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.”

Marijuana use in adolescence may cause permanent brain abnormalities

Regular marijuana use in adolescence, but not adulthood, may permanently impair brain function and cognition, and may increase the risk of developing serious psychiatric disorders such as schizophrenia, according to a recent study from the University of Maryland School of Medicine. Researchers hope that the study, published in Neuropsychopharmacology — a publication of the journal Nature – will help to shed light on the potential long-term effects of marijuana use, particularly as lawmakers in Maryland and elsewhere contemplate legalizing the drug.

"Over the past 20 years, there has been a major controversy about the long-term effects of marijuana, with some evidence that use in adolescence could be damaging," says the study’s senior author Asaf Keller, Ph.D., Professor of Anatomy and Neurobiology at the University of Maryland School of Medicine. "Previous research has shown that children who started using marijuana before the age of 16 are at greater risk of permanent cognitive deficits, and have a significantly higher incidence of psychiatric disorders such as schizophrenia. There likely is a genetic susceptibility, and then you add marijuana during adolescence and it becomes the trigger."

"Adolescence is the critical period during which marijuana use can be damaging," says the study’s lead author, Sylvina Mullins Raver, a Ph.D. candidate in the Program in Neuroscience in the Department of Anatomy and Neurobiology at the University of Maryland School of Medicine. "We wanted to identify the biological underpinnings and determine whether there is a real, permanent health risk to marijuana use."

The scientists — including co-author Sarah Paige Haughwout, a research technician in Dr. Keller’s laboratory — began by examining cortical oscillations in mice. Cortical oscillations are patterns of the activity of neurons in the brain and are believed to underlie the brain’s various functions. These oscillations are very abnormal in schizophrenia and in other psychiatric disorders. The scientists exposed young mice to very low doses of the active ingredient in marijuana for 20 days, and then allowed them to return to their siblings and develop normally.

"In the adult mice exposed to marijuana ingredients in adolescence, we found that cortical oscillations were grossly altered, and they exhibited impaired cognitive abilities," says Ms. Raver. "We also found impaired cognitive behavioral performance in those mice. The striking finding is that, even though the mice were exposed to very low drug doses, and only for a brief period during adolescence, their brain abnormalities persisted into adulthood."

The scientists repeated the experiment, this time administering marijuana ingredients to adult mice that had never been exposed to the drug before. Their cortical oscillations and ability to perform cognitive behavioral tasks remained normal, indicating that it was only drug exposure during the critical period of adolescence that impaired cognition through this mechanism. The researchers took the next step in their studies, trying to pinpoint the mechanisms underlying these changes and the time period in which they occur.

"We looked at the different regions of the brain," says Dr. Keller. "The back of the brain develops first, and the frontal parts of the brain develop during adolescence. We found that the frontal cortex is much more affected by the drugs during adolescence. This is the area of the brain controls executive functions such as planning and impulse control. It is also the area most affected in schizophrenia."

Dr. Keller’s team believes that the results have indications for humans as well. They will continue to study the underlying mechanisms that cause these changes in cortical oscillations. “The purpose of studying these mechanisms is to see whether we can reverse these effects,” says Dr. Keller. “We are hoping we will learn more about schizophrenia and other psychiatric disorders, which are complicated conditions. These cognitive symptoms are not affected by medication, but they might be affected by controlling these cortical oscillations.”

Neuroscience Research Project Examines Neural Synchronization Patterns During Addiction

A cross-disciplinary collaboration of researchers in the School of Science at Indiana University-Purdue University Indianapolis (IUPUI) explores the neural synchrony between circuits in the brain and their behavior under simulated drug addiction. The two-year study could have broad implications for treating addiction and understanding brain function in conditions such as Parkinson’s disease.

Advanced mathematical models coupled with extensive laboratory testing revealed recurrent stimulant injections in rodents resulted in neural circuits that could easily synchronize but were more likely to become unstable. In other words, the introduction and restriction of drugs over time caused neurons to lose their ability to engage supervisory control over brain function and behavior. Researchers noticed these short periods of desynchronization were much more prevalent and caused changes in neurobiology and behavior.

“A better understanding of the dynamics of neural synchrony could have very important implications for understanding the addicted brain and may provide a physiological target to understand persistent neural changes that contribute to the probability of relapse,” said Christopher Lapish, Ph.D., assistant professor of psychology at IUPUI.

Lapish, with expertise in neurophysiology and addiction, and Leonid Rubchinsky, Ph.D., associate professor of mathematical sciences, collaborated on the project with support from the IUPUI Institute for Mathematical Modeling and Computational Science. Rubchinsky is an applied mathematician and neuroscientist who has extensively studied the neurophysiology of Parkinson’s disease.

Sungwoo Ahn, Ph.D., a post-doctoral fellow in mathematical sciences, also co-authored the study, recently published in the Cerebral Cortex scientific journal.

The research was patterned after the various stages of drug addiction: the first introduction of amphetamines, periods of abstinence that model withdrawal and then relapse.

The neural synchrony patterns of models injected with a stimulant were compared to those injected with a saline solution. Short periods of desychronization were prevalent in both groups, but the drug-affected group displayed a marked connection between synchrony and brain function. Synchrony has long been considered to play an important role in how the brain processes data, so any disruption of this pattern could hold significant research value, according to the published study.

“Through these long and progressive experimental examinations, we were able to explore the different areas of the brain and how they are connected to each other,” Rubchinsky said. “In addition to understanding, monitoring, diagnosing and treating addiction, this type of study is helpful in better understanding how the normal brain works.”

This collaboration moves scientists closer to understanding brain function and disruptions, Rubchinsky said, by incorporating mathematical models that recreate events and reactions in the brain over time. Lapish agreed, saying computational science ultimately will drive the growth and success of future neuroscience research.

“Neuroscience is an inherently data-rich science and, by combining experimentalists with theorists, there is a tremendous potential for discovery,” Lapish. “The interactive effects of this collaboration are certainly greater than the sum of its parts. We’re able to create a fully dynamic picture of this process that would not be possible without combining these two areas of expertise.”

Moving forward, the team will continue to seek funding to advance their research methods and better understand the role of synchrony in brain function. By doing so, scientists could map the progress and deterioration of neural circuits in various scenarios.

Changing gut bacteria through diet affects brain function

UCLA researchers now have the first evidence that bacteria ingested in food can affect brain function in humans. In an early proof-of-concept study of healthy women, they found that women who regularly consumed beneficial bacteria known as probiotics through yogurt showed altered brain function, both while in a resting state and in response to an emotion-recognition task.

The study, conducted by scientists with UCLA’s Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and the Ahmanson–Lovelace Brain Mapping Center at UCLA, appears in the current online edition of the peer-reviewed journal Gastroenterology.

The discovery that changing the bacterial environment, or microbiota, in the gut can affect the brain carries significant implications for future research that could point the way toward dietary or drug interventions to improve brain function, the researchers said.

"Many of us have a container of yogurt in our refrigerator that we may eat for enjoyment, for calcium or because we think it might help our health in other ways," said Dr. Kirsten Tillisch, an associate professor of medicine at UCLA’s David Geffen School of Medicine and lead author of the study. "Our findings indicate that some of the contents of yogurt may actually change the way our brain responds to the environment. When we consider the implications of this work, the old sayings ‘you are what you eat’ and ‘gut feelings’ take on new meaning."

Researchers have known that the brain sends signals to the gut, which is why stress and other emotions can contribute to gastrointestinal symptoms. This study shows what has been suspected but until now had been proved only in animal studies: that signals travel the opposite way as well.

"Time and time again, we hear from patients that they never felt depressed or anxious until they started experiencing problems with their gut," Tillisch said. "Our study shows that the gut–brain connection is a two-way street."

The small study involved 36 women between the ages of 18 and 55. Researchers divided the women into three groups: one group ate a specific yogurt containing a mix of several probiotics — bacteria thought to have a positive effect on the intestines — twice a day for four weeks; another group consumed a dairy product that looked and tasted like the yogurt but contained no probiotics; and a third group ate no product at all.

Functional magnetic resonance imaging (fMRI) scans conducted both before and after the four-week study period looked at the women’s brains in a state of rest and in response to an emotion-recognition task in which they viewed a series of pictures of people with angry or frightened faces and matched them to other faces showing the same emotions. This task, designed to measure the engagement of affective and cognitive brain regions in response to a visual stimulus, was chosen because previous research in animals had linked changes in gut flora to changes in affective behaviors.

The researchers found that, compared with the women who didn’t consume the probiotic yogurt, those who did showed a decrease in activity in both the insula — which processes and integrates internal body sensations, like those form the gut — and the somatosensory cortex during the emotional reactivity task.

Further, in response to the task, these women had a decrease in the engagement of a widespread network in the brain that includes emotion-, cognition- and sensory-related areas. The women in the other two groups showed a stable or increased activity in this network.

During the resting brain scan, the women consuming probiotics showed greater connectivity between a key brainstem region known as the periaqueductal grey and cognition-associated areas of the prefrontal cortex. The women who ate no product at all, on the other hand, showed greater connectivity of the periaqueductal grey to emotion- and sensation-related regions, while the group consuming the non-probiotic dairy product showed results in between.

The researchers were surprised to find that the brain effects could be seen in many areas, including those involved in sensory processing and not merely those associated with emotion, Tillisch said.

The knowledge that signals are sent from the intestine to the brain and that they can be modulated by a dietary change is likely to lead to an expansion of research aimed at finding new strategies to prevent or treat digestive, mental and neurological disorders, said Dr. Emeran Mayer, a professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA and the study’s senior author.

"There are studies showing that what we eat can alter the composition and products of the gut flora — in particular, that people with high-vegetable, fiber-based diets have a different composition of their microbiota, or gut environment, than people who eat the more typical Western diet that is high in fat and carbohydrates," Mayer said. "Now we know that this has an effect not only on the metabolism but also affects brain function."

The UCLA researchers are seeking to pinpoint particular chemicals produced by gut bacteria that may be triggering the signals to the brain. They also plan to study whether people with gastrointestinal symptoms such as bloating, abdominal pain and altered bowel movements have improvements in their digestive symptoms which correlate with changes in brain response.

Meanwhile, Mayer notes that other researchers are studying the potential benefits of certain probiotics in yogurts on mood symptoms such as anxiety. He said that other nutritional strategies may also be found to be beneficial.

By demonstrating the brain effects of probiotics, the study also raises the question of whether repeated courses of antibiotics can affect the brain, as some have speculated. Antibiotics are used extensively in neonatal intensive care units and in childhood respiratory tract infections, and such suppression of the normal microbiota may have long-term consequences on brain development.

Finally, as the complexity of the gut flora and its effect on the brain is better understood, researchers may find ways to manipulate the intestinal contents to treat chronic pain conditions or other brain related diseases, including, potentially, Parkinson’s disease, Alzheimer’s disease and autism.

Answers will be easier to come by in the near future as the declining cost of profiling a person’s microbiota renders such tests more routine, Mayer said.

New methods to explore astrocyte effects on brain function

A study in The Journal of General Physiology [1, 2] presents new methods to evaluate how astrocytes contribute to brain function, paving the way for future exploration of these important brain cells at unprecedented levels of detail.

Astrocytes—the most abundant cell type in the human brain—play crucial roles in brain physiology, which may include modulating synaptic activity and regulating local blood flow. Existing research tools can be used to monitor calcium signals associated with interactions between astrocytes and neurons or blood vessels. Until now, however, astrocytic calcium signals have been investigated mainly in their somata (cell bodies) and large processes, rather than in distal fine processes close to neuronal synapses or the endfeet that surround blood vessels. Previous studies have also mainly investigated immature specimens rather than mature brain cells.

Now, a team of California researchers provides detailed methods to visualize calcium signals throughout entire astrocytes in hippocampal slices from adult mice. The team observed numerous spontaneous localized calcium signals throughout the entire astrocyte, including the branchlets and endfeet. Their results indicated that calcium signals in endfeet were independent of those in somata and occurred more frequently. In addition to the specific findings, their methods can be used in future studies to advance our understanding of the physiology of astrocytes and their interactions with neurons and the microvasculature of the brain.