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.”

Brain chemistry changes in children with autism offer clues to earlier detection and intervention

Between ages three and 10, children with autism spectrum disorder exhibit distinct brain chemical changes that differ from children with developmental delays and those with typical development, according to a new study led by University of Washington researchers.

The finding that early brain chemical alterations tend to normalize during the course of development in children with ASD gives new insight to efforts to improve early detection and intervention. The findings were reported July 31 in the Journal of the American Medical Assocation Psychiatry.

“In autism, we found a pattern of early chemical alterations at the cellular level that over time resolved – a pattern similar to what others have seen with people who have had a closed head injury and then got better,” said Stephen R. Dager, a UW professor of radiology and adjunct professor of bioengineering and associate director of UW’s Center on Human Development and Disability.

Neva Corrigan, a senior research fellow in radiology, was first author and Dager corresponding author of the study, titled “Atypical Developmental Patterns of Brain Chemistry in Children with Autism Spectrum Disorder.”

“The brain developmental abnormalities we observed in the children with autism are dynamic, not static. These early chemical alterations may hold clues as to specific processes at play in the disorder and, even more exciting, these changes may hold clues to reversing these processes,” Dager said.

In the study, scientists compared brain chemistry among three groups of children: those with a diagnosis of ASD, those with a diagnosis of developmental delay, and those considered typically developing. The researchers used magnetic resonance spectroscopic imaging, a type of MRI, to measure tissue-based chemicals in three age groups: 3-4 years, 6-7 years and 9-10 years.

One of the chemicals measured, N-acetylaspartate (NAA), is thought to play an important role in regulating synaptic connections and myelination. Its levels are decreased in people with conditions such as Alzheimer’s, traumatic brain injury or stroke. Other chemicals examined in the study – choline, creatine, glutamine/glutamate and myo-inositol – help characterize brain tissue integrity and bioenergetic status.

A notable finding concerned changes in gray matter NAA concentration: In scans of the 3- to 4-year-olds, NAA concentrations were low in both the ASD and developmentally delayed groups. By 9 to 10 years, NAA levels in the children with ASD had caught up to the levels of the typically developing group, while low levels of NAA persisted in the developmentally delayed group.

“A substantial number of kids with early, severe autism symptoms make tremendous improvements. We’re only measuring part of the iceberg, but this is a glimmer that we might be able to find a more specific period of vulnerability that we can measure and learn how to do something more proactively,” said Annette Estes, a co-author of the study and director of the UW Autism Center. She is an associate professor of speech and hearing sciences.

Study co-author Dennis Shaw, a UW professor of radiology and director of MRI at Seattle Children’s, observed that the findings “parallel some of the early brain structural differences we and others have found on MRI that also appear to normalize over time in children with autism. These chemical findings will help to better establish the timing and mechanisms underlying genetic abnormalities known to be involved in at least some cases of autism.”

Dager and UW colleagues are currently using more advanced MRI methods to study infants at risk for ASD because of an older sibling with autism.

“We’re looking prospectively at these children starting at 6 months to determine if we can detect very early alterations in brain cell signaling or related cellular disruption that may precede early, subtle clinical symptoms of ASD.”

Despite the encouraging finding, science has yet to pinpoint the when, what and why of autism’s inception, an event often likened to the flipping of a switch. Discovering the earliest period that a child’s brain starts to develop a profile of ASD is crucial because, as the study acknowledged, “even a relatively brief period of abnormal signaling between glial cells and neurons during early development would likely have a lasting effect” on how a child’s brain network develops.

This study also suggests that developmental delay and autism spectrum disorder are distinct disorders having different underlying brain mechanisms and treatment considerations, Dager said.

“Autism appears to have a different pathophysiology and different early biological course than idiopathic developmental disorder. There are differences in their underlying biological processes; this supports the notion that ASD is different from developmental delay and challenges the notion that the increasing prevalence of autism merely reflects a re-categorization of symptoms between autism and intellectual disabilities.”

Analysis of 26 networked autism genes suggests functional role in the cerebellum

A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.

The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied. 

The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.

Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.

Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation. 

Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.

Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe. 

The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.

“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.

Excessive cerebral spinal fluid and enlarged brain size in infancy are potential biomarkers for autism

Children who were later diagnosed with autism spectrum disorder had excessive cerebrospinal fluid and enlarged brains in infancy, a study by a multidisciplinary team of researchers with the UC Davis MIND Institute has found, raising the possibility that those brain anomalies may serve as potential biomarkers for the early identification of the neurodevelopmental disorder.

The study is the first to follow the brain-growth trajectories from infancy in children who later develop autism and the first to associate excessive cerebrospinal fluid during infancy with autism. “Early Brain Development and Elevated Extra-Axial Fluid in Infants who Develop Autism Spectrum Disorder,” is published online today in the neurology journal Brain, published by Oxford University Press.

"This is the first report of an infant brain anomaly associated with autism that is detectable by using conventional structural MRI,” said MIND Institute Director of Research David Amaral, who co-led the study.

"This study raises the potential of developing a very early method of detecting autism spectrum disorder. Early detection is critical, because early intervention can decrease the cognitive and behavioral impairments associated with autism and may result in more positive long-term outcomes for the child,” Amaral said.

The study was conducted in 55 infants between 6 and 36 months of age, 33 of whom had an older sibling with autism. Twenty-two infants were children with no family history of the condition.

The researchers reported that the brain anomaly was detected significantly more often in the high-risk infants who were later diagnosed with autism between 24 and 36 months. Prior research by Sally Ozonoff, the vice chair for research and professor in the Department of Psychiatry and Behavioral Sciences, who co-led the study, has shown that the risk of autism is nearly 20 times greater in siblings of children with autism than in the general population. The U. S. Centers for Disease Control and Prevention puts the overall incidence of autism at 1 in 88.

The excessive cerebrospinal fluid and enlarged brain volume were detected by periodically measuring the infants’ brain growth and development using magnetic resonance imaging (MRI), and by regularly assessing their cognitive, social, communication and motor development. Both the high- and low-risk infants underwent their first MRI scans at 6 to 9 months. The second MRI scans occurred when they were 12 to 15 months old. The third was conducted between 18 and 24 months. The MRIs were conducted while the infants were sleeping naturally, without the need for sedation or anesthesia.

At 6 months, the researchers began intensive behavioral assessments of the infants’ development. Their parents also periodically completed questionnaires about their babies’ behaviors. These tests were conducted until the infants were 24 to 36 months old, when each child was evaluated as having autism spectrum disorder, other developmental delays, or typical development.

In addition to the 10 children diagnosed with autism, 24 percent of the high-risk and 13.5 percent of the low-risk infants were classified as having other developmental delays. Some 45.5 percent of high-risk and over 86 percent of low-risk babies were found to be developing normally.

The researchers found that by 6 to 9 months of age, the children who developed autism had elevated cerebrospinal fluid levels in the “extra-axial” space above and surrounding the brain, and that those fluid levels remained abnormally elevated between 18 to 24 months of age. The more fluid during early infancy, the more severe were the child’s autism symptoms when diagnosed, the study found.

In the infants who would go on to be diagnosed with autism, the ”extra-axial” fluid volume was, on average, 33 percent greater at 12 to 15 months and 22 percent greater at 18 to 24 months, when compared with typically developing infants. At 6 to 9 months, the extra-axial fluid volume was 20 percent greater, when compared with typically developing infants.
The study also provided the first MRI evidence of brain enlargement in autism prior to 24 months. The infants in the study diagnosed with autism had, on average, 7 percent larger brain volumes at 12 months, compared with the typically developing infants.

The excessive extra-axial fluid and enlarged brain volume were detected by brain imaging before behavioral signs of autism were evident. “The cause of the increased extra-axial fluid and enlarged brain size is currently unknown”, Amaral said.

Early diagnosis may be of particular benefit to infants whose older siblings have been diagnosed with autism, but the researchers caution that this finding must be replicated before it could aid in the early diagnosis of ASD. The MIND Institute is currently collaborating with other research institutions to replicate these findings and to evaluate how well the potential biomarker can accurately predict a later diagnosis of ASD.

“It is critical to understand how often this brain finding is present in children who do not develop autism, as well,” said Ozonoff. “For a biomarker to be useful in predicting autism outcomes, we want to be sure it does not produce an unacceptable level of false positives.”
“If this finding of elevated extra-axial fluid is replicated in a larger sample of infants who develop autism, and it accurately distinguishes between infants who do not develop autism, it has the potential of becoming a noninvasive biomarker that would aid in early detection, and ultimately improve the long-term outcomes of these children through early intervention,” said Mark Shen, UC Davis graduate student and the study’s lead author.

A Deep Brain Disorder

An SDSU research team has discovered that autism in children affects not only social abilities, but also a broad range of sensory and motor skills.

Researchers Provide the First Comprehensive and Prospective Characterization of a Genetic Subtype of Autism

In the first prospective study of its kind, Seaver Autism Center researchers at the Icahn School of Medicine at Mount Sinai provide new evidence of the severity of intellectual, motor, and speech impairments in a subtype of autism called Phelan-McDermid Syndrome (PMS). The data are published online in the June 11 issue of the journal Molecular Autism.

Mutation or deletion of a gene known as SHANK3 is one of the more common single-gene causes of autism spectrum disorders and is critical to the development of PMS, a  severe type of autism. To date, clinicians have relied on case studies and retrospective reviews of medical records to understand  the features of this disorder and how the clinical presentation relates to the extent of the genetic changes in the SHANK3 region. In the first systematic and comprehensive prospective trial, researchers led by Alex Kolevzon, MD, Clinical Director of the Seaver Autism Center, under the direction of Joseph Buxbaum, PhD, Director of the Seaver Autism Center, enrolled 32 participants with SHANK3 deletions to comprehensively assess their clinical symptoms and examine how the size of the SHANK3 deletion correlated to those symptoms.

“Previous studies have not utilized prospective assessments to understand Phelan-McDermid Syndrome, and the prevalence of autism spectrum disorder has never been examined using gold-standard instruments” said Dr. Kolevzon. “There is no established standard for assessing  this type of autism, and our study provides important guidance in developing such a standard.”

Of the 32 patients enrolled, 84 percent met criteria for an autism spectrum disorder. Seventy-seven percent of patients exhibited severe to profound intellectual disability, with 19 percent using some form of verbal communication. Other common features included low muscle tone, gait disturbance, and seizures. The researchers also found that patients who had larger SHANK3 deletions had more severe disease.

“Our findings provide additional evidence of the significant impairment associated with SHANK3 deficiency,” said Dr. Kolevzon. “Also, knowing how large the deletion of the  SHANK3 gene is may have important implications for medical monitoring and individualizing treatment plans. Results  also provide much-needed guidance in developing a standardized methodology for evaluating the features of this disorder.”

Many of the patients who participated in this study were next enrolled in a clinical trial at Mount Sinai evaluating Insulin-Like Growth Factor-1 (IGF-1), a  commercially available compound for growth deficiency that is known to promote nerve cell survival as well as synaptic maturation and plasticity.  The primary aim of the study is to target core features of PMS, including social withdrawal and language impairment, which will be measured using both behavioral and objective assessments. The clinical studies with IGF-1 were supported by studies in a genetically modified mouse with a mutation in SHANK3. These studies, carried out by Dr. Ozlem Bozdagi of the Seaver Autism Center, carefully examined brain function in the mice when SHANK3 was mutated, and provided preclinical evidence for a beneficial effect of IGF-1. These studies were reported the April 27th issue of Molecular Autism (1, 2).

“The Seaver Autism Center has the unique capacity to evaluate autism spectrum disorders on both the molecular level and the clinical level,” said Dr. Buxbaum. “This capability puts us in a unique position to see the entire picture—the connection between genetics and behavior in these disorders—and to develop new treatments and better tailor existing ones for these children.”