Cerebrum Summer 2020

analyzed with great insight by the late Bruce McEwen . These processes that make up the acute stress response include increases in heart rate, blood pressure, energy expenditure, respiration, and adrenal secretion of the hormone cortisol. Many of the physiological processes regulated by osteocalcin are needed to escape danger. Memory, for instance, enables creatures in the wild to remember where predators are and where there is food. The capacity for exertion (i.e., to run) is also needed to escape danger, as is the ability to mobilize glucose, another function of osteocalcin. Thus, the hypothesis that osteocalcin is a hormone essential in situations of acute danger offers the most convincing argument for links between the physiological functions that it regulates. This, of course, does not exclude additional commonalities among such functions. As for any physiological process, many questions remain regarding the biology of the acute stress response. For one, how does the activity of the sympathetic nervous system surge so quickly in situations of acute danger? This is a crucial issue, given this system’s key role in controlling bodily functions that are not directed consciously, including heartbeat, breathing, and digesting. In theory, the two arms of the nervous system, the sympathetic nervous system and the parasympathetic nervous system (which conserves energy by slowing body functions like heart rate and digestion), are supposed to work in equilibrium: How is osteocalcin involved in this balancing act? A key question at this point was whether osteocalcin is actually a stress hormone (i.e., is it implicated in the initiation and/or unfolding of the acute stress response)? To qualify, only two

criteria must be met: stress hormone’s circulating levels should rise within minutes in animals facing an acute danger. And such a hormone should regulate, directly or indirectly, the physiological processes, such as those enumerated above, that are recruited to mount an acute stress response. Concrete Answers The first observation we made is that in mice, rats, and humans facing danger, circulating osteocalcin levels rise within minutes. How can acute fright quadruple concentration of the hormone so quickly? A chemogenetics approach targeting the fear center of the brain’s bilateral amygdala region provided an answer to this question by showing that, between a stressor and the release of osteocalcin by bone, there was signaling in the brain. A battery of genetic testing, of cell culture assays, and abrogation of neuronal signaling ruled out the possibility that mediators of such signaling are

circulating molecules, implicating a neurotransmitter instead. In this regard, osteocalcin’s structure illustrates the cleverness of evolution. The hormone is synthesized in osteoblasts (cells that lead to the formation of bone). It is then modified by the enzyme gamma carboxylase and enters the circulation in the carboxylated form, which is inactive, and the uncarboxylated active form. The inactive form can be blocked by the neurotransmitter glutamate, which is present in both brain and bone. Here’s how they all come together: Under acute stress conditions, signals in the amygdala (and possibly other fear centers in the brain that we have not yet tested) lead to the release of glutamate. This neurotransmitter goes to the bone, where it enters osteoblasts and blocks the inactive form of osteocalcin, so that only the hormonally active form is released into the circulation. What allows us to call osteocalcin a true stress hormone is that,

My vision of the skeleton as central to energy usage, reproduction, and memory has persuasive evidence in mice, but the extent to which these results translate to people remains an open question.

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