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Genetics of Sex Differences in Brain & Behavior

Genetics of Sex Differences in Brain & Behavior

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Published by: Alice Andrews on Oct 22, 2010
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12
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
8
a r t i c l e i n f o
9
Article history:
10Available online xxxx11
Keywords:
12Sexual differentiation13Brain anatomy14Sex differences15Sexual orientation16Gender identity17Sex chromosomes18SRY 19Dopamine20Behavior21
2 2
a b s t r a c t
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Biological differences between men and women contribute to many sex-specific illnesses and disorders.
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Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone
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secretions. However, emerging research has shown that some differences are mediated by mechanisms
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otherthantheactionof these hormonesecretions andinparticular byproducts of genes locatedontheX
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andYchromosomes,whichwerefertoasdirectgeneticeffects.Thispaperreviewstheevidencefordirect
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geneticeffectsinbehavioralandbrainsexdifferences.Wehighlightthe‘fourcoregenotypesmodelandsex
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differences in the midbrain dopaminergic system, specifically focusing on the role of 
Sry
. We also discuss
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novel research being done on unique populations including people attracted to the same sex and people
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with a cross-gender identity. As science continues to advance our understanding of biological sex differ-
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ences,anewfieldisemergingthatisaimedatbetteraddressingtheneedsofbothsexes:gender-basedbiol-
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ogyandmedicine.Ultimately,thestudyofthebiologicalbasisforsexdifferenceswillimprovehealthcarefor
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bothmenandwomen.
35
Ó
2010 Elsevier Inc. All rights reserved.
3637
38
1. Introduction
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Men and women are different in many ways. These differences
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include both biological phenotypes [e.g.191] and psychological
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traits [e.g.200]. Some of these differences are influenced by envi-
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ronmental factors[1,340]. Yet, there are fundamental differences
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between the sexes that are rooted in biology.
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Ofparticularinterestaresexdifferencesthathavebeenidentified
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inthebrain.Althoughthebrainsofmenandwomenarehighlysim-
46
ilar, theyshowconsistent differences that have important implica-
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tions for each sex. That is, brain sex differences uniquely affect
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biochemical processes, may contribute to the susceptibility to spe-
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cificdiseases, andmayinfluencespecificbehaviors. Suchbiological
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differencesshouldneverbeusedtojustifydiscriminationorsexism.
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However,webelievethatathoroughunderstandingofthesediffer-
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ences can informresearchers and clinicians so that they can better
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address important issues. Two examples include how genetic sex
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canleadtodifferencesbetweenthesexesintheetiologyandthepro-
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gressionofdiseaseandhowdifferencesinneuraldevelopmentmay
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resultindifferencesincognitionandbehavior.
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Inthispaper,wewillreviewsexdifferencesinbrainandbehavior
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that arenot due totheactionofhormonessecreted by thegonads
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which has been the dominant mechanism associated with such
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differences—but from what we term ‘direct genetic effects.’ These
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are effects that arise from the expression of X and Y genes within
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non-gonadal cells and result in sex differences in the functions of 
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thosecells.First,wewillhighlightsomesexdifferencesatthebiolog-
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icallevelandatthepsychologicallevel.Then,wewillreviewthe‘clas-
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sic’ view that dominated the field of sex differences—that most sex
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differences,especiallythoseconcernedwithreproductivephysiology
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andbehavior,wereduetotheactionofhormonesproducedbythego-
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nads.Next,wewillpresenttheemergingviewthat‘directgeneticef-
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fects’ play an important role as well. Finally, we will discuss novel
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approachestostudyingsexdifferencesbyfocusingonuniquegroups
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ofindividuals:peoplewithsex-chromosomevariations(e.g.,Klinefel-
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ter’sSyndromeandTurnerSyndrome),peoplewithgeneticmutations
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inthesexualdevelopmentpathway,peoplewithanatypicalsexual-
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orientation,andpeoplewhoexperienceacross-genderidentity.
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2. Biological sex differences
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There are many biological differences between males and fe-
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males that are beyond the obvious differences at a gross, macro le-
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vel (e.g., height, weight, and external genitalia). Specifically, there
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are several important physiological differences that have critical
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implications including the susceptibility to different diseases and
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the ability to metabolize different medications. In this section we
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will highlight some sex differences in neuroanatomy and
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neurochemistry.
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 2.1. Neuroanatomy
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The two sexes have similar but not identical brains. Most brain
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studieshavefocusedongross manifestations of thesedifferences—
0091-3022/$ - see front matter
Ó
2010 Elsevier Inc. All rights reserved.doi:10.1016/j.yfrne.2010.10.001
Corresponding author.
Q1
Fax: +1 (310) 794 5446.
E-mail address:
evilain@ucla.edu(E. Vilain).
1
These authors contributed equally to this work.
Contents lists available atScienceDirect
Frontiers in Neuroendocrinology
YFRNE 451 No. of Pages 20, Model 5G21 October 2010
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
 
87
namelythesize of specificregions or nuclei. Yet, thereis mounting
88
evidence of sex differences at a finer level including differences in
89
synaptic patterns[120,66]and neuronal density[117,211,338]. It
90
is beyond the scope of this article to provide a comprehensive re-
91
view of all known neuoranatomical differences. We have provided
92
notable sex differences in the rat brain inTable 1. There are also
93
excellent resources for those who are interested in delving deeper
94
into this topic[146,98,28].
95
We have chosen to focus on neuroanatomical differences in the
96
rat because the biological significance and origins of these differ-
97
ences are much clearer than in humans. Neuroanatomical differ-
98
ences in humans are also well-studied although ethical reasons
99
precludetheexperimental manipulationsthathaveledtothefind-
100
ings detailed inTable 1. This significantly limits the conclusions
101
that can be drawn from any observations made in humans.
102
Although these neuroanatomical differences are intriguing,
103
most are limited because the practical or functional significance
104
of these findings are unknown. Discovering the significance of 
105
these differences is often difficult, even in rodents. de Vries and
106
Soderstenhaveeloquentlyoutlinedthechallengesfacingresearch-
107
ers who want to understand the link between sex differences in
108
structure and behavior[82]. A highly relevant case study high-
109
lighted in their review concerns the sexually dimorphic nucleus
110
of the preoptic area (SDN-POA). The preoptic area (POA) has been
111
implicated in the regulation of male copulatory behavior[225],
112
but the link (if any) between the sex difference in SDN-POA size
113
and behavior remains elusive. Masculinizing the size of the SDN-
114
POA in female rats does not result in a corresponding masculiniza-
115
tion and defeminization of behavior[159]. Instead, the SDN-POA
116
may be related to inhibition of female sexual behaviors
117
[252,141], whichmightnothavebeenanobvioushypothesisgiven
118
what was known about the POA previously. As science and tech-
119
nologycontinuetoadvance, we will eventuallyknowhowtomake
120
sense of the mounting evidence of sex differences in the brain. For
121
now, it is reasonable to suspect that such differences may help ac-
122
count for observed sex differences in behavior, neurological dis-
123
eases, and cognitive abilities.
124
 2.2. Neurochemistry
125
Males and females exhibit different patterns of transmitting,
126
regulating, and processing biomolecules.Table 2presents some
127
of the neurochemical sex differences that have been identified.
128
As a specific example, we focus below on the monoaminergic
129
system, which has been implicated in several neurological
130
diseases and mental disorders that differentially affect men and
131
women.
132
Monoamines are a class of small-molecule neurotransmitters
133
that are involved in the control of a variety of processes including
134
reproduction and sexual behavior[183,170], respiration[112], and
135
stress responses[163]. Monoamines have also been implicated in
136
numerous mental disorders, including ones that differentially af-
137
fect men and women[283,303]. Likewise, sex differences in the
138
monoaminergic systems in the rat are well-documented. Reisert
139
and Pilgrim provided a comprehensive review of arguments for
140
the genetic bases of these differences[259].
141
Monoamines are subdivided into two groups—catecholamines
142
and indolamines—based on their molecular structure. The main
143
catecholamines are dopamine (DA), norepinephrine (NE) and epi-
144
nephrine, which are synthesized from the amino acid tyrosine.
145
Fig. 1highlights some of the known sex differences of the dopami-
146
nergic system. Regulation of dopamine can potentially control the
147
levels of the other two catecholamines as they are derived from
148
dopamine.
 Table 1
Selected neuroanatomical sex differences in the rat.
Structure/region Known roles Sex difference Basis of differenceSexually dimorphicnucleus of thepreoptic area(SDN-POA)ThePOAisimplicatedintheregulationofmalecopulatorybehavior[225]. Lesions of the SDN alone slow acquisitionof thisbehavior. Potential humanequivalent is INAH-3[4]2.6 times larger in males[118]Perinatal aromatized androgen decreasesneuronal apoptotic rates in males[317]Anteroventralperiventricularnucleus (AVPV)Involved in regulating the luteinizing hormone surge infemales[317]and male copulatory behavior[262] 2.2 times larger in females with ahigher cell density[45]Degenerationofcellsinthisregionisgreaterin males[308]due to prenatal action of androgenBed nucleus of striaterminalis(BNST)Plays a role in the control of male sexual behavior[100],release of gonadotropin[32], and modulation of stress[329,134]The principal nucleus (BNSTp) islarger in volume in males[85]The larger volume in males is due tosexually different apoptotic rates caused bytestosterone[109]Corpus callosum Conducts information between the two halves of thecortex[304]Larger in neonatal males[351]Organizational effects of testosterone leadto masculinization while feminizationappears to be dependent on estrogens[106,105]Arcuate nucleus(ARC)Helps regulate the estrus cycle[203], appetite and bodyweight[217]Neurokin-B neurons innervatecapillary vessels in theventromedial ARC in post-pubertalmales only[66]Dihydrotestosterone is responsible for themasculine projection pattern[67]Amygdala Strongly associated with emotion, decision-making andPavlovian conditioning[288]Adult males have a larger medialnucleus than adult females[221]Treatment of females with estradiolmasculinizes this nucleus[221]The posterodorsal aspect of themedial amygdala is 65% larger inmales[148]Activational effects of circulating androgensaccounts for the larger region in males[73]Cerebral cortex Connectedtoawiderangeofprocessesfrommemory[20]to language[33]to emotional processing[237] Right posterior cortex is thickerthan left but only in males[90]Gonadal hormones play a role inmaintainingthesexdifference(ovariectomymasculinizes the cortex of females)[90]Ventromedialhypothalamicnucleus (VMN)Involved in the control of lordosis, mounting, andnorepinephrine release[102].High concentrations of  steroid receptor mRNA have been observed in theventrolateral VMN[297]Females have less synapses in theventrolateral VMN compared tomales[211]Organizational effects of aromatizedtestosterone appear to be crucial inestablishing the masculine trait[253]Substantia nigrapars compactaMade up almost entirely of dopaminergic neurons.Dopamine is involved in control of motor activity[123]Females have 20% fewerdopaminergic neurons[86]A genetic component has beendemonstrated 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.2
T.C. Ngun et al./Frontiers in Neuroendocrinology xxx (2010) xxx–xxx
YFRNE 451 No. of Pages 20, Model 5G21 October 2010
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
 
149
Catecholaminesarereleasedbytheadrenalglandsusuallyinre-
150
sponse to stress, which affects males and females differently. For
151
instance, chronic physical stress impairs memory in male rats only
152
[201]. The sexes also show differing neurochemical responses:
153
Dopamine activity is upregulated in males only whereas norepi-
154
nephrine is upregulated in females only (Fig. 1A). Sex differences
155
have also been found in the regulation and modification of dopa-
156
mine (seeFig. 1B and C). Specifically, the enzyme tyrosine hydrox-
157
ylase (TH), which is involved in dopamine synthesis[193], is
158
regulated by
Sry
—the male sex determination gene—which is not
159
present in females. Additionally, levels of norepinehrine in the
160
amygdala differ between the sexes as a result of age. Thus, it is
161
likely that brain catecholaminergic responses to stress might also
162
differ between the sexes.
163
Another monoamine is serotonin, which is an indolamine. Un-
164
likecatecholamines,serotoninisderivedfromtheaminoacidtryp-
165
tophan. The serotonergic system shows sex differences (Fig. 2),
166
though many of these differences remain unlinked to behavioral
167
differences between men and women. Nevertheless, differences
168
in this system likely have consequences given the link between
169
serotonin and numerous mental disorders[48,275].
170
3. Psychological and behavioral sex differences
171
In addition to biological differences, men and women differ in
172
many psychological and behavioral aspects. For instance, menper-
173
form better on specific visuospatial aspects (e.g., mental rotation)
174
comparedtowomen;andwomenperformbetteronspecificverbal
175
tasks (e.g., verbal fluency) compared to men[155]. Furthermore,
176
there is a large sex difference in sexual interests and behaviors,
177
such as interest in casual sex, interest in multiple sex partners,
178
and interest in visual-sexual stimuli (e.g., pornography)
179
[198,281]. Other examples are summarized inTable 3.
180
Some contend that these differences are due to social systems
181
and gender socialization [cf.310,53,238]. Nevertheless, biological
182
traits likely contribute to many sex differences. Thus, a thorough
183
understanding of the main determinants involved in expression
184
of such sex differences can help us better explain the relationship
185
betweenbrain,behavior,andenvironment.Inaddition,itallowsus
186
todeterminehowone’ssexpotentiallyinfluencestheriskofdevel-
187
oping disorders that manifest and progress differently in men and
188
women. Such knowledge can better inform the treatment of these
189
diseases.Tables 3 and 4illustrate several factors (e.g. hormones
190
and genes) that may be causally linked to expression of sex differ-
191
ences in behavior and disease, respectively.
192
4. The classical view on sex differences
193
Researchers have examined what contributes to the differences
194
we see between males and females. Certainly for humans, social
195
environmentsinfluencesomeofthesedifferences.Forinstance,so-
196
cial stratifications (e.g., social class and the distribution of social
 Table 2
Selected neurochemical sex differences in the brain.
Neurochemicalsystem/pathwayKnown roles Species Selected sex differencesCatecholamines(also seeFig. 1)Involved in the control of a variety of processes includingreproduction and sexual behavior[183,170],respiration[112],and stress responses[163]Rat Male have higher norepinephrine (NE) levels in the amygdala andhypothalamus at day 25. Direction of this sex difference is reversedat day 300[296]In response to chronic physical stress, dopamine (DA) activity isupregulated only in males whereas NE activity is increased only infemales[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,perception, reward, and attention[39]RatandhumanSex differences in the serotonergic system are found at multiplelevels[234,333,348,305,220].SeeFig.2foranillustrationofsomeof  these differencesAromatase Plays a key role in sexual differentiation of the brain by convertingtestosterone to 17
b
-estradiol[231]Rat Aromatase activity is higher in males than females in many regionsincluding the anterior hypothalamus, BNST and POA[269]Onlymalesexperiencespikesintheexpressionofbrain-specificandtotal aromatase during embryonic development and shortly after[71]Vasopressin(VP)VP in the central nervous system (CNS) has been linked to learning,memory and motor behavior[263]. It has also been connected tothe control of social behaviors such as pair-bonding, parenting andaggression[151]Rat The number of vasopressin-positive cells is two to three timeshigher in males than in females[81]Vasopressin-positive projections are also two to three times denserin males[81]Intrahypothalamic release of VP due to an increase of plasmaosmolality is higher in females[239]Human Some studies have found that plasma VP concentrations are higherin men than in women[263]CholinergicsystemThe cholinergic system helps regulate the sleep-wake cycle andmodulates synaptic plasticity implicated in memory, learning, anddevelopment[77,165]. Sex differences are found at many points inthe cholinergic system (reviewed in Rhodes and Rubin[263])Rat Levels of acetylcholine (ACh) are higher in females, regardless of estrous cycle, than in males[153]. The maximal level of Ach infemales was found at proestrusThe binding affinity of muscarinic Ach receptors is lower in femalesthan in males[18]. Estrogens appear to modulate the bindingactivity 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 foundthroughout the CNS[346,206]. Opioids exert ananalgesic effect andalso play a role in stress response and reproduction[315]RatandmouseGenerally,
l
and
j
class opioids seem more effective in males thanfemales although in some cases the effectiveness is equal[76].In a minority of cases, they are more effective in femalesHuman
l
-opioids appear more effective in women than in men[76]
l
-opioids show significantly higher binding potential in women inthe amygdala, thalamus and the cerebellum[352]. The sexdifference in the first two regions is reversed after menopause
T.C. Ngun et al./Frontiers in Neuroendocrinology xxx (2010) xxx–xxx
3
YFRNE 451 No. of Pages 20, Model 5G21 October 2010
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

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