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Posts Tagged ‘oxytocin’

Social skill in a pill?

June 9, 2011 19 comments

As we learn more about the unique behaviors of different animal species and how circuits in the brain control those behaviors, we will come upon more options for treating brain-based disorders.  In the case of autism spectrum disorders, a surprising potential treatment for social challenges emerged from the little-known prairie vole. The new research was published in April online in Biological Psychiatry and supported by Autism Speaks.

Prairie voles may resemble pet store hamsters, but their ordinary appearance obscures unique behavior.  These voles are among the 5% of all mammals that are monogamous—that is they form a mating pair that remains for the life of the animal.  Contrast this seemingly virtuous performance with a similar species—the meadow vole—that engages a much more promiscuous mating strategy.  For each animal, the chosen mating strategy makes sense in terms of available mating partners and other environmental pressures. However, these mating strategies also produce consequences in terms of the animal’s “social skills” and the neural circuits which serve these behaviors.

Prairie vole females, who mate for life, are relatively picky.  So, when introduced to a new male, not surprisingly, female prairie voles tend to a be careful—wanting more than just a single visit before choosing her mate. This situation affords researchers an opportunity that Larry Young, Ph.D. at Emory University exploits in the partner preference task.

The partner preference task enabled researchers to dissect the social learning that occurs in voles soon after meeting.  A female prairie vole is paired with a male for up to 24 hours so they can meet, but not mate.  During this time, researchers can give the voles different drug compounds to manipulate this first date in various ways.  From the sensory cues, to the rewarding squirts of neurotransmitter, Dr. Young and his colleagues are learning the essential ingredients for effective social learning.

The first essential ingredient is oxytocin.  This well-studied hormone is involved in birth and lactation and has more recently been shown to enhance the much more subtle social perception of trust in humans. Oxytocin administration has also been shown to increase the amount of gaze to the eye region of a face in individuals with autism.

Pair bonding in the prairie vole requires oxytocin.  The brain regions that bind this hormone are closely associated with areas of the brain that signal reward and the “reward neurotransmitter”, dopamine.  In fact, if the brain binding sites for dopamine are blocked by a competing chemical, pair bonds between prairie voles do not form.  This result reveals that the reward system must actively participate for these strong social bonds to form.

Recall the very similar-looking but very differently behaving vole called the meadow vole.  What creates their very different patterns of social engagement in these two species?  Dr. Young and colleagues showed that the distribution of receptors for the hormone oxytocin was a primary difference between the two species of animals.  In fact, female meadow voles that were made to express oxytocin receptors in a prairie vole pattern began behaving just like prairie voles with regard to mating behavior.  The promiscuous voles became monogamous by changing the expression of receptors in the brain.

This background would seem to be an elaborate set up to discuss the drug that makes the difference, but the value that these animals bring to research can not be underestimated.   The overt differences in behavior led to the discovery of hidden differences in brain physiology, which can be manipulated using drugs to improve the lives of humans.

Using a compound called d-cycloserine (DCS) the research team was able to enhance the cognitive processes involved in developing a partner preference in prairie voles. The changes are likely due to two factors:  1) an enhancement of the sensory cues that accompany a social interaction, which are primarily smell-based for rodents.  2) a boost of the memory of the social interaction, so that the partner will be recognized and associated with a positive encounter when they next meet.  The dose of DCS matters as only a low dose—one that increases glutamate neurotransmission—elicits a bias for choosing the previously met partner over the stranger.  Higher doses of DCS have a different effect on the receptor causing an overall reduction in glutamate transmission and providing no bias in the partner preference task.

What is the relevance of this to autism?  Imagine if one were able to enhance the interest of social stimuli prior to a therapy session.  Could the sort of compounds Dr. Young and his colleagues are investigating be beneficial when used in addition to behavioral therapy for helping individuals on the spectrum focus develop healthy patterns of social engagement?  In an preliminary study published in 2004 by a different group of researchers, DCS decreased social withdrawal in individuals with ASD as measured by the Aberrant Behavior Checklist.  Dr. Young and colleagues continue their research with DCS and other compounds that improve the salience of social features of an environment.  We look forward to seeing more of these results translate into meaningful treatments for people as this research direction progresses.

Is oxytocin a safe treatment for autism?

December 7, 2010 1 comment

“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community.  We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.

The hormone oxytocin is believed to play a role in social bonding and affiliation.  Researchers using animal studies have shown that oxytocin released in the brain regulates social recognition, social memory, mother-infant and male-female bonding, and other aspects of attachment.  Because social impairments are one of its most consistent features of autism, a number of scientists have hypothesized that abnormal oxytocin function might play a role in autism spectrum disorders (ASD).

The data regarding whether individuals with ASD have changes in oxytocin signaling are somewhat mixed.  A few studies have found children with ASD have lower average levels of blood oxytocin in comparison to typically developing children matched for age. Several  genetic studies have found associations between autism and specific forms of the gene for the oxytocin receptor.  Recently, it was reported that post-mortem brain tissue from individuals with ASD showed lower levels of gene expression for the oxytocin receptor when compared to age/gender matched comparison individuals.

So far only a few studies have examined the effect of administering oxytocin in human beings.  The data suggest that administration of oxytocin, either nasally or intravenously, positively impacts human social behavior.  For instance, recent studies with typical individuals show that giving oxytocin can increase gaze to the eye region of human faces, increase memory for faces, and improve the ability of people to infer the mental states of others (known as Theory of Mind).  All of these are challenges that have been associated with autism.

Given the lack of pharmacologic treatments for social deficits and the possibility of dysregulated oxytocin signaling in autism, many have proposed oxytocin as a treatment for ASD.  These studies are just beginning.  The three reports published so far have suggested that a single dose of oxytocin can temporarily improve social cognition in adults and, in one study, teenagers, with ASD.  In a pilot placebo-controlled study, researchers found that twice daily oxytocin in adults with autism resulted in some improvements in social function and quality of life and reductions in certain types of repetitive behaviorsThe data are very preliminary and larger follow-up studies are now underway.

Together these first studies support a potential role of oxytocin in ASD and suggest oxytocin could have therapeutic benefits for the treatment of ASD symptoms in adults, especially in the area of social functioning.  It is important to note that there are currently no published safety or efficacy data for oxytocin in children.

Autism Speaks is funding research to better understanding the role of oxytocin in ASD.  More information on clinical trials for oxytocin as a treatment for ASD can be found at www.clinicaltrials.gov.

Many journeys to the same location – methods that 21st century scientists are using to identify genes that cause autism

April 15, 2010 11 comments

We have asked several scientists who gave presentations at the April 10-11 DAN! conference in Baltimore to share their research and perspectives from the meeting with you here on the blog.  The following piece is from Dr. Simon G. Gregory, Ph.D. Dr. Gregory is an Associate Professor in the Center for Human Genetics, Duke University Medical Center His primary area of research involves identifying the complex genetic factors that give rise to cardiovascular disease and multiple sclerosis, Dr. Gregory’s group is also applying high-resolution genomic arrays to the discovery of chromosomal abnormalities and identification of epigenetic factors associated with autism.

For decades scientists have relied on traditional genetic approaches to identify genes that contribute to the development of autism. These approaches have included collecting extended, multi-generation families that contain one or more individuals with autism. Once a sufficient number of these families have been collected, hundreds of DNA markers that can highlight differences between us all at a genetic level (a bit similar to DNA fingerprinting used in CSI) are used to identify a region of the genome is linked with the disorder in the families. More recently, higher resolution technologies that benefitted from the completion of the human genome project have been developed to allow us to look at hundreds of thousands of markers simultaneously. This approach differs from the family-based approach in that it uses thousands of unrelated cases and age/sex/ethnicity matched controls. Together, both approaches have been successful in identifying genes, or at least regions of our chromosomes, that play a role in the development of autism. However, we know that many more genes will likely contribute to autism spectrum disorders (ASDs) and that not all mechanisms that disrupt the normal function of a gene will be based on a single DNA mutation or a variant present in the general population.

My group at the Duke Center for Human Genetics recently embarked on a journey to identify autism genes using an approach that looks at chromosome content, and yet we reached an interesting finding using another technique that doesn’t rely on the sequence of our DNA. For many years it has been known that ASDs can be caused by loss (deletion) or gain (duplication) of chromosomes. These genomic rearrangements can be large or small and some have been shown to cluster in particular regions of the genome, for example on the long arm of chromosome 15 (15q11-13). Our journey began by assessing the genomic content of 119 unrelated autistic children from families that we had collected over a number of years. We used genomic microarrays (microscope slides with printed content spanning our genome) to identify novel or common regions of deletion or duplication within one autistic child from each family. Although we identified a handful of novel regions and confirmed dozens of rearrangements that have increasingly been shown to exist within the ‘normal’ population, we decided to focus on a single deletion in one individual. The deletion, which contained five genes, sparked our interest because one of the genes, the oxytocin receptor (OXTR), had been previously implicated in autism. Previous studies using the traditional genetic approaches (mentioned above) had shown that OXTR was genetically associated with autism, other studies had shown that levels of oxytocin (a neurotransmitter that the receptor binds to OXTR) is important for pro-social behavior and that a knock-out of the receptor in mice can affect this behavior, and very recent studies have tested the supplementation of oxytocin in adults with autism.

After identifying the deletion in the one affected child we screened his family to see if it was novel and causative of his autism, or if he inherited the deletion from his parents. Somewhat disappointingly, his mother also had the deletion, but interestingly she had self reported obsessive compulsive disorder (OCD) for which OXTR has also been implicated. Although we could have stopped the journey at this point, we decided try a different approach. Previous studies have shown that OXTR is controlled in the liver by a chemical group (methyl –CH3) that sits on top of the DNA but which doesn’t change its sequence (click here for more information on epigenetic changes as they relate to autism). The phenomena of DNA methylation is a normal mechanism by which our cells silence parts of the genome that they don’t want to be active (mainly repeat and retro-viral sequences) but they also use it as a switch to turn on or turn off genes for protein production. Significant in our journey was that the child with autism who had the OXTR deletion also had an affected brother. This is significant because when we assessed the methylation status of the whole family we noticed that the affected brother has very high levels of methylation in five different CG bases (among the A’s C’s G’s and T’s of our genome where the methyl group resides) in a 1,600 base pair window that had previously been identified as being methylated in the liver OXTR.

Differential methylation isn’t a novel finding as a possible cause of autism. Previous studies in Rett syndrome, which has ASD like symptoms, have shown that mutations in the methyl CpG binding protein 2 (MECP2) gene not only contributes to the development of Rett syndrome but that these mutations affect the normal functioning of the gene which regulates the expression of other genes by altering their DNA methylation state. Additionally, imprinting (the silencing of a maternal or paternal copy of a chromosome by DNA methylation) has also been established as the basis for the development of Angelman and Prader-Willi syndromes that, again, have ASD like symptoms. Our next step was to validate the observation that increased methylation of OXTR in the affected brother may be a causal mechanism of autism. We expanded our analysis to include evaluation of the methylation status of OXTR in the peripheral blood of 20 controls and 20 individuals with autism, and in a second dataset of the post-mortem samples of temporal cortex tissue (a center for language and learning) in eight controls and eight children with autism. In both datasets we were pleased to see that the individuals with autism had higher levels of methylation than the controls. We next measured the level of gene expression of OXTR because we would expect that increased DNA methylation would result in decreased gene expression – which it did in a very small number of samples that we could test.

So you’re asking yourself, how, if all these other studies had pointed to OXTR being implicated in autism, is this discovery significant? Well, we hope that we have found a unique autism-associated DNA methylation signature in a receptor for a neurotransmitter that is important in social cognition in autism. The next more exciting journey will be to substantiate what we have found in a larger number of samples and to establish if oxytocin treatment can help

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