What emotional memories are made of

Mouse experiments reveal ‘flight or fight’ hormone’s role

Contact: Nick Zagorski
nzagors1@jhmi.edu
443-287-2251
Johns Hopkins Medical Institutions

Both extensive psychological research and personal experiences confirm that events that happen during heightened states of emotion such as fear, anger and joy are far more memorable than less dramatic occurrences. In a report this week in Cell, Johns Hopkins researchers and their collaborators at Cold Spring Harbor and New York University have identified the likely biological basis for this: a hormone released during emotional arousal “primes” nerve cells to remember events by increasing their chemical sensitivity at sites where nerves rewire to form new memory circuits.

Describing the brain as a big circuit board in which each new experience creates a new circuit, Hopkins neuroscience professor Richard Huganir, Ph.D. says that he and his team found that during emotional peaks, the hormone norepinephrine dramatically sensitizes synapses – the site where nerve cells make an electro-chemical connection – to enhance the sculpting of a memory into the big board.

Image showing phosphorylated GluR1 receptors congregating around sites of neuronal synapses.

Norepinephrine, more widely known as a “fight or flight” hormone, energizes the process by adding phosphate molecules to a nerve cell receptor called GluR1. The phosphates help guide the receptors to insert themselves adjacent to a synapse. “Now when the brain needs to form a memory, the nerves have plenty of available receptors to quickly adjust the strength of the connection and lock that memory into place,” Huganir says.

Huganir and his team suspected that GluR1might be a target of norepinephrine since disruptions in this receptor cause spatial memory defects in mice. They tested the idea by either injecting healthy mice with adrenaline or exposing them to fox urine, both of which increase norepinephrine levels in brain. Analyzing brain slices of the mice, the researchers saw increased phosphates on the GluR1 receptors and an increased ability of these receptors to be recruited to synapses.

When the researchers put mice in a cage, gave a mild shock, took them out of that cage and put them back in it the next day, mice who had received adrenaline or fox urine tended to “freeze” in fear – an indicator they associated the cage as the site of a shock – more frequently, suggestive of enhanced memory.

However, in a similar experiment with mice genetically engineered to have a defective GluR1 receptor that phosphates cannot attach to, adrenaline injections had no effect on mouse memory, further evidence of the “priming” effect of the receptor in response to norepinephrine.

The researchers plan on continuing their work by going in the opposite direction and engineering another mouse strain that has a permanently phosphorylated or “primed” receptor. “We’re curious to see how these mice will behave,” Huganir says. “We suspect that they’ll be pretty smart, but at the same time constantly anxious.”

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The research was funded by the National Institutes of Health, Damon Runyon Postdoctoral Fellowship, NARSAD, and the Ale Davis and Maxine Harrison Foundation

Authors on the paper are Hailan Hu, Eleonore Real, and Roberto Malinow of Cold Spring Harbor Laboratory; Joe LeDoux of New York University; and Kogo Takamiya, Myoung-Goo Kang, and Huganir of Johns Hopkins

On the Web:
http://neuroscience.jhu.edu/RichardHuganir.php
http://www.cell.com

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A pioneering study opens roads for tailor-made antidepressants

In spite that the causes of depression have not still been fully identified, scientists acknowledge that genetic and environmental factors play a common role in the onset of this disorder. One of the environmental risk factors more often related to depression is exposure to threatening life events. On the other side, from a genetic point of view, the serotonin transporter gene, with a crucial role in communication between neurons, could predispose to depression.

An international group of scientists, headed by professors Jorge Cervilla Ballesteros and Blanca Gutiérrez Martínez, from the department of Legal Medicine, Toxicology and Psychiatry of the University of Granada, has recently published in the prestigious journal Molecular Psychiatry the pioneering study PREDICT-gene, confirming the relation between allele s in the serotonin transporter gene and exposure to threatening life events in the onset of depression. The study proves, for a population sample accounting for gender, age and family history of psychiatric disorders, that 24% of the Spanish population, comprising people with the s/s genotype, need minimal exposure to threatening life events, unlike individuals with s/l or l/l genotypes, thus confirming the relation between genetic and environmental factors in this mental disorder.

Tailor-made antidepressants

The most important consequence of research on interaction between genetic and environmental factors is that, in a foreseeable future, scientists will be able to produce measures to predict response to antidepressants taking into account each individual’s genotype, i. e. they will be able to design tailor-made drugs according to each person’s genetic configuration and their exposure to environmental factors.

The research group headed by professor Cervilla Ballesteros and Gutiérrez Martínez is currently working at the University of Granada to open roads for psycho-pharmaco-genetics, a field that will allow for individual treatments, tailor-made drugs, for each patient with depression, a disorder affecting one in every five Spaniards visiting the doctor’s.

This study is framed in the international project PREDICT and is funded by the European Union and the Spanish Ministry of Education and Science. One of its most important novelties is that it has been carried out through a very representative sample: a total of 737 people agreed to participate in the genetic tests, with ages ranging from 18 to 75, patients of nine primary care centres in the South of Spain. That is why this is the first representative population-based replication of earlier research, as until now research had been done into restricted population samples, comprising only women, adolescents, twins or people with affective disorders.

Contact: Professor Jorge Cervilla Ballesteros
jacb@ugr.es
34-663-075-835
Universidad de Granada

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New study shows half of children with autism can be accurately diagnosed at close to 1 year of age

Contact: Emily Butler
ebutler@spectrumscience.com
202-955-6222
Kennedy Krieger Institute

Researchers at the Kennedy Krieger Institute recognize children with autism earlier than ever before, paving the way for earlier intervention and improved outcomes
(Baltimore, MD) — In a study published today in the Archives of General Psychiatry, researchers from the Kennedy Krieger Institute in Baltimore, Maryland found that autism can be diagnosed at close to one year of age, which is the earliest the disorder has ever been diagnosed. The study, which evaluated social and communication development in autism spectrum disorders (ASD) from 14 to 36 months of age, revealed that approximately half of all children with autism can be diagnosed around the first birthday. The remaining half will be diagnosed later, and their development may unfold very differently than children whose ASD is diagnosable around the first birthday. Early diagnosis of the disorder allows for early intervention, which can make a major difference in helping children with autism reach their full potential.

Researchers examined social and communication development in infants at high and low risk for ASD starting at 14 months of age and ending at 30 or 36 months (a small minority of the children exited the study at 30 months). Half of the children with a final diagnosis of ASD made at 30 or 36 months of age had been diagnosed with the disorder at 14 months, and the other half were diagnosed after 14 months. Through repeated observation and the use of standardized tests of development, researchers identified, for the first time, disruptions in social, communication and play development that were indicative of ASD in 14-month olds. Multiple signs indicating these developmental disruptions appear simultaneously in children with the disorder.

Dr. Rebecca Landa, lead study author and director of Kennedy Krieger’s Center for Autism and Related Disorders, and her colleagues identified the following signs of developmental disruptions for which parents and pediatricians should be watching:

Abnormalities in initiating communication with others: Rather than requesting help to open a jar of bubbles through gestures and vocalizations paired with eye contact, a child with ASD may struggle to open it themselves or fuss, often without looking at the nearby person.

Compromised ability to initiate and respond to opportunities to share experiences with others: Children with ASD infrequently monitor other people’s focus of attention. Therefore, a child with ASD will miss cues that are important for shared engagement with others, and miss opportunities for learning as well as for initiating communication about a shared topic of interest. For example, if a parent looks at a stuffed animal across the room, the child with ASD often does not follow the gaze and also look at the stuffed animal. Nor does this child often initiate communication with others. In contrast, children with typical development would observe the parent’s shift in gaze, look at the same object, and share in an exchange with the parent about the object of mutual focus. During engagement, children have many prolonged opportunities to learn new words and new ways to play with toys while having an emotionally satisfying experience with their parent.

Irregularities when playing with toys: Instead of using a toy as it is meant to be used, such as picking up a toy fork and pretending to eat with it, children with ASD may repeatedly pick the fork up and drop it down, tap it on the table, or perform another unusual act with the toy.

Significantly reduced variety of sounds, words and gestures used to communicate: Compared to typically developing children, children with ASD have a much smaller inventory of sounds, words and gestures that they use to communicate with others.

“For a toddler with autism, only a limited set of circumstances – like when they see a favorite toy, or when they are tossed in the air – will lead to fleeting social engagement,” said Landa. “The fact that we can identify this at such a young age is extremely exciting, because it gives us an opportunity to diagnose children with ASD very early on when intervention may have a great impact on development.”

The current study reveals that autism often involves a progression, with the disorder claiming or presenting itself between 14 and 24 months of age. Some children with only mild delays at 14 months of age could go on to be diagnosed with ASD. Landa and her colleagues observed distinct differences in the developmental paths, or trajectories, of children with early versus later diagnosis of ASD. While some children developed very slowly and displayed social and communication abnormalities associated with ASD at 14 months of age, others showed only mild delays with a gradual onset of autism symptoms, culminating in the diagnosis of ASD by 36 months.

If parents suspect something is wrong with their child’s development, or that their child is losing skills during their first few years of life, they should talk to their pediatrician or another developmental expert. This and other autism studies suggest that the “wait and see” method, which is often recommended to concerned parents, could lead to missed opportunities for early intervention during this time period.

“What’s most exciting about these important advancements in autism diagnosis is that ongoing intervention research leads us to believe it is most effective and least costly when provided to younger children,” said Dr. Gary Goldstein, President and CEO of the Kennedy Krieger Institute. “When a child goes undiagnosed until five or six years old, there is a tremendous loss of potential for intervention that can make a marked difference in that child’s outcome.”

While there are currently no standardized, published criteria for diagnosing children with autism at or around one year of age, Landa’s goal is to develop these criteria based on this and other autism studies currently underway at the Kennedy Krieger Institute. Landa and her colleagues at the Institute plan on releasing preliminary diagnostic criteria for very young children with autism in an upcoming report.

Participants in the current study included infants at high risk for ASD (siblings of children with autism, n=107) and low risk for ASD (no family history of autism, n=18). Standardized tests of development and play-based assessment tools were used to evaluate social interaction, communication and play behaviors in both groups at 14, 18 and 24 months of age. Researchers assigned diagnostic impressions at every age, indicating whether there were clinically significant signs of delay or impairment. After their last evaluation at 30 or 36 months, each participant was then given a final diagnostic classification of ASD, non-ASD impairment, or no impairment. The ASD group was further divided into an Early ASD diagnosis group and a Later ASD diagnosis group based on whether they were given a diagnosis of ASD at 14 or 24 months.

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About Autism

Autism spectrum disorders (ASD) is the nation’s fastest growing developmental disorder, with current incidence rates estimated at 1 in 150 children. This year more children will be diagnosed with autism than AIDS, diabetes and cancer combined, yet profound gaps remain in our understanding of both the causes and cures of the disorder. Continued research and education about developmental disruptions in individuals with ASD is crucial, as early detection and intervention can lead to improved outcomes in individuals with ASD.

About the Kennedy Krieger Institute

Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain and spinal cord, the Kennedy Krieger Institute in Baltimore, MD serves more than 13,000 individuals each year through inpatient and outpatient clinics, home and community services and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental concerns mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop while pioneering new interventions and earlier diagnosis. For more information on Kennedy Krieger Institute, visit http://www.kennedykrieger.org.

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