NEWLY DISCOVERED BRAIN CELLS EXPLAIN A PROSOCIAL EFFECT OF OXYTOCIN

Oxytocin, the body's natural love potion, helps couples fall in love, makes mothers bond with their babies, and encourages teams to work together. Now new research at Rockefeller University reveals a mechanism by which this prosocial hormone has its effect on interactions between the sexes, at least in certain situations. The key, it turns out, is a newly discovered class of brain cells.

"By identifying a new population of neurons activated by oxytocin, we have uncovered one way this chemical signal influences interactions between male and female mice," says Nathaniel Heintz, James and Marilyn Simons Professor and head of the Laboratory of Molecular Biology.

The findings, published today in Cell (October 9), had their beginnings in a search for a new type of interneuron, a specialized neuron that relays messages to other neurons across relatively short distances. As part of her doctoral thesis, Miho Nakajima began creating profiles of the genes expressed in interneurons using a technique known as translating ribosome affinity purification (TRAP) previously developed by the Heintz lab and Paul Greengard's Laboratory of Molecular and Cellular Neuroscience at Rockefeller. Within some profiles from the outer layer of the brain known as the cortex, she saw an intriguing protein: a receptor that responds to oxytocin.

"This raised the question: What is this small, scattered population of interneurons doing in response to this important signal, oxytocin?" Nakajima says. "Because oxytocin is most involved in social behaviors of females, we decided to focus our experiments on females."

To determine how these neurons, dubbed oxytocin receptor interneurons or OxtrINs, affected behavior when activated by oxytocin, she silenced only this class of interneurons and, in separate experiments, blocked the receptor's ability to detect oxytocin in some females. She then gave them a commonly used social behavior test: Given the choice between exploring a room with a male mouse or a room with an inanimate object -- in this case a plastic Lego block -- what would they do? Generally, a female mouse will go for the non-stackable choice. Legos just aren't that interesting to rodents. But Nakajima's results were confusing: Sometimes the mice with the silenced OxtrINs showed an abnormally high interest in the Lego, and sometimes they responded normally.

This led her to suspect the influence of the female reproductive cycle. In another round of experiments, she recorded whether the female mice were in estrus, the sexually receptive phase, or diestrus, a period of sexual inactivity. Estrus, it turned out, was key. Female mice in this phase showed an unusual lack of interest in the males when their receptors were inactivated. They mostly just sniffed at the Lego. There was no effect on mice is diestrus, and there was no effect if the male love interest was replaced with a female. When Nakajima tried the same alteration in males, there was also no effect.

"In general, OxtrINs appear to sit silently when not exposed to oxytocin," says Andreas Görlich, a postdoc in the lab who recorded the electrical activity of these neurons with and without the hormone. "The interesting part is that when exposed to oxytocin these neurons fire more frequently in female mice than they do in male mice, possibly reflecting the differences that showed up in the behavioral tests."

"We don't yet understand how, but we think oxytocin prompts mice in estrus to become interested in investigating their potential mates," Nakajima says. "This suggests that the social computation going on in a female mouse's brain differs depending on the stage of her reproductive cycle."

Oxytocin has similar effects for humans as for mice, however, it is not yet clear if the hormone influences the human version of this mouse interaction, or if it works through a similar population of interneurons. The results do, however, help explain how humans, mice and other mammals respond to changing social situations, Heintz says.

"Oxytocin responses have been studied in many parts of the brain, and it is clear that it, or other hormones like it, can impact behavior in different ways, in different contexts and in response to different physiological cues," he says. "In a general sense, this new research helps explain why social behavior depends on context as well as physiology."

BRAIN CIRCUIT THAT THAT CONTROLS COMPULSIVE OVEREATING AND SUGAR ADDICTION DISCOVERED

Compulsive overeating and sugar addiction are major threats to human health, but potential treatments face the risk of impairing normal feeding behaviors that are crucial for survival. A study published January 29th in the journal Cell reveals a reward-related neural circuit that specifically controls compulsive sugar consumption in mice without preventing feeding necessary for survival, providing a novel target for the safe and effective treatment of compulsive overeating in humans

Although obesity and Type 2 diabetes are major problems in our society, many treatments do not tackle the primary cause: unhealthy eating habits," says senior study author Kay Tye of the Massachusetts Institute of Technology. "Our findings are exciting because they raise the possibility that we could develop a treatment that selectively curbs compulsive overeating without altering healthy eating behavior."

Compulsive overeating is a type of reward-seeking behavior, similar to drug addiction. But the major difference between the two behaviors is that eating is required for survival, underscoring the need to tease apart brain circuits involved in compulsive overeating versus normal feeding to develop safe and effective therapies. Tye and her team suspected that a neural pathway from the lateral hypothalamus to the ventral tegmental area might play an important role in compulsive overeating because these brain regions have been implicated in reward-related behaviors such as eating, sexual activity, and drug addiction.

To test this idea, Tye and her team used a technique called optogenetics, which involves genetically modifying specific populations of neurons to express light-sensitive proteins that control neural excitability, and then delivering either blue or yellow light through an optic fiber to activate or inhibit those cells, respectively. Activation of the pathway from the lateral hypothalamus to the ventral tegmental area caused well-fed mice to spend more time feeding and increased the number of times mice poked their nose into a port to receive a sugar reward, even when they had to cross a platform that delivered foot shocks to get to the reward. By contrast, inhibition of the same pathway reduced this compulsive sugar-seeking behavior without decreasing food consumption in hungry mice, suggesting that different neural circuits control feeding in hungry animals.

In an independent study also published January 29th in Cell, Garret Stuber of the University of North Carolina School of Medicine and his team similarly used an optogenetic approach in mice to identify neurons in the lateral hypothalamus that control both feeding and reward-seeking behavior. By imaging the activity of hundreds of individual lateral hypothalamus neurons as the mice freely explored an area with food or worked to obtain a sweet reward, they further uncovered distinct subsets of neurons that either mediate food-seeking behavior or respond to reward consumption.

According to Tye, it makes sense that brain circuits evolved to support binging on scarce, sugary foods whenever these valuable sources of energy become transiently available during certain seasons. But in the winter, it might be adaptive for separate neural circuits to drive hungry animals to eat whatever type of food is available but to consume less overall to ration out limited resources.

"However, in our modern day society, there is no scarcity of palatable foods, and high-sugar or high-fat foods are often even more available than fresh produce or proteins," Tye says. "We have not yet adapted to a world where there is an overabundance of sugar, so these circuits that drive us to stuff ourselves with sweets are now serving to create a new health problem. The discovery of a specific neural circuit underlying compulsive sugar consumption could pave the way for the development of targeted drug therapies to effectively treat this widespread problem."

ORIGIN OF SEX DISCOVERED

A profound new discovery announced in Nature today by palaeontologist, Flinders University Professor John Long, reveals how the intimate act of sexual intercourse first evolved in our deep distant ancestors

In one of the biggest discoveries in the evolutionary history of sexual reproduction, Professor Long has found that internal fertilisation and copulation appeared in ancient armoured fishes, called placoderms, about 385 million years ago in what is now Scotland.

Placoderms, the most primitive jawed vertebrates, are the earliest vertebrate ancestors of humans.

Published in Nature,  the discovery shows that male fossils of the Microbrachius dicki, which belong to the antiarch group of placoderms, developed bony L-shaped genital limbs called claspers to transfer sperm to females; and females developed small paired bones to lock the male organs in place for mating.

Measuring about 8cm long, Microbrachius lived in ancient lake habitats in Scotland, as well as parts of Estonia and China.

As the paper's lead author, Professor Long, who is the Strategic Professor in Palaeontology at Flinders University in South Australia, discovered the ancient fishes mating abilities when he stumbled across a single fossil bone in the collections of the University of Technology in Tallinn, Estonia, last year.

The fossils, he said, symbolise the most primitive known vertebrate sexual organ ever found, demonstrating the first use of internal fertilisation and copulation as a reproductive strategy known in the fossil record.

"Microbrachius means little arms but scientists have been baffled for centuries by what these bony paired arms were actually there for. We've solved this great mystery because they were there for mating, so that the male could position his claspers into the female genital area," Professor Long said.

"It was previously thought that reproduction spawned externally in water, and much later down the track in the history of vertebrate evolution," he said.

"Our earlier discoveries published in Nature in 2008 and 2009 of live birth and copulation in placoderms concerned more advanced placoderm groups. Our new discovery now pushes the origin of copulation back even further down the evolutionary ladder, to the most basal of all jawed animals.

"Basically it's the first branch off the evolutionary tree where these reproductive strategies started."

In one of the more bizarre findings of his research, Professor Long said the fishes probably copulated from a sideways position with their bony jointed arms locked together.

"This enabled the males to manoeuvre their genital organs into the right position for mating.

"With their arms interlocked, these fish looked more like they are square dancing the do-se-do rather than mating."

Flinders Postdoctoral Research Fellow Dr Brian Choo, a co-author on the paper, said the discovery signifies the first time in evolutionary history that males and females showed distinct differences in their physical appearance.

"Until this point in evolution, the skeletons of jawed vertebrates couldn't be distinguished because males and females had the same skeletal structures," Dr Choo said.

"This is the first time in vertebrate evolution that males and females developed separate reproductive structures, with males developing claspers, and females developing fixed plates to lock the claspers in for mating," he said.

The discovery highlights the importance of placoderms in the evolution of vertebrate animals, including humans, Professor Long said.

"Placoderms were once thought to be a dead-end group with no live relatives but recent studies show that our own evolution is deeply rooted in placoderms, and that many of the features we have, such as jaws, teeth and paired limbs, first originated with this group of fishes.

"Now, we reveal they gave us the intimate act of sexual intercourse as well."

Dr Matt Friedman, a palaeobiologist from the University of Oxford, UK, described the discovery as "nothing short of remarkable."

"Claspers in these fishes demand one of two alternative, but equally provocative, scenarios: either an unprecedented loss of internal fertilisation in vertebrates, or the coherence of the armoured placoderms as a single branch in the tree of life," Dr Friedman, who was not involved in the study, said.

"Both conclusions fly in the face of received wisdom, and suggest that there is still much to discover about this critical episode in our own extended evolutionary history."

The research involved a team of collaborators from Australia, Estonia, the UK, Sweden and China, who scrutinised a vast number of fossil specimens held in museum collections across the world.

Fossil specimens of male and female Microbrachius fossils will be placed on public display in the foyer of the South Australian Museum from today (October 20).