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NEUROSCIENCE: ON SEXUAL DIMORPHISM IN NEURAL CIRCUITRY

The following points are made by J.Y. Yu and B.J. Dickson (Current Biology 2006 16:R23):

1) Males and females of most species behave rather differently, particularly when it comes to sex. This makes sexual behaviors attractive models for trying to understand innate behaviors in general. Instead of trying to identify all the genes and all the neurons involved in a given behavior, and then figure out how they all work, one can just look for the genes and neurons that make the sexes different, and try to understand how these genes and neurons shape the distinct sexual behaviors of males and females. In what might be a major step towards this goal, Kimura et al [1] have now discovered a clear difference in neural circuitry in the brains of male and female fruit flies. This difference, they speculate, might just explain why male flies do the male thing and females do not.

2) Fly sex is a complicated business. To woo a female, the male must perform an elaborate song-and-dance courtship ritual [2]. The fruitless (fru) gene, the RNA transcript of which is spliced differently in males and females, plays a key role during development to lay the foundation for this behavior. In males, fru RNA is spliced in such a way as to encode male-specific FruM proteins. Males that lack the fru gene [3], or splice it the wrong way [4], make a complete mess of the courtship ritual. For the most part, they do not even bother, and if they do, they are just as likely to try to woo another male as a female. What is more, females that splice fru RNA in the male way, and therefore make FruM, behave like males and try to woo other females [4]. So, genetically, fru seems to account for much of the difference between male and female sexual behavior. Can fru also lead us to the neuronal circuits in the brain that make the difference?

3) It turns out that FruM is made in about 3000 neurons in the male brain, or about 3% of the total number of neurons [5]. These neurons are grouped into distinct clusters in various regions of the brain. Are these neurons also present in females, and if so, what is different about them? Because the female fru transcripts do not encode FruM, it has been rather difficult to identify cells in females that correspond to the FruM-expressing cells in males. To circumvent this problem, two groups recently used gene targeting to insert coding sequences for an independent marker (GAL4) into the fru locus, replacing the alternatively spliced exon so that the marker would be produced in both males and females. Surprisingly, these studies revealed that almost all of the FruM-producing neurons in the male have counterparts in the female, and at a gross level, they seem to be wired up the same way. Of course, this does not exclude more subtle differences in neuroanatomy, but without knowing which of these approximately 3000 neurons make the essential difference, there seemed little point to go on examining them all at higher resolution.

4) Kimura et al [1] took a different line of attack, both technically and strategically. They isolated a random enhancer trap insertion further downstream in the fru locus, called NP21. NP21 labels many, but not all, of the FruM neurons in males, as well as the corresponding cells in females. Kimura et al [1] then went on to characterize some of these neurons at higher resolution, undeterred by the lack of behavioral data to indicate which of them might be the most relevant. Nevertheless, two sets of NP21-positive neurons clearly differed anatomically in males and females. One of these, belonging to the so-called fru-mAL cluster [5], particularly attracted their attention. These neurons seem to serve as a relay between the primary gustatory centre of the brain and higher brain regions thought to integrate information from multiple sensory modalities.

References (abridged):

1. K. Kimura, M. Ote, T. Tazawa and D. Yamamoto, Fruitless specifies sexually dimorphic neural circuitry in the Drosophila brain, Nature 438 (2005), pp. 229-233

2. J.C. Hall, The mating of a fly, Science 264 (1994), pp. 1702-1714

3. B.S. Baker, B.J. Taylor and J.C. Hall, Are complex behaviors specified by dedicated regulatory genes? Reasoning from Drosophila, Cell 105 (2001), pp. 13-24

4. E. Demir and B.J. Dickson, fruitless splicing specifies male courtship behavior in Drosophila, Cell 121 (2005), pp. 785-794

5. G. Lee, M. Foss, S.F. Goodwin, T. Carlo, B.J. Taylor and J.C. Hall, Spatial, temporal, and sexually dimorphic expression patterns of the fruitless gene in the Drosophila central nervous system, J. Neurobiol. 43 (2000), pp. 404-426

Current Biology http://www.current-biology.com

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MEDICAL BIOLOGY: SEX DIFFERENCES IN READING DISABILITY

The following points are made by M. Rutter et al (J. Am. Med. Assoc. 2004 291:2007):

1) Are boys more likely than girls to have reading disability? The answer to this question has both theoretical implications (with respect to possible causal mechanisms) and practical implications (with respect to service provision). If boys are truly more likely to have reading disability, this would direct research attention to uncovering the possible source of the sex difference. Also, the sex difference would offer a window into the understanding of the causal processes involved in the origins of developmental reading disability.(1) In addition, if boys are more prone to have reading disability, this should motivate educational programs to address boys' early emerging disability. Given that reading disability in childhood is associated with adjustment problems and long-term adverse outcomes in multiple life domains,(2) the elucidation of this disability should constitute a high priority.

2) Thirty years ago, epidemiological studies drew attention to the preponderance of male children with reading disability. Surveys both on the Isle of Wight and in an inner London borough(3) were consistent in showing that reading disability, whether assessed through group or individual tests, was substantially more frequent in boys than in girls. Moreover, the sex difference was evident whether reading disability was considered in terms of IQ-referenced (adjusted) specific reading retardation (in which reading was markedly lower than that predicted on the basis of age and IQ) or non-IQ-referenced general low achievement in reading. Thus, in the inner London sample of 10-year-olds, the rates of specific reading retardation on group tests were 16.9% in boys compared with 7.2% in girls. Using individual testing in those with positive screens on the group reading test, the rates were 4.6% vs 2.0%. The comparable data for Isle of Wight 10-year-old boys and girls were 8.6% vs 3.7% on group tests and 5.6% vs 2.9% on individual tests.3

3) When non-IQ-referenced reading disability was defined as performance at least 28 months behind population norms on either reading accuracy or reading comprehension, the male-female difference on group tests was 15.9% vs 7.2% in inner London, with 22.2% vs 15.6% on the basis of individual testing of those who had positive screens. The comparable Isle of Wight data were 8.6% vs 3.7% on group testing and 10.5% vs 6.1% on individual testing. The sample sizes in both cases were large: 1689 for the inner London 10-year-olds and 1142 for the Isle of Wight 10-year-olds.

4) Some 15 years later, in 1990, Shaywitz et al,(4) reporting on a sample of 414 children aged 7 to 8 years, drew attention to their finding that the sex ratio in their epidemiological study was very much less than that in their sample of children identified on the basis of school records. Among the children in second grade, the rates were 8.7% in boys vs 6.9% in girls, and 1 year later (at a mean age of 8.7 years), the comparison was 9.0% vs 6.0%.

5) The authors summarize the history of research on sex differences in reading disability and provide new evidence from four independent epidemiological studies about the nature, extent, and significance of sex differences in reading disability. In all 4 studies, the rates of reading disability were significantly higher in boys. The authors conclude: "Reading disabilities are clearly more frequent in boys than in girls."(5)

References (abridged):

1. Rutter M, Caspi A, Moffitt TE. Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. J Child Psychol Psychiatry. 2003;44:1092-1115

2. Snowling MJ. Reading and other learning difficulties. In: Rutter M, Taylor E, eds. Child and Adolescent Psychiatry, 4th Edition. Oxford, England: Blackwell Science; 2002:682-696

3. Berger M, Yule W, Rutter M. Attainment and adjustment in two geographical areas, II: the prevalence of specific reading retardation. Br J Psychiatry. 1975;126:510-519

4. Shaywitz SE, Shaywitz BA, Fletcher JM, Escobar MD. Prevalence of reading disability in boys and girls: results of the Connecticut Longitudinal Study. JAMA. 1990;264:998-1002

5. Flannery KA, Liederman J, Daly L, Schultz J. Male prevalence for reading disability is found in a large sample of black and white children free from ascertainment bias. J Int Neuropsychol Soc. 2000;6:433-442

J. Am. Med. Assoc. http://www.jama.com

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SEX DIFFERENCES IN THE NEURAL BASIS OF EMOTIONAL MEMORIES.

The following points are made by T. Canli et al (Proc. Nat. Acad. Sci. 2002 99:11802):

1) Emotionally arousing experiences are more memorable than neutral experiences. There is superior memory for traumatic relative to mundane events (1) and for emotionally provocative relative to neutral words (2) and pictures (3). Memory for emotional stimuli and experiences differs between the sexes (4,5). Women recall more emotional autobiographical events than men in timed tests, produce memories more quickly or with greater emotional intensity in response to cues, and report more vivid memories than their spouses for events related to their first date, last vacation, and a recent argument (4).

2) Two explanations for the difference in memory performance have been proposed. The "affect-intensity" hypothesis posits that women have better memory because they experience life events more intensely than men and thus may better encode such events into memory (4). Controlling for affect intensity at encoding should therefore eliminate women's superior memory performance. The "cognitive-style" hypothesis posits that women may differ from men in how they encode, rehearse, or think about their affective experiences or in how they generate responses in a memory test (5). According to this view, controlling for affect intensity at encoding should not remove sex-based differences in memory performance.

3) In summary: Psychological studies have found better memory in women than men for emotional events, but the neural basis for this difference is unknown. The authors report they used event-related functional MRI to assess whether sex differences in memory for emotional stimuli is associated with activation of different neural systems in men and women. Brain activation in 12 men and 12 women was recorded while they rated their experience of emotional arousal in response to neutral and emotionally negative pictures. In a recognition memory test 3 weeks after scanning, highly emotional pictures were remembered best, and remembered better by women than by men. Men and women activated different neural circuits to encode stimuli effectively into memory even when the analysis was restricted to pictures rated equally arousing by both groups. Men activated significantly more structures than women in a network that included the right amygdala, whereas women activated significantly fewer structures in a network that included the left amygdala. Women had significantly more brain regions where activation correlated with both ongoing evaluation of emotional experience and with subsequent memory for the most emotionally arousing pictures. Greater overlap in brain regions sensitive to current emotion and contributing to subsequent memory may be a neural mechanism for emotions to enhance memory more powerfully in women than in men.

References (abridged):

1. Christianson, S.-A. & Loftus, E. F. (1987) Appl. Cogn. Psychol. 1, 225-239.

2. LaBar, K. S. & Phelps, E. A. (1998) Psychol. Sci. 9, 490-493.

3. Bradley, M. M. , Greenwald, M. K. , Petry, M. C. & Lang, P. J. (1992) J. Exp. Psychol. Learn. Mem. Cognit. 18, 379-390.

4. Fujita, F. , Diener, E. & Sandvik, E. (1991) J. Pers. Soc. Pychol. 61, 427-434.

5. Seidlitz, L. & Diener, E. (1998) J. Pers. Soc. Pychol. 74, 262-271.

Proc. Nat. Acad. Sci. http://www.pnas.org

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