Drink before sleep

Among the many humorous sayings, puns, and jokes that one inevitably encounters on any social medium account, one that was popular this year was about the similarity between putting a 2 year old to bed and putting your drunk friend to bed, which went like this: they both sing to themselves, request water, mumble and blabber incoherently, do some weird yoga posses, cry, hiccup, and then they pass out. The joke manages to steal a smile only if someone has been through both situations, otherwise it looses its appeal.

Being exposed to both situations, I thought that while the water request from the drunk friend is a response to the dehydrating effects of alcohol, the water request from the toddler is probably nothing more than a delaying tactic to postpone bedtime. Whether there may or may not be some truth to my assumption in the case of the toddler, here is a paper to show that there is definitely more to the water request than meets the eye.

Generally, thirst is generated by the hypothalamus when its neurons and neurons from organum vasculosum lamina terminalis (OVLT) in the brainstem sense that the blood is either too viscous (hypovolaemia) or too salty (hyperosmolality), both phenomena indicating a need for water. Ingesting water would bring these indices to homeostatic values.

More than a decade ago, researchers observed that rodents get a good gulp of water just before going to sleep. This surge was not motivated by thirst because the mice were not feverish, were not hungry and they did not have a too viscous or a too salty blood. So why do it then? If the rodents are restricted from drinking the water they get dehydrated, so obviously the behavior has function. But is not motivated by thirst, at least not the way we know it. Huh… The authors call this “anticipatory thirst”, because it keeps the animal from becoming dehydrated later on.

Since the behavior occurs with regularity, maybe the neurons that control circadian rhythms have something to do with it. So Gizowski et al. (2016) took a closer look at  the activity of clock neurons from the suprachiasmatic nucleus (SCN), a well known hypothalamic nucleus heavily involved in circadian rhythms. The authors did a lot of work on SCN and OVLT neurons: fluorescent labeling, c-fos expression, anatomical tracing, optogenetics, genetic knockouts, pharmacological manipulations, electrophysiological  recordings, and behavioral experiments. All these to come to this conclusion:

SCN neurons release vasopressin and that excites the OVLT neurons via V1a receptors. This is necessary and sufficient to make the animal drink the water, even if it’s not thirsty.

That’s a lot of techniques used in a lot of experiments for only three authors. Ten years ago, you needed only one, maybe two techniques to prove the same point. Either there have been a lot of students and technicians who did not get credit (there isn’t even an Acknowledgements section. EDIT: yes, there is, see the comments below or, if they’re missing, the P.S.) or these three authors are experts in all these techniques. In this day and age, I wouldn’t be surprised by either option. No wonder small universities have difficulty publishing in Big Name journals; they don’t have the resources to compete. And without publishing, no tenure… And without tenure, less research… And thus shall the gap widen.

Musings about workload aside, this is a great paper, shedding light on yet another mysterious behavior and elucidating the mechanism behind it. There’s still work to be done though, like answering how accurate is the SCN in predicting bedtime to activate the drinking behavior. Does it take its cues from light only? Does ambient temperature play a role and so on. This line of work can help people that work in shifts to prevent certain health problems. Their SCN is out of rhythm and that can influence deleteriously the activity of a whole slew of organs.

Summary of the doi: 10.1038/nature19756 findings. 1) The light is a cue for suprachiasmatic nulceus (SCN) that bedtime is near. 2) The SCN vasopressin neurons that project to organum vasculosum lamina terminalis (OVLT) are activated. 3) The OVLT generates the anticipatory thirst. 4) The animal drinks fluids.

Reference: Gizowski C, Zaelzer C, Bourque CW. (28 Sep 2016). Clock-driven vasopressin neurotransmission mediates anticipatory thirst prior to sleep. Nature, 537(7622): 685-688. PMID: 27680940. DOI: 10.1038/nature19756. ARTICLE

By Neuronicus, 5 October 2016

EDIT (12 Oct 2016): P.S. The blog comments are automatically deleted after a period of time. In case of this post that would be a pity because I have been fortunate to receive comments from at least one of the authors of the paper, the PI, Dr. Charles Bourque and, presumably under pseudonym, but I don’t know that for sure, also the first author, Claire Gizowski. So I will include here, in a post scriptum, the main idea of their comments. Here is an excerpt from Dr. Bourque’s comment:

“Let me state for the record that Claire accomplished pretty much ALL of the work in this paper (there is a description of who did what at the end of the paper). More importantly, there were no “unthanked” undergraduates, volunteers or other parties that contributed to this work.”

My hat, Ms. Gizowski. It is tipped. To you. Congratulations! With such an impressive work I am sure I will hear about you again and that pretty soon I will blog about Dr. Gizowski.


Hope for a new migraine medication

Headache clipart. Courtesy of ClipArtHut.
Headache. Courtesy of ClipArtHut.

The best current anti-migraine medication are triptans (5-HT1B/1D receptor agonists). Because these medications are contra-indicated in patients with a variety of other diseases (cardiovascular, renal, hepatic, etc.), the search for alternative drugs continues.

The heat- and pain-sensitive TRPV1 receptors (Transient Receptor Potential Vanilloid 1) localized on the trigeminal terminals (the fifth cranial nerve) have been implicated in the production of headaches. That is, if you activate them by, say, capsaicin, the same substance that gives the chili peppers their hotness, you get headaches (you’d have to eat an awful lot of peppers to get the migraine, though). On the other hand, if you block these receptors by triptans, you alleviate the migraines. All good and well, so let’s hunt for some TRPV1 antagonists, i.e. blockers. But, as theory often doesn’t meet practice, the first two antagonists that were tried were dropped in the clinical trials for lack of efficiency.

Meents et al. (2015) are giving another try to two different TRPV1 antagonists, by their fetching names of JNJ-38893777 and JNJ-17203212, respectively. Because you cannot ask a rat if it has a headache, it is very difficult to have a rodent model for migraine. Instead, researchers focused on giving rats some inflammatory soup directly into the subarachnoid space or capsaicin directly into the carotid artery, actions which they have reasons to believe produce severe headaches and some biological changes, like increase in a certain gene expression (c-fos, if you must know) in the trigeminal brain stem complex and release of the neurotransmitter calcitonin gene-related peptide (CGRP).

JNJ-17203212 got rid of all those physiological changes in a dose-dependent manner, presumably of the migraine, too. The other drug, JNJ-38893777, was effective only on the highest dose. Give these drugs a few more tests to pass, and off to the clinical trials with them. I’m joking, it takes a lot more research than just a paper between discovery and human drug trials.

Reference: Meents JE, Hoffmann J, Chaplan SR, Neeb L, Schuh-Hofer S, Wickenden A, & Reuter U (December 2015, Epub 24 June 2015). Two TRPV1 receptor antagonists are effective in two different experimental models of migraine. The Journal of Headache and Pain. 16:57. doi: 10.1186/s10194-015-0539-z. Article | FREE FULLTEXT PDF

By Neuronicus, 8 November 2015