How oxytocin regulates social reward

Why do we care about other people? Not just why do we care for them, but why do we care about – their existence? their presence? what they do and how they make us feel?

For a long time, the canonical explanation has been that the hormone oxytocin is a sort of ‘love hormone’ whereby release causes some sort of bonding between two individuals. This story comes to us from the gerbil-like prairie voles. Prairie voles, you see, are pair-bonders who hook up with one mate for life. They’re so attached to each other that once bonded, males will attack any new female that they see (so much for “love” hormone). Luckily for us scientists, there is another closely related vole that does not pair bond. This made it relatively easy to trace the difference: oxytocin receptors in the nucleus accumbens (NAcc).

The NAcc is an area of the brain that is directly involved in motivation and reward; we tend to think of it as the place where the brain keeps track of how rewarding something is. By acting as a sort of central coordination center for value, it can directly promote physical behaviors. Activating the correct neurons related to reward on the left side of the animal will cause the animal to physically turn to the left.

The bond that prairie voles form is linked to oxytocin receptors in NAcc that change neural activity (and I’m simplifying a bit by neglecting the role of the related hormone vasopressin). This change makes their social (pair-bonded) life more rewarding.

At least, that’s one view. But many animals have a social life that does not involve pair bonding, and often they do not have oxytocin receptors in their NAcc. If oxytocin in NAcc was required for strong social behaviors, if they don’t have the receptors how do they have social behaviors at all?

In what I consider the most exciting paper so far this year, Dölen et al investigate what is the neural circuit that makes social interactions rewarding. Mice are actually social creatures, living in small groups to share parental and defensive responsibilities. Dölen et al exploit this by using a variation on a classic conditioned place preference (CPP) experiment. Mice are placed in one identifiable room with other mice (social); they are then placed in another identifiable room on their own (isolated). When they are finally put in a box with two rooms, one that looks like their social condition and one that looks like the isolated one, they spend much more time in the room that reminded them of their social experience. We tend to think this means they prefer that room because it was somehow more rewarding (or less aversive).

This social conditioning requires oxytocin. Yet, when they delete the oxytocin receptors from cells in NAcc animals still become conditioned. It is only when oxytocin receptors in other areas that project into NAcc do they animals lose any social reinforcement. These receptors are in one specific area, the dorsal raphe nucleus, which is a major source of serotonin in the brain. Interestingly, serotonin is also linked to social behaviors and modification of reward circuitry.

What this suggests is that oxytocin affects reward through serotonin; blockade of certain serotonin receptors in NAcc also abolishes social conditioning. It is not surprising that oxytocin could regulate reward in multiple ways. Serotonin may represent distinct aspects of reward – on different timescales, for instance – than other cells that feed into NAcc. By modulating serotonin instead of NAcc itself, oxytocin can precisely fashion the rewarding effects of social behavior.

As a technical matter, they also propose the receptor that serotonin is acting through (5HT1B). I am under the impression that this is an autoreceptor in NAcc. In other words, it is on the serotonin-emitting cell in order to monitor how much has been released to sculpt the output. By using pharmacology to block the receptor, I worry a bit that they are not getting the receptor which oxytocin is acting through per se but just modifying serotonin release in a gross manner. I feel a little vindicated in this worry by the fact that some of their technical results do not appear to be wholly blocked by 5HT1B blockage.

Reference

Dölen G, Darvishzadeh A, Huang KW, & Malenka RC (2013). Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature, 501 (7466), 179-84 PMID: 24025838

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A mechanics of depression

There are many reactions that can be taken in response to the world going crazy on you, and depression is one of these.  Even though it is (rightly) seen as perhaps not the greatest illness to have, there is a case to be made that depression is an energetically-efficient response to overwhelming stress; it can be better to shrink back and conserve your energy than fight it.  Think about it like this: you probably know some people who are super laid back, who take things as they come and don’t seem to stress out.  And you also probably know some people who freak out at stress, work really hard, and just seem to be stressed out all the time.  These are two different strategies for dealing with stress and one seems more likely to lead into depression.  At the same time that same strategy seems like the person is fighting harder to get out of the stressful situation.  How does the brain do something like that?

It is thanks to tools from the lab of Karl Deisseroth that we are finally able to begin to really, mechanistically, understand what is going on in the brain.  And fortunately, Deisseroth is both a research scientist and a psychiatrist who is interested in helping people with mental diseases.  There are three (!) papers published in Nature over the last month with his name on them, and they shed a lot of light on the mechanisms that are at work.

No one is really sure what it is about the brain that causes depression, although we have some hints: antidepressant drugs tend to work by modifying the release of the neuromodulators serotonin and dopamine (and norepinephrin).  We also know that an area called the prefrontal cortex (PFC) is highly linked to all sorts of psychiatric disorders; the PFC is an area that receives inputs from all over the place and then sends outputs right back out.  He’s the boss, the one that hears everything people have to say and then directs other areas in order to coordinate the brain to accomplish internal goals.  You can imagine what might happen if you have a bad boss: your brain is out of sync, things don’t get coordinated properly and then BAM, schizophrenia and depression.

As you might imagine, these things are all interconnected in the brain: the PFC talks to the serotonin and dopamine areas, and the serotonin and dopamine areas talk to the PFC.  And these connections are particularly important.  Take the connection between the PFC and an area that releases serotonin, the dorsal raphe nucleus (DRN).  This connection is required to motivate an animal to avoid escapable stress.  A mouse that is in a position to escape from stress will clearly do so.  However, if you inactivate the PFC the mouse will not escape from stress and its release of serotonin will look the same as if it were in a stressful situation it can’t escape from.  If you disable the PFC in a stressful situation that it can’t escape from?  No change: the PFC seems to control motivated behavior from escapable situations only, and without it you can’t.

That’s exactly what one of the recent Deisseroth papers examined.  They were able to directly activate only the PFC neurons that send information to the DRN and by doing so they found a way to escape from a learned kind of helplessness.  Rats that are stuck in a cup of water will struggle for a while, attempting to escape.  After a while they learn that struggling isn’t getting them anywhere and they just kind of give up.  But if you activate the PFC connections to the DRN?  The rats launch back into the struggle again!  But this doesn’t happen if you just activate all the neurons of the PFC or all the neurons of the DRN: there is a specific pathway through both of these brain regions that motivates an escape from helplessness.

Release of dopamine can help motivate escape from a helpless condition as well, although it is released from a different part of the brain.  The ventral tegmental area (VTA) is one of the main release sites of dopamine in the brain and is the signal of ‘pleasure’ in the brain, although it is perhaps more accurate to say that it is the primary signal of motivation.  And if you stimulate the neurons in the VTA you get an increase in motivation to escape a depressing circumstance, just as you’d expect from that area.  And specifically, this is because of a release of dopamine from the VTA to another area of the brain, the nucleus accumbens (NAcc).  What is likely to be happening is that the VTA is sending a motivating signal to an action and learning center of the brain (the NAcc), and that center of the brain helps decide what to do next, and what to do next is to get the heck out of there.  Something exciting happens here: if you now go and record the neurons in the NAcc after additional dopamine is released from the VTA, they now respond to different things.  The whole way that an action is represented in the brain changes, and in a way that emphasizes escape.

But this ability to learn escape can have a negative side.  Take the example of another method of stressing out mice, chronic social defeat.  What you do here is force mice to get defeated in battle again and again.  Yes, this is actually a commonly studied behavior; these poor guys are basically given PTSD.  But it turns out that some mice are resilient to this stress, they can withstand it and not get depressed.  If you look at the neurons in the VTA, the susceptible animals show an increased amount of bursts of activity (technically: phasic firing) during stress while the resilient animals just hummed along with no change of activity in the VTA at all!  This natural increase in firing can be simulated in the resilient animals by artificially increasing VTA firing.  Then, when you test whether they have acquired PTSD?  Well, it turns out that they have.  This makes a certain kind of sense: dopamine reinforces behavior, so susceptible animals are seeing more dopamine and hence more reinforcing of defeat than are the resilient animals.  Again, though, different internal pathways have different effects in the brain: if you activate the neurons that send information to the ‘pleasure center’, the nucleus accumbens then you are more vulnerable to stress.  And if you inhibit the activity of neurons that send information to the PFC, then you also become more vulnerable to stress.

The same sets of neurons that can help you escape stress (the VTA to NAcc connection) are the ones that will cause you to be more depressed in the future.  This suggests that there might be a tradeoff in life: you can be stressed out but really motivated to escape stress, or you can put up with a whole bunch of stress and be laid back about it in the future.  But it seems like it might be hard to be both.  There are of course in-betweens: the PFC, the boss, has specific circuits dedicated to telling the VTA and the DRN what to do, and can tell them to do opposite things.  And of course, the more you try to escape stress and fail, the more you learn it is futile to escape stress, triggering a terrible feedback cycle.  But if you want to be learning, you better be trying.

References

Chaudhury, D., Walsh, J., Friedman, A., Juarez, B., Ku, S., Koo, J., Ferguson, D., Tsai, H., Pomeranz, L., Christoffel, D., Nectow, A., Ekstrand, M., Domingos, A., Mazei-Robison, M., Mouzon, E., Lobo, M., Neve, R., Friedman, J., Russo, S., Deisseroth, K., Nestler, E., & Han, M. (2012). Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons Nature, 493 (7433), 532-536 DOI: 10.1038/nature11713
Tye, K., Mirzabekov, J., Warden, M., Ferenczi, E., Tsai, H., Finkelstein, J., Kim, S., Adhikari, A., Thompson, K., Andalman, A., Gunaydin, L., Witten, I., & Deisseroth, K. (2012). Dopamine neurons modulate neural encoding and expression of depression-related behaviour Nature, 493 (7433), 537-541 DOI: 10.1038/nature11740
Warden, M., Selimbeyoglu, A., Mirzabekov, J., Lo, M., Thompson, K., Kim, S., Adhikari, A., Tye, K., Frank, L., & Deisseroth, K. (2012). A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge Nature DOI: 10.1038/nature11617
Amat, J., Baratta, M., Paul, E., Bland, S., Watkins, L., & Maier, S. (2005). Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus Nature Neuroscience, 8 (3), 365-371 DOI: 10.1038/nn1399

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How social status affects your brain

When you get into work in the morning, you might say hi to your coworkers and complain for awhile about your boss.  Then maybe you joke with the janitor, only to flee when you see your boss headed to your desk.  Each of these interactions – as is every interaction between individuals -is deeply embedded in the context of social status.  Social status isn’t just a construct of our world, but a state of our environment that causes profound changes in the way your brain functions.

One way social status affects the brain is through serotonin; it is well known in the scientific literature that changes in serotonin level seems to directly affect perceived social status.  Whether high social status depends on high or low serotonin depends on the species; dominant individuals of species who must fight to retain social status have high serotonin levels, whereas dominant individuals of more cooperative species such as bonobos have low serotonin levels.

Issa et al. looked at social status in crayfish.  Crayfish actually form long-lasting and complex dominance hierarchies where subordinate animals give way to dominants in contests over resources.  Issa et al. took socially isolated animals and let them interact for thirty minutes a day, even though dominance was usually established within the first fifteen minutes.  They then examined the response to these individuals to a surprise touch to the back leg.  Dominant individuals always immediately turned toward the tap, presumably because they were prepared to be aggressive toward some threat.  Submissive individuals, on the other hand, always showed one of two behaviors: they either pushed backwards and then lowered their posture, or they flexed their abdomen, dropped their posture, and then moved backward.  When they recorded from a (specific) neuron that releases serotonin, they found the same kind of stereotyped response from the dominant individuals’ neurons, and the same kind of symmetric response from the subordinates’.  The authors also have a nice model suggesting that the neural circuit itself might be reconfiguring itself by modifying thresholds for firing of excitatory and inhibitory neurons.  It’s a simple result that looks true, though in the field of circuit neuroscience, the easy answer is almost never the right one…

This means that the dominant and subordinate individuals not only have different levels of serotonin, but that their neural circuitry is fundamentally different.  The authors interpret this to mean that a change in status indicates a persistent change is enacted, perhaps by modifying the amount or type of receptors.  The fact that dominance is usually established within fifteen minutes leads one to think that perhaps there is some other underlying difference; however, isolated individuals that weren’t exposed to this dominant-subordinate training acted in roughly the same manner as dominant individuals, with similar neural responses.

For the crayfish, there is probably a trade-off: dominant individuals get more resources, but must also be prepared to fight, perhaps making them more likely to be consumed by predators.  The lessons for humans is probably more complex.  Serotonin is not just linked to social status, but also depression, so it would not be surprising if low social status can literally make us ill.

Reference

Issa, F., Drummond, J., Cattaert, D., & Edwards, D. (2012). Neural Circuit Reconfiguration by Social Status Journal of Neuroscience, 32 (16), 5638-5645 DOI: 10.1523/JNEUROSCI.5668-11.2012

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