Learning: positive and negative

Reward and punishment operate through two very different pathways in the human brain.  The general idea is that these two types of learning – positive and negative – operate through different unique types of dopamine receptors.  The D1 receptors (D1R) are generally ‘positive’ receptors, while the D2 receptors (D2R) are ‘negative’.  Specifically, D1Rs generally tend to increase the concentration of CamKII and D2Rs decrease it; this means that they are going to have opposite effects on downstream pathways such as receptor plasticity, intrinsic voltage channels, etc.

How are the D1 and D2 pathways distinct in terms of learning?  The hypothesis has been that in striatal projection neurons, D1R expressing medium spiny neurons (dMSNs) mediate reinforcement and D2R expressing indirect pathway neurons (iMSNs) mediate punishment.  Kravitz et al expressed channelrhodopsin selectively in dMSNs and iMSNs so they could use light to activate only one type of neuron at a time.  They figured that the striatum would be a good place to start looking for the effects of these neurons.  After all, it is a primary site of reinforcement and action selection (also, they probably tried a few other places and didn’t get great results…?).  These transgenic mice were then placed in a box with two triggers, one of which would stimulate the light and the other would do nothing.  So the mice are in this box, and able to turn on and off their neurons if they want to.  I wonder how that feels?

When the mice were able to activate their D1R (positively-reinforcing) neurons, they were much more likely to keep pressing the trigger.  The D2R (negatively-reinforcing) mice were more likely to press the other trigger.  But that’s not all!  By the third day, the effects of activating the D2R pathway had worn off – they no longer cared about the effect.  You can see this on the graph to the left, where 50% is chance.  The preference for the D1R pathway persisted, however.  Even on short time scales of 15 – 30 seconds, the mice kept their preference for stimulating D1R reward cells over D2R aversion cells.  In the figure to the right, this is seen with YFP being a control (it should have no effect); whereas activating the dMSN pathway over the first 30 seconds always is different than activating YFP, the iMSN pathway only shows a (statistical) different over the first 15 seconds.

The authors conclude by saying that that the dMSN pathway is sufficient for persistent reinforcement, while iMSNs are sufficient for transient punishment.  This is a nice finding; that the D1R pathway really is doing some positive reinforcement and that the D2R pathway is doing negative reinforcement, and one is more effective in the long-term than the other.  Remember this when raising your kids!

Kravitz AV, Tye LD, & Kreitzer AC (2012). Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nature neuroscience PMID: 22544310

What sleep deprivation and low social status have in common

When you wake up in the morning, you probably don’t always feel 100% on top of things.  Besides feeling drowsy, you make decisions more slowly than you do when you are wide awake.  Things are different!  But maybe that cup of coffee will help you out…

What’s going on in your brain?  It’s been known for a while that adenosine receptors are key to the whole caffeine-waking-you-up thing – caffeine binds one type of adenosine receptor – but there is something more going on.  Volkow et al. had previously implicated a dopamine receptor as somehow changing in sleepy subjects.  They measured receptor activity using a PET scan; this is a technique where a researcher injects a chemical into a subject that binds to specific receptors; when it is bound, it is detectable by the PET scanner.  This binding might increase or decrease depending on the number of receptors (up- or down- regulation) or because the receptors are bound by other things – such different levels of dopamine itself binding the receptors.

Volkow et al. cruelly sleep deprived subjects in order to understand how dopamine was changing by using PET.  What they found is that the longer you are awake, the less the dopamine receptors will bind.  But this could either mean there is more dopamine in the system or that there are fewer dopamine receptors available to be bound.  They also gave some of these subjects provigil, which acts on the dopamine reuptake transporters which carry the dopamine away; when blocked, the dopamine cannot be carried away very effectively and just hangs out, building up.  If the change in binding was due to increased dopamine, the effect of provigil should be different for sleep-deprived subjects than for well-rested patients.  Since this was not the case, Volkow et al. suggest that the number of receptors are themselves getting regulated (though I don’t understand why they don’t know that the dopamine transporters themselves can’t be being regulated instead?).

The receptors that they identified as being important are the D2-type dopamine receptors.  There are many different types of dopamine receptors in the brain, and what exactly each of them is doing is a bit of a mystery.  Broadly speaking, they can be divided into two classes: the D1-type and these D2-type receptors.  D1-type receptors tend to be exciting to the cells in some sense, while the D2-type receptors are somehow inhibitory.

It turns out that D2-type receptors are regulated in other ways; for instance, social status can affect your D2 receptor level.  Simply moving a monkey from living on its own to living in a group will change the receptor level depending on whether it is a high-status animal or a low-status one.  In humans, individuals with low social support show low levels of D2 receptor binding while individuals with high social status show high levels of receptor binding.  This is important for a variety of reasons; most importantly according to papers (ie, it gets the most funding from NIH), individuals with low social support (‘social status’) are most prone to cocaine addiction.  This is true in humans, monkeys, rats, everything.  Perhaps generalized stress results in low levels of D2 receptors?  At the least, we can now all use this as an excuse as to why we make poor decisions when we’re sleepiest.

Photo from.


Volkow, N., Tomasi, D., Wang, G., Telang, F., Fowler, J., Logan, J., Benveniste, H., Kim, R., Thanos, P., & Ferre, S. (2012). Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain Journal of Neuroscience, 32 (19), 6711-6717 DOI: 10.1523/JNEUROSCI.0045-12.2012

Morgan, D., Grant, K., Gage, H., Mach, R., Kaplan, J., Prioleau, O., Nader, S., Buchheimer, N., Ehrenkaufer, R., & Nader, M. (2002). Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration Nature Neuroscience, 5 (2), 169-174 DOI: 10.1038/nn798