This review addresses some of the primary reasons why the sex of participants is an important factor that should be considered in studies at all levels of neuroscience.
There are widespread misconceptions about brain sex differences in the field.
Sex differences exist in every major part of the brain.
New methods are revealing previously unsuspected sex differences.
Many regions of the brain that are responsible for cognitive processes, such as the hippocampus, amygdala and neocortex, are sexually dimorphic.
A consideration of sex influences can help to reconcile seemingly contradictory findings in neuroscientific research.
Active investigation of sex influences is mandatory to fully understand and treat a host of brain disorders with sex differences in the incidence and/or nature.
Sex matters for understanding brain function much more than has been widely assumed in neuroscience, and perhaps much more than we yet recognize.
A rapidly burgeoning literature documents copious sex influences on brain anatomy, chemistry and function. This article highlights some of the more intriguing recent discoveries and their implications. Consideration of the effects of sex can help to explain seemingly contradictory findings. Research into sex influences is mandatory to fully understand a host of brain disorders with sex differences in their incidence and/or nature. The striking quantity and diversity of sex-related influences on brain function indicate that the still widespread assumption that sex influences are negligible cannot be justified, and probably retards progress in our field.
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Levine, S. Sex differences in the brain. Scientific American 214, 84–90 (1966).
McFadden, D. Masculinizing effects on otoacoustic emissions and auditory evoked potentials in women using oral contraceptives. Hearing Research 142, 23–33 (2000).
Hines, M. Brain Gender (Oxford Univ. Press, New York, 2004).
Maccoby, E. E. & Jacklin, C. N. The Psychology of Sex Differences Vol. 1 (Stanford Univ. Press, Stanford, 1974).
Kimura, D. Sex, sexual orientation and sex hormones influence human cognitive function. Curr. Opin. Neurobiol. 6, 259–263 (1996).
Witelson, S. F. Neural sexual mosaicism: sexual differentiation of the human temporo-parietal region for functional asymmetry. Psychoneuroendocrinology 16, 131–153 (1991).
Fuchs, R. A., Evans, A., Mehta, R., Case, J. M. & See, R. E. Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior. Psychopharmacology 179, 662–672 (2005).
Arnold, A. P. Sex chromosomes and brain gender. Nature Rev. Neurosci. 5, 701–708 (2004). Provides an excellent overview of striking developments in molecular neurobiology that are generating new insight into neural mechanisms behind sexual differentiation of the brain.
Reisert, I. & Pilgrim, C. Sexual differentiation of monoaminergic neurons — genetic or epigenetic? Trends Neurosci. 14, 468–473 (1991).
Piefke, M., Weiss, P., Markowitsch, H. & Fink, G. Gender differences in the functional neuroanatomy of emotional episodic autobiographical memory. Hum. Brain Mapp. 24, 313–324 (2005).
Grabowski, T. J., Damasio, H., Eichhorn, G. R. & Tranel, D. Effects of gender on blood flow correlates of naming concrete entities. Neuroimage 20, 940–954 (2003).
De Vries, G. J. Sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145, 1063–1068 (2004). Excellent review of the evidence supporting an often underappreciated concept, namely, that sexual dimorphisms in the brain may exist to prevent, rather than create, sexual dimorphisms in behaviour.
Juraska, J. M. Sex differences in 'cognitive' regions of the rat brain. Psychoneuroendocrinology 16, 105–109 (1991).
Luders, E. et al. Gender effects on cortical thickness and the influence of scaling. Hum. Brain. Mapp. 27, 314–324 (2005).
Allen, J. S., Damasio, H., Grabowski, T. J., Bruss, J. & Zhang, W. Sexual dimorphism and asymmetries in the gray–white composition of the human cerebrum. Neuroimage 18, 880–894 (2003).
Shah, N. M. et al. Visualizing sexual dimorphism in the brain. Neuron 43, 313–319 (2004). Illustration of the ability of some newer methodologies to reveal sexual dimorphisms in the brain missed by more traditional methods.
Bielsky, I. F., Hu, S. B. & Young, L. J. Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice. Behav. Brain Res. 164, 132–136 (2005).
Mechelli, A., Friston, K. J., Frackowiak, R. S. & Price, C. J. Structural covariance in the human cortex. J. Neurosci. 25, 8303–8310 (2005). Findings suggest that the amygdala is probably an especially important locus of sex influences on brain function.
Madeira, M. D. & Lieberman, A. R. Sexual dimorphism in the mammalian limbic system. Prog. Neurobiol. 45, 275–333 (1995).
Goldstein, J. M. et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb. Cortex 11, 490–497 (2001).
Turner, B. B. & Weaver, D. A. Sexual dimorphism of glucocorticoid binding in rat brain. Brain Res. 343, 16–23 (1985).
Teyler, T. J., Vardaris, R. M., Lewis, D. & Rawitch, A. B. Gonadal steroids: effects on excitability of hippocampal pyramidal cells. Science 209, 1017–1018 (1980).
Cooke, B. M. & Woolley, C. S. Gonadal hormone modulation of dendrites in the mammalian CNS. J. Neurobiol. 64, 34–46 (2005).
Romeo, R. D., McCarthy, J. B., Wang, A., Milner, T. A. & McEwen, B. S. Sex differences in hippocampal estradiol-induced N-methyl-D-aspartic acid binding and ultrastructural localization of estrogen receptor-α. Neuroendocrinology 81, 391–399 (2005).
Packard, M., Kohlmaier, J. & Alexander, G. Posttraining intra-hippocampal estradiol injections enhance spatial memory in male rats: interaction with cholinergic systems. Behav. Neurosci. 110, 626–632 (1996).
Maren, S., De Oca, B. & Fanselow, M. S. Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res. 661, 25–34 (1994).
Ruecker, B. et al. Inhibitory avoidance task reveals differences in ectonucleotidase activities between male and female rats. Neurochem. Res. 29, 2231–2237 (2004).
Shors, T. Opposite effects of stressful experience on memory formation in males versus females. Dialogues Clin. Neurosci. 4, 139–147 (2002).
Jackson, E. D., Payne, J. D., Nadel, L. & Jacobs, W. J. Stress differentially modulates fear conditioning in healthy men and women. Biol. Psychiatry 59, 516–522 (2005).
Juraska, J., Fitch, J., Henderson, C. & Rivers, N. Sex differences in the dendritic branching of dentate granule cells following differential experience. Brain Res. 333, 73–80 (1985).
Korol, D. L. Role of estrogen in balancing contributions from multiple memory systems. Neurobiol. Learn. Mem. 82, 309–323 (2004). Summary of the recent studies demonstrating pronounced influences of sex hormones on learning strategies in rats.
McEwen, B. S. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 886, 172–189 (2000).
Cooke, B. M. & Woolley, C.S. Sexually dimorphic synaptic organization of the medial amygdala. J. Neurosci. 25, 10759–10767 (2005).
Ziabreva, I., Poeggel, G., Schnabel, R. & Braun, K. Separation-induced receptor changes in the hippocampus and amygdala of Octodon degus: influence of maternal vocalizations. J. Neurosci. 23, 5329–5336 (2003). Demonstrates a qualitative difference in the neurochemical response to stress of an amygdala nucleus, the basomedial nucleus, not traditionally thought to be sexually dimorphic.
Cahill, L. Sex- and hemisphere-related influences on the neurobiology of emotionally influenced memory. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 1235–1241 (2003).
Hamann, S. Sex differences in the responses of the human amygdala. Neuroscientist 11, 288–293 (2005).
McGaugh, J. L. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu. Rev. Neurosci. 27, 1–28 (2004).
Cahill, L. in The Amygdala: A Functional Analysis (ed. Aggleton, J.) 425–444 (Oxford Univ. Press, London, 2000).
Cahill, L. et al. Sex-related difference in amygdala activity during emotionally influenced memory storage. Neurobiol. Learn. Mem. 75, 1–9 (2001).
Canli, T., Desmond, J., Zhao, Z. & Gabrieli, J. D. E. Sex differences in the neural basis of emotional memories. Proc. Natl Acad. Sci. USA 99, 10789–10794 (2002).
Cahill, L., Uncapher, M., Kilpatrick, L., Alkire, M. T. & Turner, J. Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an fMRI investigation. Learn. Mem. 11, 261–266 (2004).
Lalumiere, R. T. & McGaugh, J. L. Memory enhancement induced by post-training intrabasolateral amygdala infusions of β-adrenergic or muscarinic agonists requires activation of dopamine receptors: involvement of right, but not left, basolateral amygdala. Learn. Mem. 12, 527–532 (2005).
Killgore, W. & Yurgelun-Todd, D. Sex differences in amygdala activation during the perception of facial affect. Neuroreport 12, 2543–2547 (2001). One of the first studies to document sex differences in the function of the human amygdala.
Williams, L. M. et al. Distinct amygdala–autonomic arousal profiles in response to fear signals in healthy males and females. Neuroimage 28, 618–626 (2005).
Kilpatrick, L. A., Zald, D. H., Pardo, J. V. & Cahill, L. F. Sex-related differences in amygdala functional connectivity during resting conditions. Neuroimage 30, 452–461 (2006). Examines the functional connectivities of the left and right hemisphere amygdalae in a large sample of men and women who received PET scans while resting with their eyes closed. Indicates that sexually dimorphic amygdala function exists in the brain independently of overt stimulation.
Skuse, D. H., Morris, J. S. & Dolan, R. J. Functional dissociation of amygdala-modulated arousal and cognitive appraisal, in Turner syndrome. Brain 128, 2084–2096 (2005).
Drevets, W. Neuroimaging abnormalities in the amygdala in mood disorders. Ann. NY Acad. Sci. 985, 420–444 (2003).
Naliboff, B. D. et al. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 124, 1738–1747 (2003).
Nordeen, E. J. & Yahr, P. Hemispheric asymmetries in the behavioral and hormonal effects of sexually differentiating mammalian brain. Science 218, 391–394 (1982). A striking demonstration of hemispheric lateralization in the effects of a sex hormone on the developing brain.
Wisniewski, A. B. Sexually-dimorphic patterns of cortical asymmetry, and the role for sex steroid hormones in determining cortical patterns of lateralization. Psychoneuroendocrinology 23, 519–547 (1998).
Lansdell, H. Sex differences in hemispheric asymmetries of the human brain. Nature 203, 550 (1964).
Bixo, M., Backstrom, T., Winblad, B. & Andersson, A. Estradiol and testosterone in specific regions of the human female brain in different endocrine states. J. Steroid Biochem. Mol. Biol. 55, 297–303 (1995).
Duff, S. J. & Hampson, E. A sex difference on a novel spatial working memory task in humans. Brain Cogn. 47, 470–493 (2001).
Speck, O. et al. Gender differences in the functional organization of the brain for working memory. Neuroreport 11, 2581–2585 (2000).
Bland, S. T. et al. Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress. Brain Res. 1051, 90–99 (2005).
Shansky, R. M. et al. Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction. Mol. Psychiatry 9, 531–538 (2004).
Goldman, P. S., Crawford, H. T., Stokes, L. P., Galkin, T. W. & Rosvold, H. E. Sex-dependent behavioral effects of cerebral cortical lesions in the developing rhesus monkey. Science 186, 540–542 (1974).
Tranel, D., Damasio, H., Denburg, N. L. & Bechara, A. Does gender play a role in functional asymmetry of ventromedial prefrontal cortex? Brain 128, 2872–2881 (2005).
Bolla, K. I., Eldreth, D. A., Matochik, J. A. & Cadet, J. L. Sex-related differences in a gambling task and its neurological correlates. Cereb. Cortex 14, 1226–1232 (2004). Together with reference 58, this suggests that the involvement of the prefrontal cortex in decision making is influenced both by a subject's sex and cerebral hemisphere, and suggests that attention to these variables can reconcile seemingly contradictory studies.
Craft, R. M. Sex differences in opioid analgesia: 'from mouse to man'. Clin. J. Pain 19, 175–186 (2003).
Robinson, D. S. et al. Monoamine metabolism in human brain. Arch. Gen. Psychiatry 34, 89–92 (1977).
Curtis, A. L., Bethea, T. & Valentino, R. J. Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 31, 544–554 (2005).
Nishizawa, S. et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc. Natl Acad. Sci. USA 94, 5308–5313 (1997).
Gottfries, C. G., Roos, B. E. & Winblad, B. Determination of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and homovanillic acid in brain tissue from an autopsy material. Acta. Psychiatr. Scand. 50, 496–507 (1974).
Cordero, M. E., Rodriguez, A., Torres, R. & Valenzuela, C. Y. Human raphe magnus nucleus: a morphometric Golgi-Cox study with emphasis on sex differences. Brain Res. Dev. Brain Res. 131, 85–92 (2001).
Zubieta, J. K., Dannals, R. & Frost, J. Gender and age influences on human brain mu-opiod receptor binding measured by PET. Am. J. Psychiatry 156, 842–848 (1999).
Galanopoulou, A. S. GABA receptors as broadcasters of sexually differentiating signals in the brain. Epilepsia 46, 107–112 (2005).
Klein, L. C. & Corwin, E. J. Seeing the unexpected: how sex differences in stress responses may provide a new perspective on the manifestation of psychiatric disorders. Curr. Psychiatry Rep. 4, 441–448 (2002).
Barnes, L. L. et al. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62, 685–691 (2005).
Swaab, D. F., Chung, W. C., Kruijver, F. P., Hofman, M. A. & Ishunina, T. A. Structural and functional sex differences in the human hypothalamus. Horm. Behav. 40, 93–98 (2001).
Fleisher, A. et al. Alzheimer's Disease Cooperative Study. Sex, apolipoprotein E ε 4 status, and hippocampal volume in mild cognitive impairment. Arch. Neurol. 62, 953–957 (2005).
Dal Forno, G. et al. Depressive symptoms, sex, and risk for Alzheimer's disease. Ann. Neurol. 57, 381–387 (2005).
Nopoulos, P., Flaum, M. & Andreasen, N. Sex differences in brain morphology in schizophrenia. Am. J. Psychiatry 154, 1648–1654 (1997).
Gur, R. E. et al. A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia. Biol. Psychiatry 55, 512–517 (2004).
Crow, T. J. Cerebral asymmetry and the lateralization of language: core deficits in schizophrenia as pointers to the gene. Curr. Opin. Psychiatry 17, 96–106 (2004).
Hennessy, R. J. et al. 3D morphometrics of craniofacial dysmorphology reveals sex-specific asymmetries in schizophrenia. Schizophr. Res. 67, 261–268 (2004).
Becker, J. B. Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol. Biochem. Behav. 64, 803–812 (1999).
Lynch, W. J., Roth, M. E. & Carroll, M. E. Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164, 121–137 (2002).
Kilts, C. D., Gross, R. E., Ely, T. D. & Drexler, K. P. The neural correlates of cue-induced craving in cocaine-dependent women. Am. J. Psychiatry 161, 233–241 (2004).
Waber, D. P. Sex differences in mental abilities, hemispheric lateralization, and rate of physical growth in adolescence. Dev. Psychol. 13, 29–38 (1977).
Becker, J. B. et al. Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146, 1650–1673 (2005). An excellent, comprehensive review by field leaders of various approaches taken to studying the issue of sex influences on the brain, including description of the pitfalls to be avoided. Should be mandatory reading for anyone entering the field.
Wizemann, T. M. Exploring the Biological Contributions to Human Health: Does Sex Matter? (ed. Pardue, M.L.) (National Academy, Washington, DC, 2001).
Dohanich, G. P. Gonadal steroids, learning and memory. Hormones, Brain, and Behavior Vol. 2 (ed. Pfaff, D.W.) 265–327 (Academic, San Diego, 2002).
Rubinow, M. J., Arseneau, L. M., Beverly, J. L. & Juraska, J. M. Effect of the estrous cycle on water maze acquisition depends on the temperature of the water. Behav. Neurosci. 118, 863–868 (2004).
Halpern, D. F. & Tan, U. Stereotypes and steroids: using a psychobiosocial model to understand cognitive sex differences. Brain Cogn. 45, 392–414 (2001).
Goldstein, J. M. et al. Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J. Neurosci. 25, 9309–9316 (2005).
Hausmann, M. Hemispheric asymmetry in spatial attention across the menstrual cycle. Neuropsychologia 43, 1559–1567 (2005).
Kaufman, M. J. et al. Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase. Biol. Psychiatry 49, 774–781 (2001).
Justice, A. J. & de Wit, H. Acute effects of D-amphetamine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology 145, 67–75 (1999).
Lynch, W. J., Roth, M. E. & Carroll, M. E. Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164, 121–137 (2002).
Tomizawa, K. et al. Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade. Nature Neurosci. 6, 384–390 (2003).
Geary, D. C. Male, Female: the Evolution of Human Sex Differences (American Psychological Association, Washington DC, 1998).
Seidlitz, L. & Diener, E. Sex differences in the recall of affective experiences. J. Pers. Soc. Psychol. 74, 262–271 (1998).
Packard, M. G. & McGaugh, J. L. Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiol. Learn. Mem. 65, 65–72 (1996).
The author declares no competing financial interests.
- Voxel-based morphometry
(VBM). A computational approach to neuroanatomy that measures differences in local concentrations of brain tissue through a voxel-wise comparison of multiple brain images. The value of VBM is that it allows for comprehensive measurement of differences, not just in specific structures, but throughout the entire brain.
- Long-term potentiation
(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured as an increase in the amplitude of excitatory postsynaptic potentials or in the magnitude of the postsynaptic cell population spike. LTP is most frequently studied in the hippocampus and is often considered to be part of the cellular basis of learning and memory in vertebrates.
A chronic, painful condition, primarily occurring in women, characterized by widespread musculoskeletal pain, fatigue and tender points at defined locations.
A chronic, painfull condition, Primarily occurring in women, characterized by widespread musculoskeletal pains, fatigue and tender points at defined locations.
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Cahill, L. Why sex matters for neuroscience. Nat Rev Neurosci 7, 477–484 (2006). https://doi.org/10.1038/nrn1909
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