303 the brain cells themselves can also contribute to the unequal dif- of this system as well as neurological health implications. 368
304 ferentiation of the two sides producing sex differences through
305 their local action within the brain [2]. 5.1. The ‘four core genotypes’ model 369
306 Recent work on gynandromorphic chickens strengthens the
307 case that the classical view largely does not apply to sexual dif- A 2 ! 2 mouse-model was developed to separate the effects of 370
308 ferentiation in birds. Zhao et al. showed that the ‘sex identity’ gonadal sex from chromosomal sex. This model, known as the ‘four 371
309 (or the expression of sex-specific phenotypes) of somatic cells core genotypes’ (FCG), allows researchers to establish the relative 372
310 in birds is determined by the sex chromosome complement of contribution of sex chromosomes and hormones in sexual differen- 373
311 those cells and not the gonadal hormonal environment [349,2]. tiation as well as the interaction between the two. Arnold and Chen 374
312 In mammals, transplantation of somatic cells from one sex into recently reviewed this model [14]. Here we highlight some of the 375
313 the gonad of the other sex reverses the sex identity of the donor model’s basic concepts. 376
314 somatic cells. For example, XX cells can develop into functioning Fig. 3 depicts the effect of the presence or absence of Sry—a 377
315 Sertoli cells while XY cells can become functioning granulosa cells 12 kb region on the Y chromosome that is responsible for testis 378
316 [242,56]. However, this is not the case in the chicken as male determination—using the FCG model. An XY mouse should develop 379
317 donor cells introduced into the developing ovary continued to ex- testes; however, if Sry is deleted from the Y chromosome (symbol- 380
318 press a male-specific marker and were excluded from ‘functional’ ized by Y–) then the mouse will develop ovaries [124]. If the Sry 381
319 structures of the host gonad. The host and donor somatic cells gene is inserted into any chromosome of an XX mouse (symbolized 382
320 were exposed to the same hormones, but they responded differ- by XXSry), then the mouse will develop testes. Finally, if Sry is de- 383
321 ently based on their respective sex chromosome complement. leted from the Y chromosome of an XY mouse and then inserted 384
322 A second exception to the classical view that we highlight be- into one of its autosomes (symbolized by XY–Sry), then it will devel- 385
323 low concerns the development of the tammar wallaby. As with op testes. 386
324 brain development, gonadal hormones drive the sex-specific devel- XY–Sry mice are fully fertile because the presence of Sry pro- 387
325 opment of the external genitalia in most mammals. Specifically, motes testes development. XXSry mice lack some of the genes 388
326 androgens promote the development of male genitalia. However, required for sperm production, which are found on the Y chromo- 389
327 the formation of reproductive structures in the tammar wallaby some [214], and therefore do not appear to be fertile. However, 390
328 appears to be independent of gonadal hormone control and is so-
329 lely due to the effect of sex chromosome complement.
330 The tammar wallaby is a marsupial that is much smaller than
331 the kangaroo. During fetal development, the production of testos-
332 terone, which would typically masculinize mammalian fetuses,
333 does not occur in these marsupials until about the fourth or fifth
334 day after birth [293,260,261,337]. Yet, signs of sex-specific repro-
335 ductive structures (e.g., scrotum, mammary gland, and pouch
336 formation) can be observed as early as several days before birth.
337 In mammals, the development of male-specific structures, is
338 thought to be completely dependent on the action of androgens
339 [324]. Experiments that increased or decreased the action of tes-
340 tosterone or estrogen in the tammar wallaby had no significant
341 effect on the development of the external genitalia [199,290]. This
342 suggested that such differences were not under gonadal hormone
343 control.
344 A case similar to the gynandromorphic zebra finch has also been
345 reported in tammar wallabies: This consists of wallabies that are
346 XX on one side of the body and XY on the other side of the body.
347 Such wallabies develop a hemipouch on the XX side and a hemi-
348 scrotum on the XY side even after exposure to circulating gonadal
349 hormones [13,289,74]. As with the zebra finch, such cases chal-
350 lenged the view that all sex differences were due to hormones pro- Fig. 3. 2 ! 2 comparison in the four core genotypes model. In this comparison, the
351 duced by the gonads. factors are gonadal sex and sex chromosome complement.
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391 they have small testes and are fully masculinized in terms of mea- 5.1.2. Lateral septum 456
392 sures of male copulatory behavior, social exploration behavior, and One clear example of the role of sex-chromosome genes in brain 457
393 sexually dimorphic neuroanatomical structures in the septum, and phenotypes can be found in the lateral septum. The lateral septum 458
394 lumbar spinal cord. is part of the limbic system and is involved in stress-related behav- 459
395 XY–Sry mice can be mated with XX females to produce the four iors. This nucleus is denser in male brains compared to female 460
396 types of offspring (XX, XY–, XXSry, and XY–Sry) that can then be used brains. However, it was found that the vasopressin fiber density 461
397 to assess the impact of a mouse’s chromosomal and gonadal sex on was greater in the lateral septum of XY–Sry and XY– mice compared 462
398 different phenotypes. That is, if there is a difference between mice to XX and XXSry mice [113]. In addition, an examination of vaso- 463
399 that carry the Sry gene (i.e., XXSry and XY–Sry) versus those that do pressin fiber densities in animals with the same sex chromosome 464
400 not (i.e., XX and XY–), then the observed difference can be attrib- complement indicated a role for the action of gonadal steroid hor- 465
401 uted to the gonadal type and/or presence of Sry. On the other hand, mones. No interaction was observed between gonadal sex and sex 466
402 if there is a difference between mice that have the Y chromosome chromosomes [84]. 467
403 (i.e., XY– and XY–Sry) versus those that do not (i.e., XX and XXSry),
404 then the observed difference can be attributed to complement of 5.1.3. Addiction 468
405 sex chromosomes (XX versus XY). On average, women use addictive drugs at lower levels than 469
men, but women become addicted to drugs more rapidly than 470
406 5.1.1. Limitations of the FCG model men [138]. Based on the FCG model, Quinn et al. showed that this 471
407 Some possible limits to the FCG model have been suggested. difference could be attributed to the differences in the comple- 472
408 One possible limit is that the size, morphology, and function of ment of the sex chromosomes and not to the gonadal secretions 473
409 the gonads are not exactly the same in XX and XY mice of the same and/or the expression of the Sry gene. XX mice developed habit- 474
410 gonadal type (e.g. XXsry versus XY-sry). Consequently, the level of ual behavior more rapidly than the XY animals independent of 475
411 gonadal hormone secretions in FCG mice may differ during critical their gonadal phenotype and even after gonadectomy. This im- 476
412 periods of development—a confound that has yet to be investi- plies that neither gonadal sex nor circulating steroid hormones 477
413 gated. Yet, numerous phenotypes that are responsive to the orga- exert major effects on the development of habit-driven behavior 478
414 nizational effects of gonadal hormones (including sexually in mice [256]. 479
415 dimorphic brain structures) do not differ in XX and XY mice of
416 same gonadal type [288,259,18,33], indicating that XX and XY mice 5.1.4. Aggression 480
417 of the same sex are likely experiencing similar levels of gonadal Males typically exhibit more aggressive behaviors compared to 481
418 secretions. For example, measurements of circulating testosterone females [229,69,311]. Recent reports have shown that aggression 482
419 in XX and XY males found no difference in testosterone levels be- latencies are strongly influenced by the simultaneous action of go- 483
420 tween the groups [15]. nadal hormones and sex chromosomes. Using the four core geno- 484
421 A second limit relates to the biochemical and molecular envi- types model, it was found that a significant interaction exists 485
422 ronment. That is, one cannot rule out the effect of prenatal hor- between the two variables. In this model, the XX females appeared 486
423 monal secretions, the influence of adult circulating hormones to be slower at displaying aggressive behavior on their first 487
424 produced by the gonads or other tissues, acute fluctuations in hor- encounter with an intruder compared to animals in all other 488
425 monal levels, and the influence of the Sry transgene (i.e., the poten- groups [113]. 489
426 tially higher expression-level of the Sry transgene in XY–Sry animals
427 versus XY mice). For example, the Sry transgene could hasten the 5.2. Direct role of sry in brain sex differences 490
428 early stages of testis organogenesis in XY–Sry males. Furthermore,
429 several phenotypes have been found to differ between XY and Sex differences in the brain may contribute to some of the psy- 491
430 XY–Sry males. However, it is not known whether these differences chological and behavioral differences we observe between the 492
431 are caused by the effect of Sry on androgen production or by some sexes. Furthermore, they may influence the susceptibility to differ- 493
432 other mechanisms that are not mediated through the action of go- ent diseases. For instance, Parkinson’s disease—a neurodegenera- 494
433 nadal hormones. tive disease that impairs motor function and speech—affects 495
434 To address these limits, it is best to rule out the effect of circu- more men than women. Research has established a link between 496
435 lating gonadal hormones. An effective approach would be to first Parkinson’s disease and a loss of dopaminergic neurons in the sub- 497
436 gonadectomize the mice followed by an administration of equiva- stantia nigra [114]. Such losses disrupt dopamine pathways, which 498
437 lent doses of gonadal steroid hormones. This is particularly impor- leads to many of the symptoms associated with Parkinson’s 499
438 tant in the case of XY– females since their level of ovarian steroid disease. 500
439 hormones differ from that in the XX wild type females [15]. Never- Robust sex differences have been observed in the development, 501
440 theless, a major limitation still remains: It will not be obvious activity, and number of dopaminergic neurons. The data described 502
441 whether the sex difference attributed to the complement of sex below represents a clear example of a sex difference in the brain 503
442 chromosomes within cells is caused by (a) gene or genes encoded that has a strong genetic component. 504
443 on the Y chromosome; (b) higher dosage of X genes particularly the
444 ones that escape X inactivation in XX animals [59]; or (c) the pater- 5.2.1. Dopaminergic neurons in rodents 505
445 nal imprint of the genes encoded on the X chromosome in XX ani- Sex differences in dopaminergic neurons have been found prior 506
446 mals, which changes the expression of these genes to exhibit a to exposure to gonadal steroid hormones. During in utero develop- 507
447 female-specific pattern [244,345]. If one determines that the sex ment, rat embryos are exposed to a plasma surge of hormones 508
448 difference in phenotype is due to the sex chromosome comple- around embryonic day 17 or 18 (E17 or E18). Yet, as early as 509
449 ment, then the next step would be to discover the nature of the E14, dissociated cell cultures of dopaminergic neurons obtained 510
450 gene or genes involved and identify whether those genes are en- from male and female rat brainstems were found to be fundamen- 511
451 coded on the X or Y chromosome and how and where they mediate tally different in their morphology and function prior to exposure 512
452 their role [84]. to gonadal steroid hormones [259]. Furthermore, females had 513
453 Notwithstanding these potential limitations, a variety of sex dif- higher numbers of dopaminergic, tyrosine hydroxylase-immuno- 514
454 ferences have been examined using the FCG model. We review reactive (TH-ir) cells in the midbrain; and their mesencepahlic 515
455 three of these. and diencepahlic neurons produced more dopamine when 516
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517 compared to males. On the other hand, soma measurements of 5.2.3. Sry is a direct effector of TH expression 582
518 diencephalic neurons from male cultures contained larger dopami- Sry is the gene on the Y chromosome that directs the bipotential 583
519 nergic neurons. Although it is difficult to make accurate measure- mammalian gonad to develop as testes—hence, its name: Sex 584
520 ments of hormonal levels in the embryonic brain, it is unlikely that determining region on Y. Sry is the founding member of the Sox 585
521 there is a huge sex difference due to gonadal hormone exposure at family of proteins, which play a major role in a wide range of bio- 586
522 this stage as the rat gonad only begins to differentiate at this point. logical processes such as neurogenesis, hematopoiesis, and neural 587
523 Therefore, this suggests a contribution of sex chromosome comple- crest development [189]. Sry contains a high mobility group 588
524 ment and/or sex-specific gene expression. (HMG) box domain and shows little conservation from mouse to 589
525 These differences are not altered even when gonadal hormone human outside this stretch of about 80 amino acids [335]. 590
526 levels are manipulated. Specifically, treatment with estradiol and The HMG box forms a domain that induces a sharp bend in the 591
527 testosterone does not eliminate the observed sex differences in DNA [332]. It is proposed that this bending of the DNA enhances 592
528 number, size, or function of the dopaminergic cells. Similar find- recruitment of specific transcriptional factors. In line with this 593
529 ings were later replicated in a study using mesencephalic cultures hypothesis, Sry has two nuclear localization signals within the 594
530 from the NMRI strain of mice [295]. Collectively, these observa- HMG domain [307] and its ability to activate transcription 595
531 tions strongly support the idea that some of the sex-specific prop- in vitro has been demonstrated [93]. 596
532 erties of the dopaminergic neurons appear to be under the control Recently, researchers have used genome-wide surveys to iden- 597
533 of non-hormonal mechanisms. tify targets of Sry in the gonad. The most widely known target of 598
Sry is Sox9 [286]. Two other notable targets of Sry are Cbln4 [50], 599
534 5.2.2. The Y chromosome’s role in dopaminergic neuron development which codes for the cerebellin precursor; and MAO A, which codes 600
535 A study utilizing the four core genotype model further strength- for monoamine oxidase A [344]. Wu and colleagues also found that 601
536 ened the case that a genetic component largely accounts for these MAO A was upregulated by Sry in the BE(2)C neuroblastoma cell 602
537 sex differences. Carruth et al. cultured mesencephalic neurons line suggesting that MAO A may be a neural Sry target [344]. 603
538 from E14 animals representing each of the groups from the four Most studies on Sry expression have focused on the gonad and 604
539 core genotypes [60]. Cultures from XY– and XY–Sry animals devel- Sry’s subsequent effects on sex determination and differentiation 605
540 oped significantly more TH-ir neurons compared to the XX and [312]. In the developing mouse embryo, Sry is expressed between 606
541 XXSry animals. However, gonadal sex did have a small effect: Ani- E 10.5 and E 12.5 in the developing genital ridge, prior to overt tes- 607
542 mals that had Sry (and hence testes) were associated with a higher tis differentiation [128]. Until recently, it was thought that Sry had 608
543 number TH-ir cells compared to those without Sry. Due to the de- no role other than sex determination. However, Sry expression has 609
544 sign of the four core genotypes model, it is difficult to separate the been found in numerous tissues outside of the testis (see below) 610
545 direct effects of Sry from its indirect effects on dopaminergic neu- and this expression in the adult male rat is now known to have bio- 611
546 rons or their precursors (e.g., through testis determination and the logically significant effects. Sry’s crucial role in the regulation of the 612
547 subsequent hormonal secretions). catecholaminergic system is one of the best examples of a direct 613
548 The data pertaining to sex differences in dopaminergic neuron genetic regulator of a trait that differs between the sexes. 614
549 development show sex differences in distinct directions and so
550 are difficult to interpret. In cultures from E14 rats and NMRI mice, 5.2.4. SRY in the brain 615
551 the sex difference is the reverse of what was seen with the four Clépet et al. were the first to perform a survey of SRY expression 616
552 core genotypes. However, rather than invalidating the findings, in human tissue outside of the gonads [68]. In fetal tissue, SRY was 617
553 the conflicting information highlights the complex interactions be- seen in the brain, adrenal, heart, and pancreas. In adults, transcrip- 618
554 tween genetics and gonadal hormones in leading to the sex differ- tion was detected in the kidney, heart, and liver. This study also 619
555 ences that are observed. First, the differences between data from showed that SRY was expressed in the teratocarcinoma cell line 620
556 NMRI mice and the four core genotypes may be attributable to NT2/D1, which was derived from adult male tissue and which 621
557 strain differences. Data from the former study indicate that genetic can be used as a model for dopaminergic neurons. When NT2/D1 622
558 background can significantly affect whether a sex difference is ob- was induced to differentiate into neurons by retinoic acid, SRY 623
559 served [295]. Carruth et al. had outbred their mice onto the MF1 expression remained. 624
560 background [60]. In regards to the differences seen between cul- SRY expression in the human adult brain was not surveyed until 625
561 tures from rats and the four core genotypes, one possible explana- 1998. Mayer et al. showed that SRY mRNA was present in the hypo- 626
562 tion is that both androgens and the Y chromosome are needed to thalamus, frontal, and temporal cortex of only the adult male 627
563 lead to the number of dopaminergic neurons being higher in males. [212]. Sry mRNA is also found in the adult male mouse brain where 628
564 Support for this hypothesis comes from our own studies where we it can be detected in the midbrain (including the substantia nigra) 629
565 see that the number of dopaminergic neurons in the rat substantia and hypothalamus in all developmental stages [213]. 630
566 nigra is higher in adult males [86]. Additionally, the finding that the
567 presence of testis was associated with a higher number of these 5.2.5. SRY and the regulation of TH expression 631
568 neurons fits with our hypothesis. There are also important distinc- Sry has a biologically significant role in the brain in at least one 632
569 tions in the timing of the cultures in relation to gonadal develop- instance—the regulation of tyrosine hydroxylase (TH) [86,219]. In a 633
570 ment: while both studies cultured E14 neurons, the bipotential 2004 study, Milsted et al. found that Sry is a regulator of TH gene 634
571 gonad has already differentiated into a testis to a larger extent in transcription [219]. The study looked at Sry’s role in relation to 635
572 the mice [97,182] than in the rat at this gestational stage [204]. TH in both the brain and the adrenal medulla. They demonstrated 636
573 As such, the hormonal environment from which these cultures that Sry and TH mRNA were co-localized in the locus coeruleus, 637
574 were derived may not be the same, which could account for some substantia nigra, and ventral tegmental area of the male rat 638
575 of the disparity in the direction of the sex difference. An elabora- (Fig. 4A). They then used a luciferase reporter assay to show that 639
576 tion of the hypothesis presented above is that it is not just the tes- Sry’s ability to upregulate TH expression is dependent on the AP1 640
577 tes and androgens that are essential but also Sry, the gene that binding sites in the promoter of TH. 641
578 initiates testicular development. Using a rat model, our laboratory The in vivo significance of those findings was shown and 642
579 has found evidence that this may be the case and showed that Sry expanded upon by a study from our laboratory. By in situ hybrid- 643
580 has a direct effect on the expression of TH in the substantia nigra ization, we were able to determine the spatial distribution of Sry 644
581 [86]. mRNA within the rodent brain [86]. Specific labeling of Sry was 645
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21 October 2010
observed in the substantia nigra, medial mammillary bodies of the 646

hypothalamus, and the cortex of male rats only. These transcripts 647
were translated and co-localized with the TH protein—all neurons 648
in the substania nigra positive for Sry were also positive for TH. 649
Knocking down Sry expression in the male rat substania nigra led 650
to 38% fewer TH-immunoreactive neurons and introduced a signif- 651
icant asymmetry in limb use where the animals strongly favored 652
the usage of their ipsilateral limbs (Fig. 4B and C). The reduction 653
in TH-ir neurons was not due to neural degeneration and is most 654
likely due to a reduction in TH expression. There was also a 26% de- 655
crease in TH-ir cells in the striatum when Sry expression was 656
knocked down in that region. TH-ir neuron number was not af- 657
fected in females infused with the Sry antisense cocktail. 658
The nature of Sry’s modulation on TH remains unclear. The re- 659
sults of the study by Milsted et al. argue that the TH response to 660
Sry is likely an indirect one [219]. Our data indicate that there 661
may be both direct and indirect mechanisms [86]. 662
The identification of a specific function for Sry in the dopami- 663
nergic system, specifically, and the brain, generally, is still absent. 664
Additionally, comprehensive temporal and spatial expression stud- 665
ies need to be performed on brain Sry expression. Another largely 666
unanswered question concerns the identity of a female-specific 667
‘compensatory’ factor for Sry. 668
We have shown that the attenuation of Sry expression in males 669
results in detrimental motor effects and that females have lower 670
levels of TH neurons [86]. However, female rats do not go through 671
life exhibiting motor dysfunction. The higher susceptibility of men 672
to Parkinson’s disease also implies that this factor exists and might 673
have protective effects against the nigrostriatal degeneration that 674
is the hallmark of Parkinson’s [114]. Estrogens are a viable candi- 675
date for this factor – short-term injections of estradiol benzoate 676
lead to an increase in TH mRNA [287] and ovariectomy results in 677
loss of TH-positive neurons [190]. 678
6. Novel approaches to studying sex differences 679
Traditional animal models have played an invaluable role in 680

advancing our understanding of sex differences. In particular, sci- 681
entists are able to conduct experimental manipulations that would 682
be unethical on human subjects. However, research on specific 683
groups of people has addressed some complex questions. In this 684
section, we focus on research conducted on four such groups: peo- 685
ple with sex-chromosome variations, people with genetic muta- 686
tions of the sexual development pathway, people attracted to the 687
same sex, and those with cross-sex gender identity. For readers 688
interested in learning more about disorders of sex development, 689
several comprehensive resources exist [324,107]. 690
6.1. Genetic disorders of the sex chromosomes 691
The most obvious genetic difference between females and 692

males is their sex chromosome complement (i.e., XX and XY). Var- 693
ious human sex chromosome disorders exist, which might be con- 694
sidered a human model for sex chromosome effects similar to the 695
four core genotypes. The most common variants in men involve 696
additional X or Y chromosomes: Klinefelter’s Syndrome (47,XXY); 697
and 47,XYY Syndrome. In women, the most common variants en- 698
tail the addition or absence of X chromosomes including 47,XXX; 699
Fig. 4. Sry regulates tyrosine hydroxylase (TH) levels and motor behavior. (A) Sry
and TH colocalize in the locus coeruleus (LC), ventral tegmental area (VTA) and 48,XXXX; and Turner Syndrome (45,X). 700
substantia nigra pars compacta (SNc) [86,219]. (B) Knockdown of Sry expression in Chromosomal abnormalities can highlight the role that sex 701
the SNc leads to a reduction in the number of TH-immunoreactive (TH-ir) neurons. chromosomes play in the phenotypic differences typically seen be- 702
Unilateral infusion of antisense oligodeoxynucleotides (ODN) against Sry decreased tween 46,XY men and 46,XX women. For instance, adolescent girls 703
the number of TH-if neurons by 38% compared to the contralateral side infused
with sense ODN [86]. (C) Unilateral downregulation of TH expression by Sry leads to
with Turner Syndrome are more likely to have social difficulties 704
asymmetric limb use. Animals preferentially used the forelimb ipsilateral to the compared to 46,XX girls [215], which may be partly related to fa- 705
side of the antisense ODN infusion (preferred limb highlighted in yellow) [86]. cial and emotional-processing impairments [188]. Furthermore, 706
j.yfrne.2010.10.001
21 October 2010
707 46,XX girls score better than boys on tests of social cognitive skills identification, which may be mediated by numerous social and 769
708 [300]. The fact that both 46,XY boys and 45,X girls experience more psychological factors [65,143,194]. Nevertheless, most people 770
709 social adjustment problems compared to 46,XX girls suggests the report primarily opposite-sex or heterosexual attractions. Yet, a 771
710 presence of a genetic locus involved in social cognitive skills on significant number of people (approximately 2–6%) report pre- 772
711 the X chromosome. Data from Skuse et al. [301], suggest that this dominantly homosexual attractions [89]. 773
712 locus may be subject to imprinting. Significant differences between The distribution of sexual behavior differs between men and 774
713 45,XpO Turner-syndrome girls (in which the X was of paternal ori- women. In men, the distribution is largely bimodal [133]. That is, 775
714 gin) and 45,XmO girls (in which the X was maternally derived) in men are either attracted to one sex or the other. Although there 776
715 terms of social skills have been reported. 45,XpO had superior so- is disagreement regarding bisexuality among men [342], physio- 777
716 cial competence and better social skills than 45,XmO girls suggest- logical research has found that very few men (even those who 778
717 ing that the genes in this locus are expressed only from the openly identify as bisexual) show comparable physical attraction 779
718 paternal X. This could potentially be one of the reasons why boys to both men and women [265]. The distribution is more complex 780
719 are more susceptible to disorders such as autism that affect social in women, in which the fraction of women that show exclusive 781
720 adjustment and social skills such as language. In boys the X is only same-sex attraction is lower than men (1–3%), but many more wo- 782
721 of maternal origin and therefore this locus would be silenced. men than men report erotic fantasies towards both sexes [154]. 783
722 In other cases, however, the characteristics of individuals with In this section we will highlight some of the biological research 784
723 sex chromosome abnormalities may augment the expected sex dif- that has focused on same-sex attraction. A more thorough review 785
724 ference. On average, men in the general population have better vis- is available for interested readers [278]. 786
725 uospatial skills than women, and women have better verbal skills
726 than men—which suggests that increased dosage of X chromosome 6.3.1. Neuroanatomy differences in sexual orientation 787
727 genes may contribute to these skills. However, women with Turner Neuroanatomical differences have been reported for three brain 788
728 Syndrome have impaired visuospatial abilities yet greater language regions based on sexual orientation in human males: the arginine 789
729 skill compared to control women [272,314]. vasopressin neuronal population of the suprachiasmatic nucleus, 790
730 The role of the Y chromosome in psychosexual differentiation is which was larger in gay men than in male and female controls 791
731 still unclear. Work by McCarty et al. indicates that genes on the Y [309]; the third interstitial nucleus of the anterior hypothalamus 792
732 chromosome outside of SRY and the pseudoautosomal region have (INAH-3), which is smaller in gay men and more similar in size 793
733 ‘‘no obvious role. . .on psychosexual differentiation in genetic to female controls [192]; and the anterior commissure, which is 794
734 males [214].” This is difficult to ascertain because (a) the incidence larger in gay men than in control males and females [3]. The most 795
735 of XY gonadal dysgenesis is extremely rare, estimated to be 1 in discussed anatomical finding was in INAH-3 [192]. Although sub- 796
736 20,000 [64]; and (b) these individuals have been poorly studied sequent researchers reported inconsistent findings [57], a compa- 797
737 in regards to sexual differentiation of the brain. rable difference was found in sheep [271]. 798
Approximately 8–10% of the domestic ram population has been 799
738 6.2. Androgen Insensitivity Syndrome found to sexually prefer other males. Unlike other animal models 800
showing atypical sexual behavior, these male-oriented rams 801
739 The role of the androgen receptor (AR) in brain sexual differen- mount and ejaculate on other males versus simply exhibiting a 802
740 tiation has been discussed in patients with Androgen Insensitivity passive stance (i.e., lordosis). Consequently, they are an ideal ani- 803
741 Syndrome (AIS). AIS is an X-linked recessive disorder that is seen in mal model of male homosexuality because their coital behavior 804
742 1 out of 20,400 live male births [250]. There are two forms of AIS: is masculine but their sexual partner preference is feminine. 805
743 Complete (cAIS) and Partial (pAIS). People with Complete AIS are An analog of the sexually dimorphic nucleus (ovine SDN or 806
744 genetically male (46,XY with undescended testes) but phenotypi- oSDN)—a hypothalamic nucleus thought to be involved in mate 807
745 cally female. However, individuals with Partial AIS typically have selection—was identified in the sheep brain [271]. The oSDN was 808
746 ambiguous genitalia. found to be larger in female-oriented rams compared to male-ori- 809
747 AIS is caused by mutations in the androgen receptor (AR) gene ented rams (MORs), and ewes; the latter two groups had oSDN’s 810
748 [255]. There is an important difference in the behavioral phenotype comparable in size. It was hypothesized that the oSDN corresponds 811
749 between humans and rats with Complete AIS. Humans with Com- with human INAH-3, which suggests that the relevant neuroana- 812
750 plete AIS are female-typical in their play behavior and sexual ori- tomical pathways are conserved between mammalian species. 813
751 entation [353]. In contrast, XY rats with AR mutations behave
752 sexually like wild-type males and have a male-typical partner pref- 6.3.2. The role of prenatal androgens 814
753 erence [353]. The reasons behind this difference remain unclear One of the main hypotheses on the determinants of sexual ori- 815
754 although the implication is that androgens play an important role entation was that same-sex attraction was the result of atypical 816
755 in masculinizing the human brain. However, we cannot completely sex-hormone levels during gestation. Studies in rodents and ferrets 817
756 discount the role of estradiol as the expression of aromatase showed that pre- or perinatal hormonal manipulation could lead to 818
757 (which converts testosterone to estradiol) is dependent on andro- changes in partner preference, sexual behavior, and coital perfor- 819
758 gen signaling via AR [26]. mance largely controlled by the hypothalamus [92,306]. Yet, 820
extending this hypothesis from animal research to humans is diffi- 821
759 Q2 6.3. Sexual orientation cult in our opinion. Atypical sexual behavior in rodents is hard to 822
equate to human sexuality. For example, the induction of lordosis 823
760 Of all behavioral differences between males and females, part- in male rats does not change their partner preference. Instead, what 824
761 ner choice is one of the most pronounced. With very few excep- changes is the rat’s entire sexual behavior, which is different from 825
762 tions in the Animal Kingdom, males typically choose females to sexual orientation. Rather, an animal that consistently chooses 826
763 mate with, and females typically choose males to mate with. same-sex partners—such as the above-mentioned ram whose adult 827
764 Although sexual selection is a driving force of evolution, little is hormone levels are within the male-typical range [268]—would be 828
765 known about the molecular basis of partner preference. a better model. Furthermore, the treatment necessary to change 829
766 Human sexual orientation is a complex phenotype to study. Part the sexual behavior of rodents goes far beyond any naturally occur- 830
767 of this difficulty comes from the accurate assessment of sexual ori- ring variation in androgen levels [247], and as such is unlikely to 831
768 entation [218,223], especially when researchers depend on self- reflect natural causes of human variation in sexual orientation. 832
j.yfrne.2010.10.001
21 October 2010
833 Additionally, hormonal manipulations have failed to make male The inactive chromosome remains inactive in all resulting daugh- 898
834 animals mount other males. ter cells [54]. If inactivation is completely random, this means that 899
835 Case studies on humans with various genetic defects in the in a population of female cells the maternal X will be inactivated in 900
836 androgen pathway show only limited support for the hypothesis. 50% of the cells whereas the paternal X is inactive in the remaining 901
837 There are no reports showing an increase in attraction to men in half. If a particular X chromosome, whether maternal or paternal, is 902
838 hypovirilized XY individuals relative to the general population. inactivated in more than 90% of cells, that individual is considered 903
839 This implies that disruption of the androgen pathway does not to be extremely skewed in regards to X-inactivation. Mothers with 904
840 have a strong effect on male sexual orientation. The role of andro- gay sons were found to have extreme skewing of X-inactivation 905
841 gens in female sexual orientation appears more complex. Women when compared to mothers with no gay sons: Skewing in mothers 906
842 with congenital adrenal hyperplasia (CAH) experience abnormal with one gay son = 13/97 or 13%; skewing in mothers with two or 907
843 activity of the embryonic adrenal glands. This leads to a much more gay sons = 10/44 or 23% [47]. This suggested an involvement 908
844 higher exposure of female fetuses to androgens, greatly exceeding of the X chromosome in the molecular mechanisms of sexual ori- 909
845 female-typical levels. The exposure is often high enough to cause entation. Arguably, the effect of the X-chromosome gene(s) or 910
846 some degree of genital masculinization. Several studies have found mechanisms that influence sexual orientation in the sons is visible 911
847 that CAH women reported more same-sex sexual activity and that in the blood of their mothers. 912
848 more self-identified as homosexual compared to the general popu- A genome-wide linkage scan on gay-brother pairs showed sug- 913
849 lation, which suggests that typical female sexual development is gestive linkage to loci on chromosome 7 and 8 [230]. A maternal 914
850 disrupted by extreme prenatal androgen exposure [149]. It is origin effect was found near marker D10S217, located at 10q26, 915
851 important to note that while women with CAH reported more gen- with significant linkage for maternal meioses but no paternal con- 916
852 der atypical attitudes, interests, and behavior, the majority still tribution. This result suggested the presence of a maternally-ex- 917
853 identified as heterosexual. The role of androgens in the sexual ori- pressed, paternally-silenced imprinted gene for sexual 918
854 entation of lesbian women who have no genital masculinization is orientation in 10q26. The relatively small sample size (N = 456) 919
855 still unclear. likely underpowered this study. However, a larger linkage scan 920
856 Two studies looked at genetic variation in genes related to the on 1000 homosexual male sibling pairs is currently underway 921
857 steroid pathway. A candidate gene study on the human androgen (A.R. Sanders, personal communication). 922
858 receptor gene [202] and one on the aromatase gene (CYP19) [94] The presence of a possible imprinted gene on chromosome 10 is 923
859 found no evidence that variations in these genes play a role in vari- particularly interesting. Previously reported evidence of maternal 924
860 ations in human sexual orientation. A variety of anthropomorphic loading of sexual orientation transmission was initially used to 925
861 measures have been used as indirect measures of prenatal andro- implicate the X-chromosome in human sexual orientation, but it 926
862 gen exposure, but results have been inconsistent. A recent prospec- could just as well indicate epigenetic factors acting on autosomal 927
863 tive study showed no correlation between maternal circulating genes. A role for imprinted genes in human sexual orientation 928
864 androgen concentration at 18 and 34 weeks of gestation and digit was hypothesized earlier [46]. 929
865 ratio in girls [145]. An in-depth discussion of these studies and a One of the most replicated findings in sexual orientation re- 930
866 speculation on their widely varying results falls outside of the search is known as the ‘fraternal birth order effect’: Each older 931
867 scope of this manuscript. For a review on the often cited 2D:4D fin- brother increases the odds of male homosexuality by approxi- 932
868 ger-length ratio in sexual orientation, see McFadden et al. [216]. Fi- mately 33% [41,166]. This is relative to the baseline frequency of 933
869 nally, studies retrospectively examining the influence of stressful homosexuality, and the odds of being homosexual are about twice 934
870 events during pregnancy have been inconclusive [23,99]. Therefore as high for the fourth-born son relative to the first-born son. Yet, 935
871 we believe that there is little evidence that naturally occurring this finding is not so simple: The effect is only influenced by older 936
872 variations of prenatal circulating gonadal hormones within one brothers born via the same mother, it is not influenced by the num- 937
873 sex play a role in determining variants of sexual orientation ber of older sisters, and it only seems to be true for right-handed 938
874 although diverging views have been expressed on this topic. homosexual men [44]. The dominant hypothesis for this effect, 939
which lacks empirical support, is that each successive male preg- 940
875 6.3.3. The genetics of sexual orientation nancies increases the mother’s immunity against male-specific 941
876 Evidence is mounting that there is a strong genetic component antigens expressed by the fetus [42,43], and this immune response 942
877 influencing sexual orientation. Family studies [249,21,243,24] have affects any subsequent male fetuses. Although this phenomenon 943
878 found an increased rate of homosexuality among siblings and in does not directly implicate genetics, at the very least it demon- 944
879 the maternal uncles of gay men (a median rate of 9% for brothers strates a biological basis for human male sexual orientation and 945
880 of gay men) [22]. Although the concordance rates of homosexuality suggests the immune system as an alternative, gonadal hormone- 946
881 in monozygotic twins vary depending on ascertainment methods independent mechanism through which sex differences can be 947
882 [21,25,174,180], twin studies have found that there is a substantial mediated. 948
883 genetic component in the development of sexual orientation. Altogether, there is mounting evidence for a genetic role of 949
884 There has been limited molecular genetics research. In 1993, human sexual orientation. The overwhelming dominance of heter- 950
885 Hamer et al. reported that male homosexuality was more often osexual behavior in the animal kingdom points at a tight molecular 951
886 on the mother’s side of the family versus the father’s side [133]. regulation of this trait. 952
887 A linkage scan showed significant linkage of male homosexuality
888 to the X-chromosome region Xq28 [133]. This finding was subse-
889 quently replicated by two studies [154,279] but not by an indepen- 6.4. Gender identity 953
890 dent group [264]. However, a meta-analysis of the results across all
891 four studies yielded an estimated level of Xq28 allele sharing be- Gender identity, or our sense of maleness or femaleness, plays 954
892 tween gay brothers of 64% instead of the expected 50% [132]. Nev- an important role throughout our development affecting both 955
893 ertheless, the exact gene(s) involved has (have) yet to be identified. our sense of self and our relationships [278,277,282]. Our gender 956
894 A different method also implicated the role of the X-chromo- identity and the roles ascribed to that gender are heavily 957
895 some. Unlike male cells, female cells contain two X-chromosomes. influenced by social factors [e.g. 226]. Most people adopt a gender 958
896 Consequently, each female cell randomly inactivates one X-chro- identity congruent with the sex assigned at birth, which remains 959
897 mosome during embryogenesis to create dosage compensation: constant throughout life [339]. The best approach to study the 960
j.yfrne.2010.10.001
21 October 2010
961 biological basis of gender identity is to study individuals who de- proposed that observed molecular sex differences may compensate 1024
962 velop a cross-gender identity—in particular transsexuals. for other sex differences rather than generating differences be- 1025
963 Zhou et al. were the first to describe a sex difference in the cen- tween males and females themselves [80]. It will be crucial to tease 1026
964 tral subdivision bed nucleus of the stria terminalis (BSTc) in hu- out whether small imbalances influence specific differences in 1027
965 mans and a potential biological marker for gender identity [350]. neuropsychological function. Finally, it will be essential to trans- 1028
966 The type and direction of the sex difference mirrored that of the late our knowledge of sex differences to improve the quality of 1029
967 rat: the volume of the BSTc is larger in men than in women. The medical and psychological care. 1030
968 study also found that the BSTc of male-to-female (MtF) transsexu- As science continues to advance our understanding of sex dif- 1031
969 als is female-sized but the interpretation of this finding is compli- ferences, a new field is emerging focused on better addressing 1032
970 cated. The MtF subjects used in the study had all received estrogen the needs of men and women: gender-based biology and medicine. 1033
971 therapy so it remains unclear if the sex difference is related to gen- The ultimate aim of this field is to translate scientific data into 1034
972 der identity or hormonal exposure since estrogens can modify the practical applications that are effective for each sex [158]. From 1035
973 structure of the brain. A second confound is the relatively small tailoring preventive screenings to treating sex-specific illnesses, 1036
974 size of the sample pool as the authors were only able to gain access this field recognizes that ‘‘one-size-fits-all” healthcare has its lim- 1037
975 to tissue from six MtF transsexuals. its. Rather, our biological sex is an important variable that must be 1038
976 The literature on the genetic basis of transsexualism is extre- considered in our mental and physical health. 1039
977 mely limited. Although there are reports of families where several
978 members identify as transsexuals [119], such reports are rare. Acknowledgment 1040
979 There are few twin case studies, and they have reported differing
980 concordance rates for transsexualism [284,111,157,276]. Since no This work was funded in part by the National Institutes of 1041
981 systematic twin study has been reported, it is impossible to sepa- Health. 1042
982 rate genetic from environmental influences. Consequently, there is
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Genetics of Sex Differences in Brain &amp; Behavior

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of Pages 20, Model 5G

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Contents lists available at ScienceDirect

3 The genetics of sex differences in brain and behavior

2 T.C. Ngun et al. / Frontiers in Neuroendocrinology xxx (2010) xxx–xxx

Structure/region Known roles Sex difference Basis of difference

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Neurochemical Known roles Species Selected sex differences

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observed in the substantia nigra, medial mammillary bodies of the 646

6. Novel approaches to studying sex differences 679

Traditional animal models have played an invaluable role in 680

6.1. Genetic disorders of the sex chromosomes 691

The most obvious genetic difference between females and 692

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