When your neurons are sparking, chances are something else is making your blood boil.

by John McManamy


NEUROTRANSMITTERS get all the attention, but they are merely one partner in an infinitely complex two-step that involves hormones. Robert Sapolsky of Stanford explains it best when he asks us to figure out went on in an organism a half-second before that behavior occurred to cause it to occur. This, he says, is the world of what's going on with neurons and circuitry.

But then we have to step back and ask what smell, what sound, what sensory stimulation in the environment caused those neurons to get activated and produce that behavior. And then we need to push it one step further behind, to hormone levels in the blood in the last few hours that changed how sensitive you are to those sounds and smells.

But it's a two-way street. Hormones are also activated by neurons and their neurotransmitter messengers. The various regions of the limbic system are literally one synapse from the hypothalamus, which partners with the pituitary gland in dispatching hormones through the blood to all regions of the body.

Consider this completely counter-intuitive proposition posed by the psychologist-philosopher William James, back in 1884: We meet a bear. Do we run because we are afraid or are we afraid because we are running? In other words, suppose your fight-or-flight response activated before your cortex became aware of the bear? Hormones are flowing throughout your blood stream, shutting down digestion and other functions, priming others, converting glycogen into muscle food.

And there you are, not sure what is happening. But you are running, your heart is racing. Therefore - you must be afraid. Suddenly it registers: Oh, crap! Is that a bear I'm running from?


Also popularly known as cortisol, glucocorticoids are a type of steroid released by the adrenal glands, via signaling from the hypothalamus through the pituitary gland. Glucocorticoids figure mightily in the body's fight-or-flight response, resulting in energy on tap, plus ancillary superpowers including heightened awareness, increased immune function, and a lower pain threshold. In short, all the things we need to handle a bear in the woods, except bear repellent.

Where fight-or-flight does not work are those zillions of stressful anxiety-inducing situations modern life throws at us every day of the week, when we merely need to be alert and on our game.

A lot of what glucocorticoids do is keep the body in a state of homeostasis, not too amped up, not too sluggish - just right. But too many stressful situations can launch us into a state of allostatic overload, where we essentially fail to reset to normal. Constant glucocorticoid bombardment sets us up for all manner of catastrophes, from heart attack to immune system breakdown to depression.

Addison's disease - characterized, among many other things, by extreme fatigue - is a failure of the adrenal glands to produce glucocorticoids. The most famous Addison's patient, JFK, required daily steroid injections just to boot him up to normal. By contrast, Cushing's Disease, which can over-activate body and soul, results from a tumor that causes the pituitary gland to signal the adrenals to over-produce glucocorticoids. Of all things, depression is a feature of both illnesses. Thus, too little of this hormone and we can't get out of bed. Too much, and we may stress our way into depression, eventually reaching a state of "learned helplessness" where we simply give up.

Hippocampal neurons are dense with glucocorticoid receptors. The hippocampus lays down new memory and is the one area of the brain where new cell growth (neurogenesis) takes place. Reduced hippocampal mass has been linked to depression. Sustained high glucocorticoid levels appear to compromise the neuron's ability to regulate the excitatory effects of glutamate, effectively turning the neurotransmitter into a neurotoxin.



Other HPA Axis Hormones

Glucocorticoids are the end-product of a cascade that begins when the hypothalamus, which links the neural system to the endocrine system, secretes CRF (corticotropin releasing factor). The CRF travels through small blood vessels into the pituitary, the "master gland," which is now primed to manufacture and release ACTH (corticotropin). ACTH in turn stimulates the adrenal glands to pump glucocorticoids into the blood stream.

A 2008 GSK-sponsored phase II clinical trial of a "CRF-1 antagonist" testing for efficacy in depression revealed no benefit over the placebo. Trials are underway for PTSD and stress-induced alcoholic cravings.





Also known as epinephrine, adrenaline is the other hormone released by the adrenal glands in response to stress. As a neurotransmitter with a slight chemical variant, norepinephrine, which is involved in alertness, is released from neurons in the locus coeruleus in the brain.

Occasionally, you wll hear references to "adrenaline junkies" and "adrenaline rush." In light of what we are learning, these terms appear to be going out of fashion. Adrenaline merely helps prime various organs into action. It has nothing directly to do with pleasure. We may derive pleasure from our state of excitement, but what makes our pleasure circuits light up is dopamine. In reality, it is the dopamine rush that so-called adrenaline junkies are addicted to.

Estrogen and Progesterone

Estrogen and progesterone are most associated with female sexuality (though estrogen is also found in males). They also affect mood, with altered levels the prime suspects in postpartum depression and other postpartum disorders, premenstrual dysphoric disorder, and the emotional distress from menopausal transitions. This strongly suggests that these two hormones may also be a complicating factor concerning depression in women, who experience this illness at twice the rate as men and who tend to express their distress more openly.




Testosterone, an androgen steroid, is most associated with male sexuality and vitality (but also figures in the female hormonal equation). Testosterone levels lower with age, and one result may involve a form of male depression. Testosterone has been associated with male aggression, but scientific evidence has failed to establish a direct link in humans. But with males accounting for the lion's share of the violence in this planet, and young males standing out disproportionately, expect science to come up with a host of indirect links.

Thyroid Hormones

Underproduction of thyroid hormones (Hashimoto's Disease) may account for one in five depressions. The depression may lift with thyroid pills.

See also: Our Favorite Neurotransmitters

Feb 12, 2012, reviewed Dec 17, 2016


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