The story of stress

A history of the science behind stress:

“He would subject them to extreme temperatures, make them go hungry for long periods, or make them exercise a lot,” the medical historian Mark Jackson says. “Then what he would do is kill the rats and look at their organs.”

What was interesting to Selye was that no matter how different the tortures he devised for the rats were — from icy winds to painful injections — when he cut them open to examine their guts it appeared that the physical effects of his different tortures were always the same.

“Almost universally these rats showed a particular set of signs,” Jackson says. “There would be changes particularly in the adrenal gland. So Selye began to suggest that subjecting an animal to prolonged stress led to tissue changes and physiological changes with the release of certain hormones, that would then cause disease and ultimately the death of the animal.”

And so the idea of stress — and its potential costs to the body — was born.

But here’s the thing: The idea of stress wasn’t born to just any parent. It was born to Selye, a scientist absolutely determined to make the concept of stress an international sensation.

Study: Men smell and that will stress you out

ferret-specific neurons

A study in Nature Methods has kicked up a bit of a fuss:

In 2007, his lab observed that mice spend less time licking a painful injection—a sign that they’re hurting—when a person is nearby, even if that “person” is a cardboard cutout of Paris Hilton. Other scientists began to wonder if their own data were biased by the same effect. “There were whisperings at meetings that this was confounding research results,” Mogil says.

—–

Male, but not female, experimenters induce intense stress in rodents that can dampen pain responses, according to a paper published today in Nature Methods. Such reactions affect the rodents’ behaviour and potentially confound the results of animal studies, the study suggests.

Yup, the paper says that the stench of men is just plain stressful to rodents. And it’s just human males, but males from many (most?) species.

It is pretty well-established that many animals have neurons that have an innate response to the odor of other animal species. Look at the percent of neurons in the vomeronasal organ (VNO) of the mouse that detect the scent of specific other animals:

Conspecific cells

 

I suppose that means it shouldn’t be surprising that there would be a way to detect males across species. And the data from this paper kinda-sorta points to that: bedding from male guinea pigs, rats, cats, and dogs induced stress-related behaviors but not when the bedding came from castrated males (poor guys). Overall, the affect of the stress was stronger on the female than the male mice.

There are three interesting take-aways from this paper. First, obviously, is that males stress out mice they handle more than females do – and they stress out female mice more than male mice. Second, certain male-specific effects seem to require both an odor and the physical presence of the (male/female) handler. Third, the odor isn’t likely to be a pheromone but rather a complex mix of odors. Three of the stress-inducing odors that they identify are 300 μM (E)-3-methyl-2-hexenoic acid (3M2H), 0.75–3 mM androstenone and 0.75–3 mM androstadienone (4,16-androstadien-3-one), which I’m sure everyone is familiar with! The first is a fatty acid that contributes to “Caucasian male underarm odor” (yum), the second is a steroid found in sweat and urine (and celery), and the third is a metabolite of testosterone.

Also, let’s take a moment to pity the poor grad students who had to take “repeated rectal measurement of core [mouse] body temperature”.

References

Isogai Y, Si S, Pont-Lezica L, Tan T, Kapoor V, Murthy VN, & Dulac C (2011). Molecular organization of vomeronasal chemoreception. Nature, 478 (7368), 241-5 PMID: 21937988

Sorge, R., Martin, L., Isbester, K., Sotocinal, S., Rosen, S., Tuttle, A., Wieskopf, J., Acland, E., Dokova, A., Kadoura, B., Leger, P., Mapplebeck, J., McPhail, M., Delaney, A., Wigerblad, G., Schumann, A., Quinn, T., Frasnelli, J., Svensson, C., Sternberg, W., & Mogil, J. (2014). Olfactory exposure to males, including men, causes stress and related analgesia in rodents Nature Methods DOI: 10.1038/nmeth.2935

On bumpology: what neuroscience knows

Adam Gopnik has a review in the New Yorker of several neuroscience-themed books. Or perhaps I should say, he has a review of several books that use neuroscience-related words. As he points out, one of the problems with neuroscience happens to be the people who love the sound of neuroscience:

A core objection is that neuroscientific “explanations” of behavior often simply re-state what’s already obvious. Neuro-enthusiasts are always declaring that an MRI of the brain in action demonstrates that some mental state is not just happening but is really, truly, is-so happening. We’ll be informed, say, that when a teen-age boy leafs through the Sports Illustrated swimsuit issue areas in his brain associated with sexual desire light up. Yet asserting that an emotion is really real because you can somehow see it happening in the brain adds nothing to our understanding. Any thought, from Kiss the baby! to Kill the Jews!, must havesome route around the brain. If you couldn’t locate the emotion, or watch it light up in your brain, you’d still be feeling it. Just because you can’t see it doesn’t mean you don’t have it. Satel and Lilienfeld like the term “neuroredundancy” to “denote things we already knew without brain scanning,” mockingly citing a researcher who insists that “brain imaging tells us that post-traumatic stress disorder (PTSD) is a ‘real disorder.’ ” The brain scan, like the word “wired,” adds a false gloss of scientific certainty to what we already thought. As with the old invocation of “culture,” it’s intended simply as an intensifier of the obvious.

It’s always perplexing that you can take a study that shows something “lights up” an area of the brain and the press will ooooh and aaaah over it. The problem is not that it’s bad science – it often isn’t – the problem is that it doesn’t tell the lay-person anything. At all. To a scientist, these studies can be fascinating springboards to further research, or clarity for previous technical research. Take, for instance, two fantastic studies that used electrode recordings to localize two types of uncertainty to the pulvinar and the septum. As a scientist, the results were nontrivial and important for our understanding of how uncertainty is represented and used in the brain. To a non-specialist the takeaway message is: uncertainty exists in two strangely-named areas in the brain…? It’s a prime reason why, despite being important, I don’t highlight those kinds of papers in this blog.

But then Gopnik undermines his point:

She discusses whether the hormone testosterone makes men angry. The answer even to that off-on question is anything but straightforward. Testosterone counts for a lot in making men mad, but so does the “stress” hormone cortisol, along with the “neuromodulator” serotonin, which affects whether the aggression is impulsive or premeditated, and the balance between all these things is affected by “other hormones, other neuromodulators, age and environment.”

Yes, the role of neuromodulators is unfortunately complicated (I’ll let out a personal sigh, here). Yet this example of a seemingly convoluted mechanism is a fantastic example of something we actually know a fair bit about. Serotonin levels actually have a causative role in the rate of aggression – animals that are given a serotonin inhibitor will begin exhibiting less aggression. You can actually map out some of this circuitry in crustaceans to find out exactly how serotonin is acting! In mammals, serotonin seems to have two ways of affecting aggressive behavior. Serotonin release in the striatum will modify dopamine activity, a proxy for the rewarding value of an [aggressive?] action. In other words, serotonin makes being aggressive seem like a less attractive option. Simultaneously, serotonin in the prefrontal cortex inhibits the transmission of signals coming from the amygdala – or, the top-down (self-control) area begins regulating the aggressive signal coming from another area. Complicated? Yes, it can be. But why would you expect the brain to be so simple?

More importantly, there are areas where neuroscience has provided fantastic explanations for how we perceive the physical world. The greatest success in my mind is in the realm of optical illusions. We’ve known about these illusions for a long time but it is only recently that we can give firm physical and neurological explanations for why they occur.  There are many examples out there.

The problem is that once something is explained it is no longer interesting. I think Gopnik is hoping for a concise answer to hard problems – but we’re not there yet.

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.

References

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