Archive for the ‘DAT’ Category

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** PODCAST accompanies this post**

I have a little boy who loves to run and jump and scream and shout – a lot.  And by this, I mean running – at full speed and smashing his head into my gut,  jumping – off the couch onto my head,  screaming – spontaneous curses and R-rated body parts and bodily functions.  I hope you get the idea.  Is this normal? or (as I oft imagine) will I soon be sitting across the desk from a school psychologist pitching me the merits of an ADHD diagnosis and medication?

Of course, when it comes to behavior, there is not a distinct line one can cross from normal to abnormal.  Human behavior is complex, multi-dimensional and greatly interpreted through the lens of culture.  Our present culture is highly saturated by mass-marketing, making it easy to distort a person’s sense of “what’s normal” and create demand for consumer products that folks don’t really need (eg. psychiatric diagnoses? medications?).   Anyhow, its tough to know what’s normal.  This is an important issue to consider for those (mass-marketing hucksters?) who might be inclined to promote genetic data as “hard evidence” for illness, disorder or abnormality of some sort.

With this in mind, I really enjoyed a recent paper by Stollstorff et al., “Neural response to working memory load varies by dopamine transporter genotype in children” [doi:10.1016/j.neuroimage.2009.12.104] who asked how the brains of healthy children functioned, even though they carry a genotype that has been widely associated with the risk of ADHD.  Healthy children who carry genetic risk for ADHD. Hmm, might this be my boy?

The researchers looked at a 9- vs. 10-repeat VNTR polymorphism in the 3′-UTR of the dopamine transporter gene (DAT1).  This gene – which encodes the very protein that is targeted by so many ADHD medications – influences the re-uptake of dopamine from the synaptic cleft.  In the case of 10/10 genotypes, it seems that DAT1 is more highly expressed, thus leading to more re-uptake and hence less dopamine in the synaptic cleft.  Generally, dopamine is needed to enhance the signal/noise of neurotransmission, so – at the end of the day – the 10/10 genotype is considered less optimal than the 9/9-repeat genotype.  As noted by the researchers, the ADHD literature shows that the 10-repeat allele, not the 9-repeat, is most often associated with ADHD.

The research team asked these healthy children (typically developing children between 7 and 12 years of age) to perform a so-called N-back task which requires that children remember words that are presented to them one-at-a-time.  Each time a new word is presented, the children had to decide whether that word was the same as the previous word (1-back) or the previous, previous word (2-back).  Its a maddening task and places an extreme demand on neural circuits involved in active maintenance of information (frontal cortex) as well as inhibition of irrelevant information that occurs during updating (basal ganglia circuits).

As the DAT1 protein is widely expressed in the basal ganglia, the research team asked where in the brain was variation in the DAT1 (9- vs. 10-repeat) associated with neural activity?  and where was there a further difference between 1-back and 2-back?  Indeed, the team finds that brain activity in many regions of the basal ganglia (caudate, putamen, substantia nigra & subthalamic nucleus) were associated with genetic variation in DAT1.  Neat!  the gene may be exerting an influence on brain function (and behavior) in healthy children, even though they do not carry a diagnosis.  Certainly, genes are not destiny, even though they do influence brain and behavior.

What was cooler to me though, is the way the investigators examined the role of genetic variation in the 1-back (easy or low load condition) vs. 2-back (harder, high-load condition) tasks.  Their data shows that there was less of an effect of genotype on brain activation in the easy tasks.  Rather, only when the task was hard, did it become clear that the basal ganglia in the 10/10 carriers was lacking the necessary brain activation needed to perform the more difficult task.  Thus, the investigators reveal that the genetic risk may not be immediately apparent under conditions where heavy “loads” or demands are not placed on the brain.  Cognitive load matters when interpreting genetic data!

This result made me think that genes in the brain might be a lot like genes in muscles.  Individual differences in muscle strength are not associated with genotype when kids are lifting feathers.  Only when kids are actually training and using their muscles, might one start to see that some genetically advantaged kids have muscles that strengthen faster than others.  Does this mean there is a “weak muscle gene” – yes, perhaps.  But with the proper training regimen, children carrying such a “weak muscle gene” would be able to gain plenty of strength.

I guess its off to the mental and physical gyms for me and my son.

** PODCAST accompanies this post** also, here’s a link to the Vaidya lab!

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Mother and Child
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The roles of nature and nurture in child development have never been easy to disentangle.  Parents, in particular, seem to know this all too well, when it comes to their own children.  For example, when one of my children throws a tantrum, my wife can be mercilessly quick to point out that “those are your genes at work “.  I for one, can’t help but admire Mother Nature’s sense of justice (or is it humor?) as I’m forced to grapple with an unreconcilable 5-year old.  What can I do?  How can I get some type of optimal gene-by-environment (parenting style) going here?  Afterall, they are MY genes (expressed in said unreconcilable 5-year old) right?  Can I break out of the infinitely recurrent loop of me (my genes) trying to positively interact with my child (also my genes).  What’s a stubborn parent of a stubborn child to do?

In thinking about this, it was great to read a recent article by Lee and colleagues entitled, “Association of maternal dopamine transporter genotype with negative parenting: evidence for gene x environment interaction with child disruptive behavior” [doi: 10.1038/mp.2008.102].  In this article, the team examined how children (4 to 7 years old)  interacted with their mothers during a session where they were induced to cooperate in tasks involving free play with specific toys, tasks involving organizing items in a room and several pencil and paper tasks.  A set of observations were made (through 1-way glass) on aspects of parenting (negative feedback or contact, positive feedback and encouragement, and, total number of maternal commands).

In principle, the complexities of whose genes & behavior is influencing whose in such a situation are vast.  The authors point out that such interactions can be divided into passive GxE wherein children with certain genes (lets say genes for stubborness) may have inherited those genes from parents who exhibit a stubborn (negative) parenting style – hence leading to correlations in child genotype and parenting style.  Alternatively, such correlations can occur when a child (perhaps a stubborn child) evokes negative parenting response from a parent who did not (as my wife claims) transmit said stubborness genes – an example of an evocative GxE interaction.  In this study, the team examined the mother’s genotype at a 40-bp repeat polymorphism in the 3’UTR of the dopamine transporter (DAT) gene.  This is an apt candidate gene, since animal models of DAT loss-of-function show disrupted maternal behavior.

As an initial step, the team evaluated whether maternal genotype was correlated with maternal parenting style.  They found that the 10-repeat allele of the DAT gene was associated with more of a negative style of parenting.  However, the association of the 10-repeat allele of DAT was rather stronger in mothers whose children were categorized as disruptive than among mothers whose children were categorized as compliant – an example of an interaction of the mother’s genotype with her child’s disruptive behavior (which itself may be due to genes inherited by her – and so on – and so on).

Hard to pin down the genetic blame somewhere here.  Maddening actually.  Maddening enough to make dealing with my unreconcilable 5-year old seem a simple and welcoming task.

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