Monday question: Do neuromodulators have a unifying role?

We would never say that glutamate or GABA, the “basic” neurotransmitters, have a particular function. So why do attempt to give modulators like dopamine or oxytocin a defined role? Dopamine, for instance, is not only spread across the brain, but is also in the retina!

Or take oxytocin, “the love molecule”. It is not only involved in social behaviors but also cross-modal plasticity and modulating hippocampal fast spiking interneurons.

Do either dopamine or oxytocin – or any other neuromodulator for that matter – have a unifying function? Or did the brain evolve multiple independent uses for the modulators?

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

Oxytocin, the complicated hormone

Over at the Notes&Theories blog, there is a good post about the complicated role of oxytocin.  Oxytocin is commonly called the ‘love hormone’, a striking simplification that should immediately set off your Overly Anthropomorphized radar.  Meadow voles are the promiscuous cousins of the monogamous prairie voles:

But oxytocin and vasopressin are released in brains of all mammals, not just those that are monogamous. The differences between species have nothing to do with how much oxytocin or vasopressin is released, but rather they depend on exactly where these hormones act. Vasopressin and oxytocin act only at specific receptors – and in the brain, these receptors are only made in certain places…Then they modified a harmless virus in such a way that it carried the code for making prairie vole vasopressin receptors, and injected it into a small part of the brains of male meadow voles. This part of the brain now began to make vasopressin receptors where none had been before – and the meadow voles began to behave like prairie voles, forming strong attachments to their current sexual partners.

Like so many things in the nervous system, oxytocin and vasopressin have a multitude of possibly contradictory roles that are determined by when they are released, where their receptors are expressed, and what else is released at the same time.  A burst of dopamine+oxytocin and a burst of oxytocin+testosterone will surely have different meanings in the brain!  And with highly plastic gene expression, what they mean will vary between individuals.

The basic unit of human relationship is the pair

Posting has been light (ie, nonexistent) because I’ve been preparing for/been at a conference.  While I was gone, I read the book Escape From Camp 14, about someone who not only was born and raised in a North Korean political prison, but also managed to escape from it.  Not only was the story interesting, but there was a lot of good stuff in it relating to how the human brain interacts with the environment.  Take this:

“It was in the pairs that the prisoners kept alive the semblance of humanity,” concluded Elmer Luchterhand, a sociologist at Yale who interviewed fifty-two concentration camp survivors shortly after liberation.

Pairs stole food and clothing for each other, exchanged small gifts, and planned for the future.  If one member of a pair fainted from hunger in front of an SS officer, the other would prop him up.

“Survival … could only be a social achievement, not an individual accident,” wrote Eugene Weinstock, a Belgian resistance fighter and Hungarian-born Jew who was sent to Buchenwald in 1943.

The death of one pair often doomed the other.  Women who knew Anne Frank in the Bergen-Belsen camp said that neither hunger nor typhus killed the young girl who would become the most famous diarist of the Nazi era.  Rather, they said, she lost the will to live after the death of her sister, Margot.

There was a bit more to the quote, but the book has already been returned to the library and I only have Google Books to quote from.  The point here is that the pair-bond seems to be the basic unit of human relationship.  This shouldn’t be too surprising; humans are generally monogamous on the order of a few years at a time.  But this pair-bonding isn’t solely romantic, but also extends to friendships.  What we know about pair-bonding comes primarily from work on prairie voles who are a uniquely monogamous species of vole.  This monogamy (or should I say, “monogamy”) connect to the neurohormone oxytocin.  Oxytocin seems to stimulate pair-bonding and social recognition.  It unfortunately gets a lot of press as the ‘love hormone’, even though it can have some darker effects.

Escapees from North Korea also seem to share certain personality traits that make it hard for them to prosper as refugees: they have a hard time holding down a job, they refuse to take personal responsibility for their actions, they are exceedingly suspicious of others, etc.  Not too surprising, obviously.  But taken together this illustrates certain facts about how the brain interacts with the environment to create personality: some things are hardwired in pretty solidly, like pair-bonding.  Others are plastic and interact with the environment, albeit in stereotyped ways.  In order to fully understand the brain, we will have to understand how interactions with the environment create neural mechanisms – the neuroscience of ecology.

How little we know about the neuroscience of fatherhood

Fathers caring for their children is the general rule across most vertebrates; almost all nonmammalian vertebrates use fathers as a prime caregiver.  And yet, the world of neuroscience knows little about paternal care. This is partly because the males of our common laboratory species, the lab mouse and rat, are more likely to eat their young than show any special care for them.  The resulting deficit in knowledge is obvious with any cursory look through a textbook on the neurobiology of parental behavior: after ten chapters detailing maternal behavior, there might be one perfunctory chapter detailing how little we know about paternal behavior.  But here’s a cool fact I learned from one of those chapters: did you know that male Djungarian hamsters assist in delivering pups by tearing away the membranes just after birth.  They play midwife!

It seems like the precise neural circuitry for maternal and paternal care are different; lesioning the amygdala decreases paternal care and increases maternal care.  Likewise, many neurohormones that cause maternal behavior have little effect on males.  But some of these pathways are likely to be the same.  I’ll quickly discuss a paper which describes the influence of the neuropeptides prolactin and oxytocin on paternal care.  Oxytocin is the ‘love hormone’ and strongly stimulates pair-bonding, influences social recognition, and has strong effects on general sociality.  Although it is typically thought of as having a pro-social influence, the reality is a bit more complicated (of course!).  Prolactin is a bit of a sex hormone, providing the body with sexual gratification after intercourse and counteracting the effects of testosterone, estrogen, and dopamine.  It clearly has a stronger social effect as well or I wouldn’t be talking about it in relation to child-rearing!

In order to assess the relationship between these two neuropeptides and fatherhood, Gordon et al. first measured  their concentration in fathers across time and found them to be fairly stable.  When they compared the of these neuropeptides to the propensity of the fathers to play with their children, they found them to be strongly related.  Each were associated with a specific paternal behavior: prolactin with facilitation of a child’s exploratory behavior and oxytocin with how much the fathers matched their facial emotions with that of their children.  Since this is only a correlational study, we cannot say for sure whether or not these neuropeptides are directly causing these behaviors.  However, these are similar to what are seen with maternal behaviors, allowing the researchers to compare their results to the richer maternal literature in the future.  It will be interesting to see if future work can relate receptor variants for these neuropeptides to differences in paternal behavior.  Perhaps we can get a genetics of daddyhood?

Reference

Gordon I, Zagoory-Sharon O, Leckman JF, & Feldman R (2010). Prolactin, Oxytocin, and the development of paternal behavior across the first six months of fatherhood. Hormones and behavior, 58 (3), 513-8 PMID: 20399783

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