Cerebrum Summer 2020

surge higher under stress than in sham-operated animals. This raises the hypothesis that adrenalectomized animals develop a normal acute stress response simply because they are hyper-osteocalcinemic. We reasoned that if this hypothesis was true, then reducing circulating osteocalcin levels and preventing them from surging in mice that had been adrenalectomized, should prevent the development of an acute stress response when exposed to stressors. We found that mice with osteocalcin that lack only one allele were not hyperosteocalcinemic and that their circulating osteocalcin levels did not increase when exposed to stressors. When these mice with osteocalcin were adrenalectomized, they were now unable to develop an acute stress response when exposed to stressors, indicating genetically that osteocalcin is not only necessary , it is also sufficient to mount an acute stress response, at least in the case of adrenal insufficiency. From an evolutionary standpoint, this study also

illustrated, one more time, that with the appearance of bone, the way many physiological functions are achieved or regulated had changed. When it comes to the acute stress response per se, the data cited above raise many questions. Is osteocalcin needed for the development of all stress manifestations, or only for the ones we studied in the mouse? Does osteocalcin act only through regulation of parasympathetic tone, or does it also signal directly in organs whose activity is recruited under stress? What is the molecular identity of the glutamatergic neurons found in bone? Where are their cell bodies? Where do they connect in the brain? Can we use osteocalcin signaling in the parasympathetic nervous system to identify novel functions of the hormone? Finally, why do circulating glucocorticoid levels go up during the acute stress response? Although we have learned a great deal about this mysterious but elusive hormone along this long and winding road, so much more needs to be explored. l

> From Our Podcast with Gérard Karsenty

“Do our bones influence ourminds?” “There is no question, absolutely. There are always naysayers who said I prefer the world as it was 50 years ago, and I prefer bone as it was before it became an endocrine organ. But, no, the evidence is overwhelming, and they're overwhelming because they come from so many labs, in so many countries. So, there is no way to stop data right now.”

“Is osteocalcin being studied by other geneticists or

neuroscientists? It's interesting in the sense that it's kind of the merging of two, almost completely different, fields. It is a great example of how science works cross-functionally.” “About 25 to 30 labs in the world are working on osteocalcin in mice and in humans. Neuroscience is part of our project as you see with this article, but we are also delving into new areas of research that are all centered around the notion that the bone may have been invented by evolution, in part, as a survival tool when animals left the sea to go to land. And what we are trying to write now is a new chapter of the physiology of danger through osteocalcin. But the function of bones, the classical function of bones, fits this definition because while you are sitting and listening to me, if the ceiling falls on your head, you will be unhappy, but you will not die, because bone protects your brain.”

Neuroscience came to the fore in our 2013 paper, published in the journal Cell , when we showed that bone plays a direct role in memory and mood.

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