Study reveals potential role of ‘love hormone’ oxytocin in brain function

Findings of NYU Langone researchers may have relevance in autism-spectrum disorder

In a loud, crowded restaurant, having the ability to focus on the people and conversation at your own table is critical. Nerve cells in the brain face similar challenges in separating wanted messages from background chatter. A key element in this process appears to be oxytocin, typically known as the “love hormone” for its role in promoting social and parental bonding.

In a study appearing online August 4 in Nature, NYU Langone Medical Center researchers decipher how oxytocin, acting as a neurohormone in the brain, not only reduces background noise, but more importantly, increases the strength of desired signals. These findings may be relevant to autism, which affects one in 88 children in the United States.

“Oxytocin has a remarkable effect on the passage of information through the brain,” says Richard W. Tsien, DPhil, the Druckenmiller Professor of Neuroscience and director of the Neuroscience Institute at NYU Langone Medical Center. “It not only quiets background activity, but also increases the accuracy of stimulated impulse firing. Our experiments show how the activity of brain circuits can be sharpened, and hint at how this re-tuning of brain circuits might go awry in conditions like autism.”

Children and adults with autism-spectrum disorder (ASD) struggle with recognizing the emotions of others and are easily distracted by extraneous features of their environment. Previous studies have shown that children with autism have lower levels of oxytocin, and mutations in the oxytocin receptor gene predispose people to autism. Recent brain recordings from people with ASD show impairments in the transmission of even simple sensory signals.

The current study built upon 30-year old results from researchers in Geneva, who showed that oxytocin acted in the hippocampus, a region of the brain involved in memory and cognition. The hormone stimulated nerve cells – called inhibitory interneurons – to release a chemical called GABA. This substance dampens the activity of the adjoining excitatory nerve cells, known as pyramidal cells.

“From the previous findings, we predicted that oxytocin would dampen brain circuits in all ways, quieting both background noise and wanted signals,” Dr. Tsien explains. “Instead, we found that oxytocin increased the reliability of stimulated impulses – good for brain function, but quite unexpected.”

To resolve this paradox, Dr. Tsien and his Stanford graduate student Scott Owen collaborated with Gord Fishell, PhD, the Julius Raynes Professor of Neuroscience and Physiology at NYU Langone Medical Center, and NYU graduate student Sebnem Tuncdemir. They identified the particular type of inhibitory interneurons responsible for the effects of oxytocin: “fast-spiking” inhibitory interneurons.

The mystery of how oxytocin drives these fast-spiking inhibitory cells to fire, yet also increases signaling to pyramidal neurons, was solved through studies with rodent models. The researchers found that continually activating the fast-spiking inhibitory neurons – good for lowering background noise – also causes their GABA-releasing synapses to fatigue. Accordingly, when a stimulus arrives, the tired synapses release less GABA and excitation of the pyramidal neuron is not dampened as much, so that excitation drives the pyramidal neuron’s firing more reliably.

“The stronger signal and muffled background noise arise from the same fundamental action of oxytocin and give two benefits for the price of one,” Dr. Fishell explains. “It’s too early to say how the lack of oxytocin signaling is involved in the wide diversity of autism-spectrum disorders, and the jury is still out about its possible therapeutic effects. But it is encouraging to find that a naturally occurring neurohormone can enhance brain circuits by dialing up wanted signals while quieting background noise.”

How to learn successfully even under stress

Predicting the weather under stress

The team from Bochum has examined 80 subjects, 50 per cent of whom were given a drug blocking mineralocorticoid receptors in the brain. The remaining participants took a placebo drug. Twenty participants from each group were subjected to a stress-inducing experience. Subsequently, all participants underwent a learning test, the so-called weather prediction task. The subjects were shown playing cards with different symbols and had to learn which combinations of cards meant rain and which meant sunshine. The researchers used MRI to record the respective brain activity.

Learning unconsciously or consciously

There are two different approaches to master the weather prediction test: some subjects tried consciously to formulate a rule that would enable them to predict sunshine and rain. Others learned unconsciously to give the right answer, following their gut feeling, as it were. The team of Lars Schwabe demonstrated in August 2012 that, under stress, the brain prefers unconscious to conscious learning. “This switch to another memory system happens automatically,” says Lars Schwabe. “It makes sense for the organism to react in this manner. Thus, learning efficiency can be maintained even under stress.” However, this works only with fully functional mineralocorticoid receptors. Once the researchers blocked these receptors by applying the drug Spironolactone, the participants switched over to the unconscious strategy less frequently, thus demonstrating a poorer learning efficiency.

Effects also visible in brain activity

These effects also became evident in MRI data. Usually, stress causes the brain activity to shift from the hippocampus – a structure for conscious learning – to the dorsal striatum, which manages unconscious learning. However, this stress-induced switch took place only in the placebo group, not in subjects who had been given the mineralocorticoid receptor blocker. Consequently, the mineralocorticoid receptors play a crucial role in enabling the brain to adapt to stressful situations.

(Image: Shutterstock)

A neural code for navigation

Neurons in the rat brain use a preexisting set of firing sequences to encode future navigational experiences

Specialized neurons called place cells, located in the hippocampus region of the brain, fire when an animal is in a particular location in its environment, and it is the linear sequence of their firing that encodes in the brain movement trajectories from one location to another. Building on previous work, George Dragoi and Susumu Tonegawa from the RIKEN–MIT Center for Neural Circuit Genetics have now shown that place cells have a preexisting inventory of firing sequences that they can use to encode multiple novel routes of exploration.

Specific sequences of place cells are known to encode spatial experiences, but it has been debated whether such sequences are formed during a new experience or preformed and adapted to specific experiences when required. Dragoi and Tonegawa recently showed that ‘future’ place cells fire in sequence while the animal is asleep, prior to experiencing a novel environment, and that animals use this preexisting neuronal firing pattern to rapidly learn how to navigate their surroundings.

To confirm and investigate this mechanism further, the researchers first recorded the neuronal activity of place cells in rats during one hour of sleep. Next, they monitored this activity during movement along a track that the rat had not previously explored, and later recorded it during movement along the same track with two additional lengths separated by right-angle turns. They then correlated the temporal pattern of place cell activity recorded during sleep with the spatial pattern of activity recorded while the animals were freely exploring the longer track.

The researchers found that the sequences of place cell activity were unique for each of the three lengths of the track and matched those recorded during sleep. “We had observed the same sequences as independent clusters of correlated temporal sequences during the preceding sleep period,” explains Dragoi. 

The results suggest that rapid encoding of particular trajectories within novel environments is achieved during exploration by selecting from a set of preexisting temporal sequences that fired during sleep. In other words, hippocampal place cells appear to be prearranged into sets of sequential firing cells that can be adapted rapidly to encode for multiple spatial trajectories that the animal could undertake in its surroundings. Based on their data, Dragoi and Tonegawa predict that the sets of hippocampal place cells could encode for at least 15 unique future spatial experiences. In addition, their findings could explain the role that the hippocampus plays in humans in imagining future encounters within our own complex environment.

Neuroscientists plant false memories in the brain

The phenomenon of false memory has been well-documented: In many court cases, defendants have been found guilty based on testimony from witnesses and victims who were sure of their recollections, but DNA evidence later overturned the conviction.

In a step toward understanding how these faulty memories arise, MIT neuroscientists have shown that they can plant false memories in the brains of mice. They also found that many of the neurological traces of these memories are identical in nature to those of authentic memories.

“Whether it’s a false or genuine memory, the brain’s neural mechanism underlying the recall of the memory is the same,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of a paper describing the findings in the July 25 edition of Science.

The study also provides further evidence that memories are stored in networks of neurons that form memory traces for each experience we have — a phenomenon that Tonegawa’s lab first demonstrated last year.

Neuroscientists have long sought the location of these memory traces, also called engrams. In the pair of studies, Tonegawa and colleagues at MIT’s Picower Institute for Learning and Memory showed that they could identify the cells that make up part of an engram for a specific memory and reactivate it using a technology called optogenetics.

Lead authors of the paper are graduate student Steve Ramirez and research scientist Xu Liu. Other authors are technical assistant Pei-Ann Lin, research scientist Junghyup Suh, and postdocs Michele Pignatelli, Roger Redondo and Tomas Ryan.

Seeking the engram

Episodic memories — memories of experiences — are made of associations of several elements, including objects, space and time. These associations are encoded by chemical and physical changes in neurons, as well as by modifications to the connections between the neurons.

Where these engrams reside in the brain has been a longstanding question in neuroscience. “Is the information spread out in various parts of the brain, or is there a particular area of the brain in which this type of memory is stored? This has been a very fundamental question,” Tonegawa says.

In the 1940s, Canadian neurosurgeon Wilder Penfield suggested that episodic memories are located in the brain’s temporal lobe. When Penfield electrically stimulated cells in the temporal lobes of patients who were about to undergo surgery to treat epileptic seizures, the patients reported that specific memories popped into mind. Later studies of the amnesiac patient known as “H.M.” confirmed that the temporal lobe, including the area known as the hippocampus, is critical for forming episodic memories.

However, these studies did not prove that engrams are actually stored in the hippocampus, Tonegawa says. To make that case, scientists needed to show that activating specific groups of hippocampal cells is sufficient to produce and recall memories.

To achieve that, Tonegawa’s lab turned to optogenetics, a new technology that allows cells to be selectively turned on or off using light.

For this pair of studies, the researchers engineered mouse hippocampal cells to express the gene for channelrhodopsin, a protein that activates neurons when stimulated by light. They also modified the gene so that channelrhodopsin would be produced whenever the c-fos gene, necessary for memory formation, was turned on.

In last year’s study, the researchers conditioned these mice to fear a particular chamber by delivering a mild electric shock. As this memory was formed, the c-fos gene was turned on, along with the engineered channelrhodopsin gene. This way, cells encoding the memory trace were “labeled” with light-sensitive proteins.

The next day, when the mice were put in a different chamber they had never seen before, they behaved normally. However, when the researchers delivered a pulse of light to the hippocampus, stimulating the memory cells labeled with channelrhodopsin, the mice froze in fear as the previous day’s memory was reactivated.

“Compared to most studies that treat the brain as a black box while trying to access it from the outside in, this is like we are trying to study the brain from the inside out,” Liu says. “The technology we developed for this study allows us to fine-dissect and even potentially tinker with the memory process by directly controlling the brain cells.”

Incepting false memories

That is exactly what the researchers did in the new study — exploring whether they could use these reactivated engrams to plant false memories in the mice’s brains.

First, the researchers placed the mice in a novel chamber, A, but did not deliver any shocks. As the mice explored this chamber, their memory cells were labeled with channelrhodopsin. The next day, the mice were placed in a second, very different chamber, B. After a while, the mice were given a mild foot shock. At the same instant, the researchers used light to activate the cells encoding the memory of chamber A.

On the third day, the mice were placed back into chamber A, where they now froze in fear, even though they had never been shocked there. A false memory had been incepted: The mice feared the memory of chamber A because when the shock was given in chamber B, they were reliving the memory of being in chamber A.

Moreover, that false memory appeared to compete with a genuine memory of chamber B, the researchers found. These mice also froze when placed in chamber B, but not as much as mice that had received a shock in chamber B without having the chamber A memory activated.

The researchers then showed that immediately after recall of the false memory, levels of neural activity were also elevated in the amygdala, a fear center in the brain that receives memory information from the hippocampus, just as they are when the mice recall a genuine memory.

These two papers represent a major step forward in memory research, says Howard Eichenbaum, a professor of psychology and director of Boston University’s Center for Memory and Brain.

“They identified a neural network associated with experience in an environment, attached a fear association with it, then reactivated the network to show that it supports memory expression. That, to me, shows for the first time a true functional engram,” says Eichenbaum, who was not part of the research team.

The MIT team is now planning further studies of how memories can be distorted in the brain.

“Now that we can reactivate and change the contents of memories in the brain, we can begin asking questions that were once the realm of philosophy,” Ramirez says. “Are there multiple conditions that lead to the formation of false memories? Can false memories for both pleasurable and aversive events be artificially created? What about false memories for more than just contexts — false memories for objects, food or other mice? These are the once seemingly sci-fi questions that can now be experimentally tackled in the lab.”

Brain imaging study reveals our brains ‘divide and conquer’

University of Queensland (UQ) researchers have found human brains ‘divide and conquer’ when people learn to navigate around new environments.

The research by UQ’s Queensland Brain Institute (QBI) could provide hope for people with spatial memory impairments.

The study found that the mental picture people create to help navigate to a new location is split into two sections.

The size of the environment is coded by one area of the brain and its complexity is coded in another.

QBI postdoctoral research fellow and lead researcher Dr Oliver Baumann said the work shed new light on how learning the layout of a new environment, and then accessing this information from memory, was represented in the brain.

“We’ve known for some time that a part of the brain called the hippocampus is important for building and maintaining cognitive maps,” he said.

“The results of our study have shown for the first time that different aspects of a learned environment – specifically its size and complexity – are represented by distinct areas within the hippocampus.”

QBI Cognitive Neuroscience Laboratory Head Professor Jason Mattingley said the findings could have important implications for people suffering from spatial memory impairments.

“This research is important for understanding how our brain normally stores and manages spatial information,” Professor Mattingley said.

“It also gives us clues as to why people with memory loss due to Alzheimer’s disease often become lost in new or previously familiar surroundings.”

Dr Baumann said 18 people navigated their way through three virtual mazes that differed either in the number of corridors through which they could travel or the length of the corridors.

After learning the task, the participants were asked to recall mental maps from each of the mazes while their brain activity was measured using functional magnetic resonance imaging.

“We found that one region in the hippocampus was more active when participants recalled a complex maze in which there were many corridors to choose from, irrespective of the overall size of the maze,” Dr Baumann said.

“Conversely, we found that a separate area of the hippocampus was more active when the overall size of the maze increased, regardless of the number of corridors.”

The study, “Dissociable representations of environmental size and complexity in the human hippocampus”, is published in The Journal of Neuroscience.

(Image: iStockphoto)

Exercise reorganizes the brain to be more resilient to stress

Physical activity reorganizes the brain so that its response to stress is reduced and anxiety is less likely to interfere with normal brain function, according to a research team based at Princeton University.

The researchers report in the Journal of Neuroscience that when mice allowed to exercise regularly experienced a stressor — exposure to cold water — their brains exhibited a spike in the activity of neurons that shut off excitement in the ventral hippocampus, a brain region shown to regulate anxiety.

These findings potentially resolve a discrepancy in research related to the effect of exercise on the brain — namely that exercise reduces anxiety while also promoting the growth of new neurons in the ventral hippocampus. Because these young neurons are typically more excitable than their more mature counterparts, exercise should result in more anxiety, not less. The Princeton-led researchers, however, found that exercise also strengthens the mechanisms that prevent these brain cells from firing.

The impact of physical activity on the ventral hippocampus specifically has not been deeply explored, said senior author Elizabeth Gould, Princeton’s Dorman T. Warren Professor of Psychology. By doing so, members of Gould’s laboratory pinpointed brain cells and regions important to anxiety regulation that may help scientists better understand and treat human anxiety disorders, she said.

From an evolutionary standpoint, the research also shows that the brain can be extremely adaptive and tailor its own processes to an organism’s lifestyle or surroundings, Gould said. A higher likelihood of anxious behavior may have an adaptive advantage for less physically fit creatures. Anxiety often manifests itself in avoidant behavior and avoiding potentially dangerous situations would increase the likelihood of survival, particularly for those less capable of responding with a “fight or flight” reaction, she said.

"Understanding how the brain regulates anxious behavior gives us potential clues about helping people with anxiety disorders. It also tells us something about how the brain modifies itself to respond optimally to its own environment," said Gould, who also is a professor in the Princeton Neuroscience Institute.

The research was part of the graduate dissertation for first author Timothy Schoenfeld, now a postdoctoral fellow at the National Institute of Mental Health, as well as part of the senior thesis project of co-author Brian Hsueh, now an MD/Ph.D. student at Stanford University. The project also included co-authors Pedro Rada and Pedro Pieruzzini, both from the University of Los Andes in Venezuela.

For the experiments, one group of mice was given unlimited access to a running wheel and a second group had no running wheel. Natural runners, mice will dash up to 4 kilometers (about 2.5 miles) a night when given access to a running wheel, Gould said. After six weeks, the mice were exposed to cold water for a brief period of time.

The brains of active and sedentary mice behaved differently almost as soon as the stressor occurred, an analysis showed. In the neurons of sedentary mice only, the cold water spurred an increase in “immediate early genes,” or short-lived genes that are rapidly turned on when a neuron fires. The lack of these genes in the neurons of active mice suggested that their brain cells did not immediately leap into an excited state in response to the stressor.

Instead, the brain in a runner mouse showed every sign of controlling its reaction to an extent not observed in the brain of a sedentary mouse. There was a boost of activity in inhibitory neurons that are known to keep excitable neurons in check. At the same time, neurons in these mice released more of the neurotransmitter gamma-aminobutyric acid, or GABA, which tamps down neural excitement. The protein that packages GABA into little travel pods known as vesicles for release into the synapse also was present in higher amounts in runners.

The anxiety-reducing effect of exercise was canceled out when the researchers blocked the GABA receptor that calms neuron activity in the ventral hippocampus. The researchers used the chemical bicuculine, which is used in medical research to block GABA receptors and simulate the cellular activity underlying epilepsy. In this case, when applied to the ventral hippocampus, the chemical blocked the mollifying effects of GABA in active mice.

Study Shows a Solitary Mutation Can Destroy Critical ‘Window’ of Early Brain Development

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown in animal models that brain damage caused by the loss of a single copy of a gene during very early childhood development can cause a lifetime of behavioral and intellectual problems.

The study, published this week in the Journal of Neuroscience, sheds new light on the early development of neural circuits in the cortex, the part of the brain responsible for functions such as sensory perception, planning and decision-making.

The research also pinpoints the mechanism responsible for the disruption of what are known as “windows of plasticity” that contribute to the refinement of the neural connections that broadly shape brain development and the maturing of perception, language, and cognitive abilities.

The key to normal development of these abilities is that the neural connections in the brain cortex—the synapses—mature at the right time.

In an earlier study, the team, led by TSRI Associate Professor Gavin Rumbaugh, found that in mice missing a single copy of the vital gene, certain synapses develop prematurely within the first few weeks after birth. This accelerated maturation dramatically expands the process known as “excitability”—how often brain cells fire—in the hippocampus, a part of the brain critical for memory. The delicate balance between excitability and inhibition is especially critical during early developmental periods. However, it remained a mystery how early maturation of brain circuits could lead to lifelong cognitive and behavioral problems.

The current study shows in mice that the interruption of the synapse-regulating gene known as SYNGAP1—which can cause a devastating form of intellectual disability and increase the risk for developing autism in humans—induces early functional maturation of neural connections in two areas of the cortex. The influence of this disruption is widespread throughout the developing brain and appears to degrade the duration of these critical windows of plasticity.

“In this study, we were able to directly connect early maturation of synapses to the loss of an important plasticity window in the cortex,” Rumbaugh said. “Early maturation of synapses appears to make the brain less plastic at critical times in development. Children with these mutations appear to have brains that were built incorrectly from the ground up.”

The accelerated maturation also appeared to occur surprisingly early in the developing cortex. That, Rumbaugh added, would correspond to the first two years of a child’s life, when the brain is expanding rapidly. “Our goal now is to figure out a way to prevent the damage caused by SYNGAP1 mutations. We would be more likely to help that child if we could intervene very early on—before the mutation has done its damage,” he said.