oxytocin

Michael Gliksberg, left, and Prof. Gil Levkowitz are among the researchers who have discovered that oxytocin in a developing zebrafish brain determines later social behaviour. (photo from Weizmann Institute)

Whenever we decide to throw a party, invite in-laws to dinner or embark on a cruise, we are driven by the most basic component of social behaviour: the desire to hang out with other humans. Considering that the drive to form groups with members of one’s own species has been conserved throughout evolution, it’s evident that social behaviour is governed by genes, at least to some degree. But our parents and teachers help us hone our social graces, so teasing apart the effects of nature and nurture on this behaviour is hard, if not impossible. By studying zebrafish, Weizmann Institute of Science researchers, in collaboration with scientists in Portugal, have managed to solve part of the riddle of how social behaviour is hardwired into the developing brain.

Zebrafish are perfect for studying the inborn basis of behaviour because they receive zero nurturing from parents. “Some fish species take care of their young, but not zebrafish,” explained Prof. Gil Levkowitz of the Weizmann Institute’s molecular cell biology and molecular neuroscience departments, who headed the research team together with Prof. Rui F. Oliveira of Instituto Gulbenkian de Ciência in Portugal. “The female zebrafish spawns several hundred eggs, which are fertilized by sperm released into the water by the male. She does provide her offspring with a ‘lunchbox’ – a protein sac, or yolk, that makes up part of the egg – but, otherwise, her message to her children is: manage on your own.”

At about four weeks of age, the centimetre-long juvenile fish, just out of the larval stage, begin to socialize. Though not as exquisitely synchronized as the schools of moonfish in the movie Finding Nemo, they do exhibit a strong tendency to swim together as a group, termed a shoal. Much like humans, they have an incentive to seek company; in their case, the group provides them with advantages in searching for food, overcoming currents, avoiding predators and finding mates. The shoaling behaviour of zebrafish requires sophisticated processing of visual and social cues, very similar to that which takes place in the brains of socializing humans. In particular, the zebrafish must be able to identify other fish as belonging to their own, “friendly” – as opposed to different or, worse yet, predatory – species.

To learn how the social behaviour of zebrafish develops, the researchers focused on the hormone oxytocin, one of the most important neurochemicals known to enhance social interactions, including bonding. Postdoctoral fellow Dr. Ana Rita Nunes and doctoral student Michael Gliksberg created a system for exploring the effects of oxytocin on the developing brains of zebrafish larvae. They produced transgenic larvae whose oxytocin-making neurons harboured a bacterial gene encoding fatal sensitivity to antibiotics. The researchers could then eliminate these neurons from the brains of the larvae at different stages of their development by adding antibiotics to the water, and they later observed the zebrafish behaviour as they became adults.

The scientists discovered that the larvae whose brains lacked oxytocin early on – specifically, in the first two weeks of life – grew into adult fish with an impaired capacity for social interaction, namely, swimming in a shoal. Although their brains regenerated the oxytocin neurons later in life, this capacity was not restored. This meant that, for adults to be capable of social behaviour, their brains had to be organized by oxytocin in a certain manner during a critical time window of brain development in which the social traits are established.

The researchers further discovered the mechanisms by which oxytocin primes the growing brain for socializing. They showed that oxytocin-producing neurons were critical to the birth of another type of neuron, one that releases the neurotransmitter dopamine, which is known to regulate feelings of reward and motivation. Zebrafish whose brains had not been exposed to oxytocin during the first two weeks of life had reduced numbers of dopamine-making neurons, as well as a reduced number of connections to these neurons, in two distinct brain areas.

One of these areas was responsible for processing visual stimuli, apparently of the kind essential for recognizing potential swimming partners. An analogous area in the brains of mammals, including humans, is involved in processing visual cues in social situations. It controls eye movements that scan, for example, different elements of the face in a particular order to decipher facial expressions. This pattern is often absent in people with autism, suggesting that their brains respond to social-based visual cues differently.

The other dopamine-deficient brain area in the zebrafish was analogous to a major reward centre in the mammalian brain, which is involved in the positive reinforcement of social interactions.

A lack of oxytocin in the critical early developmental period also disrupted a system of neuronal connections known as the social decision-making network – a group of brain areas that work together to process social information. In fish whose brains had developed without oxytocin, the synchronization patterns of neuronal activities among these centres were completely different from those of regular fish.

Nunes summarized: “Oxytocin organizes the developing brain in a way that’s essential for responding to social situations.”

– Courtesy Weizmann Institute

Oxytocin, a peptide produced in the brain, may bring hearts together – or it can help induce aggression. (image from Weizmann Institute)

During the pandemic lockdown, as couples have been forced to spend days and weeks in each other’s company, some have found their love renewed while others are on their way to divorce court. Oxytocin, a peptide produced in the brain, is complicated in that way: a neuromodulator, it may bring hearts together or it can help induce aggression. This conclusion arises from research led by Weizmann Institute of Science researchers in which mice living in semi-natural conditions had their oxytocin-producing brain cells manipulated in a precise manner. The findings, which were published in Neuron, could shed new light on efforts to use oxytocin to treat a variety of psychiatric conditions, from social anxiety and autism to schizophrenia.

Much of what we know about the actions of neuromodulators like oxytocin comes from behavioural studies of lab animals in standard lab conditions. These conditions are strictly controlled and artificial, in part so that researchers can limit the number of variables affecting behaviour. But a number of recent studies suggest that the actions of a mouse in a semi-natural environment can teach us much more about natural behaviour, especially when we mean to apply those findings to humans.

Prof. Alon Chen’s lab group in the institute’s neurobiology department have created an experimental setup that enables them to observe mice in something approaching their natural living conditions – an environment enriched with stimuli they can explore – and their activity is monitored day and night with cameras and analyzed computationally. The present study, which has been ongoing for the past eight years, was led by research students Sergey Anpilov and Noa Eren, and staff scientist Dr. Yair Shemesh in Chen’s lab group.

The innovation in this experiment was to incorporate optogenetics – a method that enables researchers to turn specific neurons in the brain on or off using light. To create an optogenetic setup that would enable the team to study mice that were behaving naturally, the group developed a compact, lightweight, wireless device with which the scientists could activate nerve cells by remote control. With the help of optogenetics expert Prof. Ofer Yizhar of the same department, the group introduced a protein previously developed by Yizhar into the oxytocin-producing brain cells in the mice. When light from the wireless device touched those neurons, they became more sensitized to input from the other brain cells in their network.

“Our first goal,” said Anpilov, “was to reach that ‘sweet spot’ of experimental setups in which we track behaviour in a natural environment, without relinquishing the ability to ask pointed scientific questions about brain functions.”

Shemesh added that “the classical experimental setup is not only lacking in stimuli, the measurements tend to span mere minutes, while we had the capacity to track social dynamics in a group over the course of days.”

Delving into the role of oxytocin was sort of a test drive for the experimental system. It had been believed that this hormone mediates pro-social behaviour. But findings have been conflicting, and some have proposed another hypothesis, termed “social salience,” stating that oxytocin might be involved in amplifying the perception of diverse social cues, which could then result in pro-social or antagonistic behaviours, depending on such factors as individual character and the environment.

To test the social salience hypothesis, the team used mice in which they could gently activate the oxytocin-producing cells in the hypothalamus, placing them first in the enriched, semi-natural lab environments. To compare, they repeated the experiment with mice placed in the standard, sterile lab setups.

In the semi-natural environment, the mice at first displayed heightened interest in one another, but this was soon accompanied by a rise in aggressive behaviour. In contrast, increasing oxytocin production in the mice in classical lab conditions resulted in reduced aggression.

“In an all-male, natural social setting, we would expect to see belligerent behaviour as they compete for territory or food,” said Anpilov. “That is, the social conditions are conducive to competition and aggression. In the standard lab setup, a different social situation leads to a different effect for the oxytocin.”

If the “love hormone” is more likely a “social hormone,” what does that mean for its pharmaceutical applications?

“Oxytocin is involved, as previous experiments have shown, in such social behaviours as making eye contact or feelings of closeness,” said Eren, “but our work shows it does not improve sociability across the board. Its effects depend on both context and personality.”

This implies that, if oxytocin is to be used therapeutically, a much more nuanced view is needed in research: “If we want to understand the complexities of behaviour, we need to study behaviour in a complex environment. Only then can we begin to translate our findings to human behaviour,” she said.

Participating in this research were scientists at the Max Planck Institute for Psychiatry in Munich, including research students Asaf Benjamin and Stoyo Karamihalev, staff scientist Dr. Julien Dine and postdoctoral fellow Dr. Oren Forkosh of the Chen lab; Prof. Shlomo Wagner and postdoctoral fellow Dr. Hala Harony-Nicolas of Haifa University; Prof. Inga Neumann and research student Vinicius Oliveira of Regensburg University, Germany; and electrical engineer Avi Dagan.

Tag: oxytocin

Studying the “love hormone”