Extra male brain cells remember sex more than food

A pair of neurons have been found in the brain of male nematode worms that allows them to remember and seek sex at the expense of seeking food.

These neurons are male-specific and found in sex-based differences in learning, all of which suggests that in our ability to think, sex differences may be genetically hardwired. This is important as very little is known about how brains vary to give the two sexes different preferences, aptitudes and judgment.

The study by the University College London [UCL] in the United Kingdom, and Albert Einstein College of Medicine in the USA, is published in the esteemed journal Nature. It shows that a direct link exists between the contrasting behaviors of male and female worms and differences found in their brain development and structures in areas of higher order processing.

"Areas of the brain involved in learning display sex differences in many animals, including humans, but how these differences directly affect behaviour is unclear.

"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."

Arantza Barrios PhD, UCL Cell & Developmental Biology, and Senior author.

The team was surprised to find there are unidentified cells responsible for behavior changes in worms, especially as worms are extremely well studied model organisms. These previously unidentified cells give rise to male worm brain neurons which share common characteristics with cells that give rise to human brain neurons. Both are glial cells - the companion and support cells to neurons.

"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", added Co-senior author Dr Richard Poole, of UCL, Cell & Developmental Biology.

The newly identified pair of neurons - called 'mystery cells of the male' or 'MCMs' - create behavior 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 behavior assays. Worms were taught to associate aversive experiences such as starvation or pleasant experiences such as finding mates, with another stimulus such as the taste of salt. Then they were taught to change their behavior in conjunction with that other stimulus. Worms that were previously starved in the presence of salt, learned to move away from areas with high concentrations of salt. This indicated they had learned to perceive salt as a sign of the absence of food.

Both males and hermaphrodites perform this type of learning. When males were starved in the presence of salt and with their sexual partners, and then placed in a new environment with only 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 did not occur in hermaphrodites. Importantly, it also did 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 those circuits and changed the way information was processed.

"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."

Scott Emmons PhD, Professor Departments, Genetics and Neuroscience at Albert Einstein College of Medicine, ane paper Co-author

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

Abstract
Sex differences in behaviour extend to cognitive-like processes such as learning, but the underlying dimorphisms in neural circuit development and organization that generate these behavioural differences are largely unknown. Here we define at the single-cell level—from development, through neural circuit connectivity, to function—the neural basis of a sex-specific learning in the nematode Caenorhabditis elegans. We show that sexual conditioning, a form of associative learning, requires a pair of male-specific interneurons whose progenitors are fully differentiated glia. These neurons are generated during sexual maturation and incorporated into pre-exisiting sex-shared circuits to couple chemotactic responses to reproductive priorities. Our findings reveal a general role for glia as neural progenitors across metazoan taxa and demonstrate that the addition of sex-specific neuron types to brain circuits during sexual maturation is an important mechanism for the generation of sexually dimorphic plasticity in learning.

The work was funded by the Wellcome Trust, National Institutes of Health, Marie Curie, and the G. Harold & Leila Y. Mathers Charitable Foundation,

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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An artistic rendition of the adult male (blue) and hermaphrodite (pink) C. elegans head.
RED - male-specific addition of glial-derived interneurons remodeling brain circuits
during sexual maturation — which generates sexually dimorphic plasticity in learning.
Image Credit: Justina Yeung, UCL