One of the weird things about chronic pain is that it can sometimes be more “in your brain” than, say “in your back” or “in your elbow“. Take for example, a phenomenon known as phantom limb pain – where individuals who lose a limb, can still complain of feeling pain in that very missing limb. As described here, it is possible to “unlearn” this pain – which is a learning process involving changes in synaptic connectivity in the brain.
Where then, and how, might pain and learning related to chronic pain be happening “in your brain” rather than in your back or elbow. Well, a recent paper from Min Zhuo’s lab at the University of Toronto have reported some new insights into synaptic mechanisms of pain. In their recent paper [doi:10.1186/1744-8069-4-40], “Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex” they evaluate the role of presynaptic glutamamte release in a brain region known as the anterior cingulate cortex – a region whose activity is well-known to correlate with reports of pain.
One of the cool tricks they used to evaluate the role of pre- vs. post-synaptic actions of glutamate was to use mice that carry a G-protein coupled receptor from the sea slug (Aplysia) which can respond to octopamine (a chemical not normally found in mouse brains) to activate glutamate release pre-synaptically. When mice were administered octopamine in the cingulate cortex, became more sensitive to chronic pain. This identifies a very specific biochemical pathways and brain area for which pharmacologic and behavioral therapeutics might be designed for the treatment of chronic pain.
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The small neuropeptides oxytocin (OT) and arginine-vasopressin (AVP) are well known for their influence on promoting warm-and-fuzzy social behaviors in mammals. The G-protein coupled OTR and AVPR1a receptors are also the subject of much research in this area – particularly AVPR1a – since it shows differences in brain expression in polygamous vs. monogamous vole species, and also shows genetic associations with dysfunction in human social affiliation. In a recent foray into this line of research, Richard Ebstein and colleagues examine whether an individual’s willingness to give away a cache of money is related to genetic variation in the promoter of the AVPR1a. In their paper, “Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA“, the researchers asked 203 college students to play the “dictator game” where, simply, one person gets a sum of money and can choose to keep it or give some of it away to the other player. Thats it. Give some of it away if you like, or just walk away with all of it, no questions asked & no consequences (your identity and the identity of the other player are masked). Amazingly, individuals actually DO give some of the money away (15% gave none of it away, 35% gave half away and 7% gave all – yes, all of it – away) … and more amazing still … those with longer stretches of microsatellite repeats at the RS1 & RS3 promoter sites in the AVPR1a gene, gave away significantly more money than individuals with shorter version of the repeats.
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Posted in G-protein, GPR6, Striatum, tagged Addiction, B.F. Skinner, Basal Ganglia, Cognition, Dopamine, Genetics, inhibition, Neuron, Operant conditioning on November 24, 2007|
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I’m not sure what Skinner would have thought, but its clear that, nowadays, mechanisms of behavior can be understood in terms of dynamic changes in neural systems and, furthermore, that individual differences in these neural dynamics are heavily regulated by genetic variation. Consider the recent paper by Lobo et al., “Genetic control of instrumental conditioning by striatopallidal neuron–specific S1P receptor Gpr6” (DOI). The authors use molecular genetics to seek out and find key genetic regulators of a specific and fundamental form of learning – operant or instrumental conditioning, pioneered by B.F. Skinner – wherein an individual performs an act and, afterwards, receives (+ or -) reinforcing feedback. This type of learning is distinct from classical conditioning where, for example, Pavlov’s dogs heard a bell before dinner and eventually began to salivate at the sound of the bell. In classical conditioning, the cue comes before the target, whereas in operant conditioning, the feedback comes after the target. Interestingly, the brain uses very different neural systems to process these different temporal contingencies and Lobo and company dive straight into the specific neural circuits – striatopallidal medium spiny neurons – to identify genes that are differentially expressed in these cells as compared to other neurons and, in particular, striatonigral medium spiny neurons. The GPR6 gene was found to be the 6th most differentially expressed gene in these cells and resultant knockout mice, when placed in an operant chamber, were much faster than control animals in learning the bar press association with a sugar pellet reward. The expression of GPR6 in striatopallidal cells predicts that they should have a normal function in inhibiting or slowing down such associations, so it makes sense that the GPR6 knockout animals are faster to learn these associations. This is one of the first genes whose function seems specifcially linked to a core cognitive process – Skinner might have been impressed after reading the paper.
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