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Archive for the ‘ADRA2A’ Category

lie_robot

Let’s be honest.  We are all great liars … to ourselves, and others.  The big blatant lies (I swear I never had sex with Monica Lewinsky) and the little well-meaning lies (No honey, that dress does not make your butt look big) and especially the lies that contain just enough truth as to seem believable on a global scale (Lowering taxes on the rich will spur economic growth) … are what make our lives, and daytime TV, so interesting.

Pity the poor human brain … for some people think that IT cannot tell a lie. Scientists in collaboration with law enforcement have been measuring the  P300 brain wave  as a sort of lie detector (here, here, here) more specifically  “an accurate, and countermeasure (CM)-resistant P300-based Guilty Knowledge Test.”

Interestingly, the properties of the P300 neural biomarker are highly heritable and associated with a variety of genetic polymorphisms – including rs521674 located in the noradrenergic receptor ADRA2A gene (functions in the alerting and stress response elicited when lying/trying not to lie).

I’m an AT heterozygote at rs521674 and proud of my pro-deceitful suppressed P300 … because sometimes all you have to cling to are the lies you tell yourself.

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[picapp src=”e/7/8/1/Children_Attend_Classes_9572.jpg?adImageId=4955179&imageId=1529412″ width=”380″ height=”253″ /]

This year, my 5 year-old son and I have passed many afternoons sitting on the living room rug learning to read.  While he ever so gradually learns to decode words, eg. “C-A-T”  sound by sound, letter by letter – I can’t help but marvel at the human brain and wonder what is going on inside.  In case you have forgotten, learning to read is hard – damn hard.  The act of linking sounds with letters and grouping letters into words and then words into meanings requires a lot of effort from the child  (and the parent to keep discomfort-averse child in one place). Recently, I asked him if he could spell words in pairs such as “MOB & MOD”, “CAD & CAB”, “REB & RED” etc., and, as he slowly sounded out each sound/letter, he informed me that “they are the same daddy“.  Hence, I realized that he was having trouble – not with the sound to letter correspondence, or the grouping of the letters, or the meaning, or handwriting – but rather – just hearing and discriminating the -B vs. -D sounds at the end of the word pairs.  Wow, OK, this was a much more basic aspect of literacy – just being able to hear the sounds clearly.  So this is the case, apparently, for many bright and enthusiastic children, who experience difficulty in learning to read.  Without the basic perceptual tools to hear “ba” as different from “da” or “pa” or “ta” – the typical schoolday is for naught.

With this in mind, the recent article, “Genetic determinants of target and novelty-related event-related potentials in the auditory oddball response” [doi:10.1016/j.neuroimage.2009.02.045] caught my eye.  The research team of Jingyu Liu and colleagues asked healthy volunteers just to listen to a soundtrack of meaningless beeps, tones, whistles etc.  The participants typically would hear a long stretch of the same sound eg. “beep, beep, beep, beep” with a rare oddball “boop” interspersed at irregular intervals.  The subjects were instructed to simply press a button each time they heard an oddball stimulus.  Easy, right?  Click here to listen to an example of an “auditory oddball paradigm” (though not one from the Liu et al., paper).  Did you hear the oddball?  What was your brain doing? and what genes might contribute to the development of this perceptual ability?

The researchers sought to answer this question by screening 41 volunteers at 384 single nucleotide polymorphisms (SNPs) in 222 genes selected for their metabolic function in the brain.  The team used electroencephalogram recordings of brain activity to measure differences in activity for “boop” vs. “beep” type stimuli – specifically, at certain times before and after stimulus onset – described by the so-called N1, N2b, P3a, P3b component peaks in the event-related potentials waveforms.  800px-Erp1Genotype data (coded as 1,0,-1 for aa, aA, AA) and EEG data were plugged into the team’s home-grown parallel independent components analysis (ICA) pipeline (generously provided freely here) and several positives were then evaluated for their relationships in biochemical signal transduction pathways (using the Ingenuity Pathway Analysis toolkit.  A very novel and sophisticated analytical method for certain!

The results showed that certain waveforms, localized to certain areas of the scalp were significantly associated with the perception of various oddball “boop”-like stimuli.  For example, the early and late P3 ERP components, located over the frontal midline and parieto-occipital areas, respectively, were associated with the perception of oddball stimuli.  Genetic analysis showed that several catecholaminergic SNPs such as rs1800545 and rs521674 (ADRA2A), rs6578993 and rs3842726 (TH) were associated with both the early and late P3 ERP component as well as other aspects of oddball detection.

Both of these genes are important in the synaptic function of noradrenergic and dopaminergic synapses. Tyrosine hydroxylase, in particular, is a rate-limiting enzyme in catecholamine synthesis.  Thus, the team has identified some very specific molecular processes that contribute to individual differences in perceptual ability.  In addition to the several other genes they identified, the team has provided a fantastic new method to begin to crack open the synaptic complexities of attention and learning.  See, I told you learning to read was hard!

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Clonidine
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A recent report by Katayama and colleagues [doi 10.1038/mp.2008.97] shows that the the gene slitrk1 – a known risk factor for the developmental disorders  Tourette’s syndrome and trichotillomania gives rise to increased levels of noradrenaline when the gene is inactivated in a developing mouse model.  In the U. S., the most frequently prescribed medications for these disorders are clonidine hydrochloride (Catapres®) and guanfacine (Tenex®), which inhibit the synaptic transmission from presynaptic nerve terminals that express the alpha 2-adrenergic receptor.  Thus, the mouse model (mice with the inactive slitrk1 gene were healthy but showed behavioral abnormalities that were normalized upon treatment with clonidine) seems to validate the current form of treatment since a reduction in noradrenergic release, might counteract the higher levels of noradrenaline associated with the risk-promoting slitrk1 mutation.

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Map showing principal routes in RwandaImage via Wikipedia

Dominique JF de Quervain and colleagues provide an elegant example of how genetic differences can relate to complex traits such as the ability to recall emotionally laden experiences. In their recent Nature Neuroscience paper, they looked at a deletion of 3 glutamic acid residues (301–303) in the third intracellular loop of the alpha-2-adrenergic receptor and its relation to emotional memory. Since emotion-laden experience (fight-or-flight) is often accompanied by surges in noradrenaline, it makes sense that adrenergic receptors might facilitate such memories. In this case, the deletion genetic variant encodes a slightly less effective receptor whose carriers show enhanced recall of positive and negatively charged images – a memory effect that is similarly achieved when the receptor is blocked using the antagonist yohimbine.

Such genetic findings can lend themselves quickly to practical applications. One first step to begin to understand how the ADRA2B genetic influence might be used to help alleviate the sometimes debilitating effects of persistent emotional memory was an examination of individuals who fled from the Rwandan civil war and were living in the Nakivale refugee camp in Uganda at the time of investigation. Individuals who carry the deletion genetic variant were more likely to re-experience symptoms of traumatic events although, this particular variant is present at relatively low frequencies (about 1 in 8 individuals are carriers).

Readers may wish to learn more about the Rawandan Civi War and explore channels for aid including Rawanda-Aid and Genocide Intervention.

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