Oxytocin: same source, released in two places
The hormone oxytocin - and its close relative vasopressin - plays, arguably, one of the broadest roles of any signal in the body. Coming from the pituitary gland in the base of the brain it affects how we bond and respond to others, and in the bloodstream it influences salt and water balance, lactation, and uterine contractions. What's interesting is that the same nerve cells make it for all of these different applications, but can release it just where and when it's needed - either centrally for the brain, or peripherally for the rest of the body. Speaking with Chris Smith, from the University of Florida, Charles Frazier explains how he has been finding out how…
Charles - In the simplest sense, what we were trying to find out in this study is how neurons that release a very important peptide called oxytocin regulate the release of that peptide. The relationship between their cellular activity when they're firing action potentials, and when they're likely to be releasing peptide into the brain.
Chris - Because it's a pretty important hormone, oxytocin, isn't it? I mean, it's got effects that manifest both in the brain, but also around the body. And there are various situations when it gets released and they range from people having sex, to breastfeeding, to bonding with a partner.
Charles - Honestly, that's one of the things that was really fascinating to me about oxytocin in general. All of the oxytocin that is active comes from a very small set of cells that lives in just two discrete nuclei in the brain. And that means that the cells that live in those nuclei have to have ways to release the peptide, both into the peripheral circulation, and into the central nervous system. And it turns out that they have overlapping, but distinct mechanisms for regulating those types of release.
Chris - It sounds like a terrific example of efficiency. You use one source of oxytocin, but you've got ways of making it come out in different places at different times. Presumably we don't, or didn't know what those mechanisms were?
Charles - Well, we knew a number of things about what the mechanisms are. And to think about what they are, we have to talk in a little bit more detail about the neurons themselves, and how they're divided into various compartments. So the oxytocin neurons have one structure called an axon, which is the classic kind of signalling structure of a neuron. Yet unlike many neurons, where their axons project to other places in the CNS, a lot of the axons of oxytocinergic neurons project to the posterior pituitary, where they have mechanisms to release oxytocin, right from their axons into the bloodstream. By contrast, there's this other compartment, the dendrites, and the dendrites typically you think of as kind of an input structure, where they receive inputs and integrate them, and decide when the cells should fire an action potential. But in oxytocinergic neurons, not only do the dendrites do that, they also have their own independent ability to release peptide.
Chris - So how do the cells discriminate between, I want to just squirt some oxytocin into the brain, versus I want to deluge the bloodstream with oxytocin. How do they achieve the, the two different effects when they want to do that?
Charles - That's a great question, and very close to the question that originally motivated this study.
Chris - How were you studying it then?
Charles - We were doing in vitro electrophysiology. Making tissue slices through the brain. Taking living tissue slices and putting them under a microscope where we can record from individual genetically identified, oxytocin synthesising neurons. And then we can use a combination of electrical and optical techniques to both stimulate them, and using imaging techniques that let us know when calcium is coming into those structures. And we're using that calcium influx really as a proxy for when they are likely to be releasing oxytocin.
Chris - So have you solved the riddle? Do we now know how it works?
Charles - Well, I'd say that one of the central findings of this study is that there are certain types of signals that act on the dendrites, to modulate the way that they respond to electrical activity in the cell. Signals that can change the amount of calcium influx that shows up in the dendrites, in response to a consistent electrical stimulus in the cell body.
Chris - And what are those external factors that make that difference?
Charles - One type of signal that we studied is called an osmotic stimulus. And in a simple sense, what this is, it's just a stimulus that changes the extracellular salt concentration in the solutions that is around the neurons. And we found that increasing the osmolarity of the extracellular solution decreases the ability of the dendrites to conduct electrical activity from the soma to the likely sites of oxytocin release.
Chris - Okay, so that explains one part of it, but what other factors matter?
Charles - Well, we also found a very common inhibitory transmitter that exists in the brain called GABA, is similarly able to act on the dendrites to modulate the relationship between activity in the soma and calcium influx at the likely sites of oxytocin release. In my opinion, it's plausible that there will be a number of other endogenously available modulators that can act on the dendrites to control this process, that have not yet been discovered.
Chris - Putting all this together. How do you think that this changes our understanding of the physiology of this bit of the body?
Charles - I guess the reason that I think this is really a potentially exciting finding, is because there's a fair amount of interest in targeting central oxytocin receptors to treat a range of conditions that impact mental health. And really doing that is pretty difficult, because oxytocin is not particularly permeant to the blood brain barrier. So if you give it to a human as a medication peripherally, not a lot of it reaches the brain, and the oxytocin that does reach the brain probably doesn't do a fantastic job of mimicking the natural, spatial, or kinetic, or contextual profiles of normal healthy oxytocin signalling. And so the thing that I think is exciting about our findings, is it starts shedding a little light on possible ways to control how the brain releases its own oxytocin, and that might eventually produce a therapeutic strategy that is more effective than bringing in an exogenous bit of oxytocin.