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Extra brain cells make males remember sex

University College London

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IMAGE: The image is an artistic rendition of the adult male (blue) and hermaphrodite (pink) C. elegans head connectivity. The male-specific addition of glial-derived interneurons (red) remodels brain circuits during sexual... view more

Credit: Justina Yeung, UCL

A pair of neurons have been found in the brain of male nematode worms that allow them to remember and seek sex even at the expense of food. These neurons, which are male-specific, are required for sex-based differences in learning, suggesting that sex differences in cognitive abilities can be genetically hardwired.

This is important as very little is known about how brains vary to give the two sexes different preferences, aptitudes and judgments.

The study by UCL (UK) and Albert Einstein College of Medicine (USA), published today in Nature and funded by the Wellcome Trust, NIH, Marie Curie, and the G. Harold & Leila Y. Mathers Charitable Foundation, shows a direct link between contrasting behaviour of male and female worms and differences in brain development and structure in areas involved in higher order processing.

Senior author Dr Arantza Barrios, UCL Cell & Developmental Biology, said: "Areas of the brain involved in learning display sex differences in many animals, including humans, but how these differences directly affect behaviour is not clear.

"We've shown how genetic and developmental differences between the two sexes lead to structural changes in the brain of male worms during sexual maturation. These changes make male brains work differently, allowing males to remember previous sexual encounters and prioritise sex in future situations."

The team were surprised to find previously unidentified cells are responsible for the behavioural change, as worms are an extremely well studied model organism. They were able to show that the cells from which these male brain neurons are born share common characteristics to the cells that give rise to human brain neurons. They are glial cells - companion and support cells of neurons.

Co-senior author Dr Richard Poole, UCL Cell & Developmental Biology, said: "This is the first well-described example of glia making neurons outside vertebrates and is particularly exciting as we find that the glial cells in question are fully differentiated cells, an issue that has been tricky to address in higher organisms.

"We can now exploit this system to understand how fully differentiated glia can re-enter the cell cycle and generate neurons. This could have important therapeutic implications in the future".

The newly identified pair of neurons - called 'mystery cells of the male' or 'MCMs' - create behavioural differences between the sexes by changing a brain circuit common to both. Whether the neurons are born or not depends on the genetic sex of the glial cells from which they arise and not on the sex of the animal or on hormones. The MCM neurons are only made from glial cells that have male chromosomes.

Dr Barrios added: "Our findings suggest that differences in learning and perception depend not just on the sex of the animal but also on the sex of the individual neural progenitor cells. This means that different aspects of an animal's behavior may well develop independently of each other in some circumstances, instead of through the co-ordinated action of hormones. Of course not all behavioural differences are genetically hardwired, environment can also play an important role."

The worm species used in the study, Caenorhabditis elegans, has two sexes: males and hermaphrodites. These hermaphrodites are essentially modified females that carry their own sperm and do not need to have sex in order to reproduce. The MCMs were identified using fluorescently tagged markers and their function could be probed by surgically removing them using a laser microbeam.

The effect of the cells on the worms' behaviour was tested using classic conditioning behavioural assays in which worms learn to associate aversive or pleasant experiences (such as starvation or mates) with another stimulus (salt) and change their behavioural responses to that stimulus. Worms that were previously starved in the presence of salt, learned to move away from areas with high concentrations of salt when placed in a new environment that had various different salt concentrations. This indicated that worms had learned to perceive salt as a sign for the absence of food.

Both males and hermaphrodites perform this type of learning. In contrast, when males were starved in the presence of salt and mates (i.e. sexual partners), and then placed in a new environment that had different salt concentrations, males sought areas of high concentrations of salt. This indicated that the association of salt with sex was stronger than and preferred over the association of salt with lack of food. This change in behaviour does not occur in hermaphrodites. Importantly, it also does not occur in males whose MCM neurons were surgically removed - demonstrating that these neurons are required for sex-based differences in learning.

The team at Albert Einstein College of Medicine used electron micrographs of serial sections to reconstruct and analyse the connections made by the MCMs with other neurons in the male brain. They found that the MCMs connected with neurons that are present in both sexes and that the presence of MCMs only in males remodeled these circuits to change the way information is processed.

Co-author Professor Scott Emmons, from the Departments of Genetics and Neuroscience at Albert Einstein College of Medicine, said: "Only in C. elegans, at the moment, is it possible to identify every synapse in a neural circuit in the way we have done here. Though the work is carried out in a small worm, it nevertheless gives us a perspective that helps us appreciate and possibly understand the variety of human sexuality, sexual orientation, and gender identification."

The scientists hope to discover how glial cells make neurons, as it is a promising avenue for repairing damaged areas of the brain. They also want to determine what specific properties of brain circuits regulate the acquisition and retention of information in order to understand how learning occurs.

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Notes to Editors

1.) For a copy of the paper or to speak to the researchers, please contact Ruth Howells in the UCL press office, T: +44 (0)20 3108 3845 / +44 (0)7990 675 947 E: ruth.howells@ucl.ac.uk

2.) M. Sammut, S. Cook, K. Nguyen, T. Felton, D. Hall, S. Emmons, R. Poole, A. Barrios, 'Glia-derived neurons are required for sex-specific learning in C. elegans', will be published in Nature on 15 October 2015 and is under embargo until 1800 London time / 1300 US Eastern Time on 14 October 2015.

About UCL (University College London)

UCL was founded in 1826. We were the first English university established after Oxford and Cambridge, the first to open up university education to those previously excluded from it, and the first to provide systematic teaching of law, architecture and medicine. We are among the world's top universities, as reflected by performance in a range of international rankings and tables. UCL currently has over 35,000 students from 150 countries and over 11,000 staff. Our annual income is more than £1 billion. http://www.ucl.ac.uk | Follow us on Twitter @uclnews | Watch our YouTube channel YouTube.com/UCLTV

About Albert Einstein College of Medicine

Albert Einstein College of Medicine is one of the nation's premier centers for research, medical education and clinical investigation. During the 2014-2015 academic year, Einstein is home to 742 M.D. students, 212 Ph.D. students, 102 students in the combined M.D./Ph.D. program, and 292 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2014, Einstein received $158 million in awards from the National Institutes of Health (NIH). This includes the funding of major research centers at Einstein in aging, intellectual development disorders, diabetes, cancer, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center--Einstein's founding hospital, and three other hospital systems in the Bronx, Brooklyn and on Long Island, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit http://www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.

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