Fight Control: Researchers link individual neurons to regulation of aggressive behavior in flies

Scientists have long pondered the roots of aggression—and ways to temper it. Now, new research is beginning to illuminate the cellular-level circuitry responsible for modulating aggression in fruit flies, with the hope of someday translating the findings to humans.

Researchers at Harvard Medical School have identified two pairs of dopamine-producing neurons, also called dopaminergic neurons, and traced their aggression-modulating action to a common structure in the fly brain called the central complex, suggesting that important components of aggression-related behaviors may be processed there.

“This is the first research to identify single dopaminergic neurons that modulate a complex behavior—aggression—in fruit flies,” said Edward Kravitz, George Packer Berry Professor of Neurobiology at HMS and lead author of the study.

“We don’t know how complex this modulatory circuit is, but we now have a key element of it. If we eliminate or increase the function of that dopaminergic neuron, it affects the circuit of the brain responsible for controlling aggression,” Kravitz said.

The findings were published last week in PNAS.

Flies are an ideal animal model for neurological research because genetic methods allow scientists to manipulate neurons and simultaneously observe the resulting behaviors. Many fundamental nervous system mechanisms in flies are similar to those in humans. In fact, both flies and humans share the same neurohormones.

Dopamine is one such neurohormone, and across species it affects a range of behaviors, from learning and memory to motivation and movement. In humans, neurohormones are associated with conditions such as Parkinson’s disease and psychiatric disorders.

Dopaminergic neurons are found in small numbers in particular parts of nervous systems. In humans, there are about 200,000 to 400,000 of these neurons; in fruit flies there are about 100. While their numbers are few, these neurons influence a vast array of behaviors.

Kravitz, along with Olga Alekseyenko, a postdoctoral fellow in the Kravitz lab and first author on the paper, set out to discover how these few dopaminergic neurons can influence such a wide range of behaviors.

To do this, study co-first author, Yick-Bun Chan, HMS research associate in neurobiology, genetically engineered 200 lines of fruit flies. He then used them to target select dopaminergic neurons that could be activated or silenced while the flies engaged in various behaviors.

The team detected two pairs of dopaminergic neurons that affected aggressive behavior in the flies. Interestingly, aggression was increased in the flies either by augmenting the function of these cells or by deactivating them.

In fruit flies, males fight for territory and form stable hierarchical relationships. Using previous observations and analysis of more than 20,000 interactions in fly fights, the team established quantitative measures of aggressive behavior, such as lunging, that allowed them to compare aggression levels in different fly attacks.

“When we turned off the pairs of dopaminergic neurons, the flies fought with more lunging; when we turned them on, they also fought at higher intensity levels. Apparently normal levels of aggression require a precise amount of dopamine released at a specific time and place in the nervous system. These results suggest that these neurons ordinarily hold aggression in check,” said Alekseyenko.

Also significant was the finding that while the two sets of dopaminergic neurons modulated aggression, they did not influence other behaviors.

The first pair of neurons are found in the PPM3 cluster of neurons in the fly brain and the second are within the T1 cluster. Both pairs innervate different parts of the central complex, an important structure in the fly brain.

“We already knew that dopamine receptors are present in the central complex, but we didn’t know which dopamine neurons connected to the receptors or what behaviors those neurons affected,” said Alekseyenko.

“Now we know that two pairs of aggression-mediating dopaminergic neurons terminate in different regions of the central complex, and we know that those regions have different types of dopamine receptors. Our study shows that aggression is one of the behaviors coordinated in these regions of the brain, but we still don’t fully understand the process,” he said.

In a third group of flies, a neuron pair that projected into a different part of the brain was identified. These neurons affected locomotion and sleep, but did not influence aggression.

Kravitz said the next phase of the research will be to use genetic tools to allow his team to identify the subsequent steps in the brain circuitry—which neurons are pre- and post-synaptic to the T1 and PPM3 neurons and how that affects neuronal network function.

The goal will be to establish fundamental principles for how dopaminergic neurons work in the fruit fly system, with the hope that the research will one day translate to how these neurons work in higher species. This may ultimately aid in the development of new dopamine-targeted medications for humans.

“We can now relate these two pairs of neurons specifically to one behavior, and that is aggression,” Kravitz said. “That means we have one piece of the puzzle.”

Babies develop conscious perception from five months of age

Infants develop the ability to consciously process their environment as early as five months of age, according to a study published in the journal Science.

The team of French and Danish researchers, led by neuroscientist Sid Kouider, discovered a signal in the nervous system of infants that reliably identifies the beginning of visual consciousness, or the ability to see something and recall that you have seen it.

The team set out believing infants had the capacity for conscious reflection, but they had to overcome the barrier that babies could not report their thoughts.

They used electroencephalography (EEG) to record electrical activity in the brains of 80 infants aged five, 12 and 15 months while they were shown pictures of faces and random patterns for a fraction of a second.

When adults are aware of a stimulus, their brains show a two-stage pattern of activity. When they see a moving object, the sensors in the vision centre of the brain activate with a spike of activity.

The signal then moves from the back of the brain to the prefrontal cortex, which deals with higher-level cognition. This is known as the late slow wave.

Conscious awareness begins after the second stage of neural activity reaches a specific threshold.

The new study found this two-stage pattern of brain activity was present in the three groups of infants, though it was weaker and more drawn out in the five-month-olds.

The researchers say neurological markers of visual consciousness may help paediatricians better manage infant pain and anaesthesia.

But they note the research does not provide direct proof of consciousness. “Indeed, it is a genuine philosophical problem whether such a proof can ever be obtained from purely neurophsysiological data,” the paper said.

Professor Louise Newman, Director of the Centre for Developmental Psychiatry & Psychology at Monash University, said the study was novel in its ability to measure the way very young brains register stimuli.

But five months should not be seen as a fixed point at which infants start to process information, she said.

“Although this group has studied five months and up, my suspicion would be that if we had different techniques, young infants – from birth on – would show the capacity of registering these sorts of stimuli.

“Infants are born with quite sophisticated capacities to observe, respond to and interact with the environment, particularly the social environment,” she said.

“Very soon after birth, infants will maintain gaze with their parents or parent: they’ve got quite sophisticated visual tracking capacity from an early age.”

Professor Newman, who has undertaken behavioural studies in two- to four-month olds, said young infant brains were extremely sensitive to their mother’s emotional reaction.

“They learn that ‘if I do this, or if I smile or signal in this way, this is what usually happens’. If you manipulate that so they don’t get that response, they’re very sensitive to that and they show signs that it’s very aversive to them.”

Video games: bad or good for your memory?

After the horrific shooting sprees at Columbine High School in 1999 and Virginia Tech in 2007, players of violent video games, such as First Person Shooter (FPS) games, have often been accused in the media of being impulsive, antisocial, or aggressive.

Positive effects

However, the question is: do First Person Shooter games also have positive effects for our mental processes? At the University of Leiden, we investigated whether gaming could be a fast and easy way to improve your memory.

Develop an adaptive mindset

Indeed, the new generations of FPS (compared to strategic) games are not just about pressing a button at the right moment but require the players to develop an adaptive mindset to rapidly react and monitor fast moving visual and auditory stimuli.

Gamers compared to non-gamers

In a study published in Psychological Research Journal, Dr. Lorenza Colzato and her fellow researchers compared, on a task related to working memory, people who played at least five hours weekly with people who never played video games.  

More flexible brain

The researchers found that gamers outperformed non-gamers. They suggest that video game experience trains your brain to become more flexible in the updating and monitoring of new information enhancing the memory capacity of the gamers.

Video about the research

Autistic Children’s Love For Video Games Could Lead To New Treatment Options

Kids and teenagers suffering from autism spectrum disorder (ASD) are more likely to use television and video games and less likely to spend time on social media than their normally-developing counterparts, claims new research set for publication in a future issue of the Journal of Autism and Developmental Disorders.

Micah Mazurek, an assistant professor of health psychology and a clinical child psychologist at the University of Missouri, recruited 202 children and adolescents with ASD and 179 of their typically developing siblings for the study.

Those with ASD spent more time playing video games and watching TV than spending time on physical or pro-social activities (including spending time on websites like Facebook or Twitter). The opposite was also true: typically-developing children spent more time on non-screen-related activities than they did watching shows or playing on the PS3 or the Xbox 360, according to the soon-to-be-published study.

“Many parents and clinicians have noticed that children with ASD are fascinated with technology, and the results of our recent studies certainly support this idea,” Mazurek said in a statement. “We found that children with ASD spent much more time playing video games than typically developing children, and they are much more likely to develop problematic or addictive patterns of video game play.”

In a separate study of 169 boys with ASD, excessive video game use had been linked to oppositional behaviors, such as refusal to follow directions or getting into arguments with others. Mazurek said that the issues will need to be further examined in future, closely-controlled research.

“Because these studies were cross-sectional, it is not clear if there is a causal relationship between video game use and problem behaviors,” she said. “Children with ASD may be attracted to video games because they can be rewarding, visually engaging and do not require face-to-face communication or social interaction. Parents need to be aware that, although video games are especially reinforcing for children with ASD, children with ASD may have problems disengaging from these games.”

Despite those issues, Mazurek also believes that autistic children’s love for video games and television could be used for beneficial purposes. The professor believes that discovering what makes these screen-related pastimes so attractive to kids with ASD could help researchers and medical experts develop new treatment options.

“Using screen-based technologies, communication and social skills could be taught and reinforced right away,” Mazurek explained. “However, more research is needed to determine whether the skills children with ASD might learn in virtual reality environments would translate into actual social interactions.”

High Levels of Glutamate in Brain May Kick-Start Schizophrenia

An excess of the brain neurotransmitter glutamate may cause a transition to psychosis in people who are at risk for schizophrenia, reports a study from investigators at Columbia University Medical Center (CUMC) published in the current issue of Neuron.

The findings suggest 1) a potential diagnostic tool for identifying those at risk for schizophrenia and 2) a possible glutamate-limiting treatment strategy to prevent or slow progression of schizophrenia and related psychotic disorders.

“Previous studies of schizophrenia have shown that hypermetabolism and atrophy of the hippocampus are among the most prominent changes in the patient’s brain,” said senior author Scott Small, MD, Boris and Rose Katz Professor of Neurology at CUMC. “The most recent findings had suggested that these changes occur very early in the disease, which may point to a brain process that could be detected even before the disease begins.”

To locate that process, the Columbia researchers used neuroimaging tools in both patients and a mouse model. First they followed a group of 25 young people at risk for schizophrenia to determine what happens to the brain as patients develop the disorder. In patients who progressed to schizophrenia, they found the following pattern: First, glutamate activity increased in the hippocampus, then hippocampus metabolism increased, and then the hippocampus began to atrophy.

To see if the increase in glutamate led to the other hippocampus changes, the researchers turned to a mouse model of schizophrenia. When the researchers increased glutamate activity in the mouse, they saw the same pattern as in the patients: The hippocampus became hypermetabolic and, if glutamate was raised repeatedly, the hippocampus began to atrophy.

Theoretically, this dysregulation of glutamate and hypermetabolism could be identified through imaging individuals who are either at risk for or in the early stage of disease. For these patients, treatment to control glutamate release might protect the hippocampus and prevent or slow the progression of psychosis.

Strategies to treat schizophrenia by reducing glutamate have been tried before, but with patients in whom the disease is more advanced. “Targeting glutamate may be more useful in high-risk people or in those with early signs of the disorder,” said Jeffrey A. Lieberman, MD, a renowned expert in the field of schizophrenia, Chair of the Department of Psychiatry at CUMC, and president-elect of the American Psychiatric Association. “Early intervention may prevent the debilitating effects of schizophrenia, increasing recovery in one of humankind’s most costly mental disorders.”

In an accompanying commentary, Bita Moghaddam, PhD, professor of neuroscience and of psychiatry, University of Pittsburgh, suggests that if excess glutamate is driving schizophrenia in high-risk individuals, it may also explain why a patient’s first psychotic episodes are often caused by periods of stress, since stress increases glutamate levels in the brain.

Increased brain activity predicts future onset of substance use

Do people get caught in the cycle of overeating and drug addiction because their brain reward centers are over-active causing them to experience greater cravings for food or drugs? In a unique prospective study Oregon Research Institute (ORI) senior scientist Eric Stice, Ph.D., and colleagues tested this theory, called the reward surfeit model. The results indicated that elevated responsivity of reward regions in the brain increased the risk for future substance use, which has never been tested before prospectively with humans. Paradoxically, results also provide evidence that even a limited history of substance use was related to less responsivity in the reward circuitry, as has been suggested by experiments with animals. The research appears in the May 1, 2013 issue of Biological Psychiatry.

In a novel study using functional Magnetic Resonance Imaging (fMRI) Stice’s team tested whether individual differences in reward region responsivity predicted overweight/obesity onset among initially healthy weight adolescents and substance use onset among initially abstinent adolescents. The neural response to food and monetary reward was measured in 162 adolescents. Body fat and substance use were assessed at the time of the fMRI and again one year later.

"The findings are important because this is the first test of whether atypical responsivity of reward circuitry increases risk for substance use," says Dr. Stice. "Although numerous researchers have suggested that reduced responsivity is a vulnerability factor for substance use, this theory was based entirely on cross-sectional studies comparing substance abusing individuals to healthy controls; no studies have tested this thesis with prospective data."

Investigators examined the extent to which reward circuitry (e.g., the striatum) was activated in response to receipt and anticipated receipt of money. Monetary reward is a general reinforcer and has been used frequently to assess reward sensitivity. The team also used another paradigm to assess brain activation in response to the individual’s consumption and anticipated consumption of chocolate milkshake. Results showed that greater activation in the striatum during monetary reward receipt at baseline predicted future substance use onset over a 1-year follow-up.

Noteworthy was that adolescents who had already begun using substances showed less striatal response to monetary reward. This finding provides the first evidence that even a relatively short period of moderate substance use might reduce reward region responsivity to a general reinforcer.

"The implications are that the more individuals use psychoactive substances, the less responsive they will be to rewarding experiences, meaning that they may derive less reinforcement from other pursuits, such as interpersonal relationships, hobbies, and school work. This may contribute to the escalating spiral of drug use that characterizes substance use disorders," commented Stice.

Although the investigators had expected parallel neural predictors of future onset of overweight during exposure to receipt and anticipated receipt of a palatable food, no significant effects emerged. It is possible that these effects are weaker and that a longer follow-up period will be necessary to better differentiate who will gain weight and who will remain at a healthy weight.

(Image courtesy: West Virginia University)