Cerebrum Summer 2020

Bruce McEwen, a neuroendocrinologist at Rockefeller University, was a pioneer in studying acute stress response,

or the so-called “flight or fight” response.

cannot synthesize glucocorticoid and mineralocorticoid hormones or epinephrine—develop an absolutely normal acute stress response when exposed to stressors. The same is true in patients with adrenal insufficiency. In other words, the acute stress response does not seem to require the adrenal glands to develop. An added and precious benefit of asking if adrenal glands are necessary to mount an acute stress response was to illuminate the role of osteocalcin in the initiation of the acute stress response. How could we explain that the acute stress response does not need glucocorticoid hormones ? The answer came from general endocrinology. It has been known for decades that glucocorticoid hormones (corticosterone in rodents, cortisol in humans) are powerful inhibitors of osteocalcin expression in osteoblasts. As a result of that, mice and rats whose adrenal glands have been removed have elevated circulating osteocalcin levels at baseline, and these levels

such as breathing and heartbeat), and leaving the sympathetic nervous system unopposed and ready to initiate the acute stress response. We cannot rule out the possibility that osteocalcin signaling has other effects as well, such as contributing directly to the increase in energy expenditure in target organs. Acute Stress Response in the Absence of Adrenal Glands If osteocalcin is necessary to trigger the acute stress response, the next question is whether it is sufficient to trigger this response. There is ample evidence that, at the time, the acute stress response develops a surge of circulating glucocorticoid hormones— the role of which has not been fully understood. So, in view of the results we had obtained, the elephant in the room was to determine whether adrenal glands are actually necessary to mount an acute stress response. In a totally unambiguous manner, mice or rats that have had their adrenal glands removed—and thus

furthermore, in its absence (in mice in which osteocalcin has been bred out), typical responses to acute stress are either abolished or severely blunted: These animals show little or no increase in energy expenditure, heart rate, and blood oxygenation. Hence, on genetic grounds, osteocalcin is necessary to trigger the acute stress response. How, most fundamentally, does osteocalcin work to create an acute stress response ? Since it synthesizes the chemical norepinephrine in the brain, we thought that it would do the same in the peripheral nervous system. But it does not. Instead, studies show that osteocalcin sends its signals through a receptor found on neurons, and these signals then travel from the central nervous system to peripheral organs. The net result: The surge in circulating levels of osteocalcin inhibit the recycling of acetylcholine molecules and the electrical activity of certain neurons, reducing activity of the parasympathetic nervous system (the system that slows down responses


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