Third Eye? The suprachiasmatic nucleus, major circadian oscillator and retinohypothalamic tract.

Big Bend

If you are a nurse or physician friend, you probably already know that chronic, excessive stress leads to excess stress hormones cortisol, epinephrine, norepinephrine. These hormones, which serve an essential survival function under normal short duration high stress circumstances (like running away from a predator), are making us fat, impairing our immune system, promoting cancer and cardiovascular disease.  This is due to chronic excessive stress (Read: Why Zebras Don't Get Ulcers).  We know this, yet, we live in America, and as Americans, will likely die of some disease for which stress cannot be excluded as a contributing factor.

I'll bet this information I'm about to share will be as new to my medical friends as it is to my nonmedical friends. More importantly, it's another reason to consider getting outside to go for a hike.

A recently published research study (J Exerc Nutrition Biochem. 2014 Sep; 18(3): 293-9) on the effects of exercise with or without sunlight exposure on sleep quality and hormone responses revealed some amazing findings. In the study, participants were enrolled in structured exercise program with or without exposure to sunlight, or were randomized to rest with or without sunlight exposure for 5 days per week for five weeks. Sleep quality and the levels of the hormones melatonin, cortisol, epinephrine, and norepinephrine were measured. As you might expect, participants who exercised in sunlight had statistically better sleep duration and quality than those who did the same exercise without exposure to sunlight.  Individuals who did not exercise, but had sunlight exposure also slept better than those kept indoors. The participants who exercised in sunlight also had higher blood levels of melatonin, and lower levels of the stress hormones cortisol, epinephrine, and norepinephrine than their indoor exercising counterparts. This suggests that outdoor exercise is associated with improvements in sleep, lower levels of stress hormones, and higher levels of melatonin. This may help explain a recent study which showed improvement in emotional wellbeing and executive function in association with nature experience.

Reading this study led to a digression. Epinephrine / norepinephrine and cortisone have well known effects, and are connected to high blood pressure, high blood sugar, poor sleep, increased fat storage, and a plethora of other effects. Melatonin is a molecule I was less familiar with, which inspired a literature review. What is the significance of the findings that show an association between higher melatonin levels and outdoor exercise? What comes next is a departure from my normal blog posts, down the rabbit trail that is the melatonin pathway: 

Melatonin is a versatile biological signal made primarily in the pineal gland in the brain, but also in small quantities in other tissues, including the digestive tract, skin, bone marrow and lymphocytes. Melatonin is famous for its important role in in sleep/wake cycles (circadian rhythm). 

Now for the part that is not routinely included in standard dicactic of  Medical and Nursing programs: Mechanistically, there is a little known but probably important pathway known as the retinohypothalamic tract, which is basically a connection between the retina of the eye and the hypothalamus which is the part of the brain responsible for connecting the brain to the hormone signalling in the body.  When light stimulates specialized cells in the retina, a chemical called melanopsin undergoes a conformational change, which in turn initiates a signal which is routed through the hypothalamus, leading to increased norepinephine levels in the pinealocytes of the pineal gland. This in turn leads to elevation in melatonin levels. In the brain, this promotes appropriate circadian rhythm.

To understand the importance of this little known pathway, consider patients who undergo pinealectomy (surgical or radiation induced destruction/removal of the pineal gland). These patients experience narcolepsy, severe emotional disturbances, and even psychotic symptoms.

As it turns out melatonin is involved in much more than just sleep and wake cycle:  

Antioxidant: One of the primary drivers of disease is oxidative damage. Oxidative damage occurs when reactive molecules directly damage cells and DNA at the cellular levels. Antioxidants detoxify these reactive chemicals, and in doing so reduce oxidative damage which is ultimately a protective process. Melatonin is not only a potent antioxidant, but it is more efficient than most naturally occurring antioxidants. An example of the way oxidative damage impacts disease progression is found in neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s chorea and amyotrophic lateral sclerosis (Lou Gehrig’s Disease).  While oxidative damage is not the whole story of these disorders, it does play a key role in the progression of disease, and there is at least some evidence that melatonin can modify the course of the disease, which has been supported by data showing slower disease progression and increased preservation of function in individuals with Alzhiemer’s disease who were given melatonin.

Anticancer effect: There is evidence that a normal nighttime surge in melatonin levels has an inhibitory effect on the initiation, promotion, and progression of cancer. Melatonin has been shown to have an anticancer effect in certain breast cancers (specifically, estrogen-receptor positive), liver cancer, ovarian cancer, uterine cancer, intestinal cancers, and certain melanomas (ocular melanoma). On the flip side, there have been studies showing increased rates of colorectal and breast cancer in nurses who work nights as compared with nurses who work the day shift. A proposed mechanism for this trend is that the nurses working days have a significantly lower exposure to daylight and consequently melatonin. This theory is also supported by a study which showed a more rapid progression of cancer in lab rats deprived of light as compared to lab rats with normal light exposure.

Another very interesting study showed that blood samples collected from healthy volunteers had the ability to slow tumor growth in vitro (in a petri dish) significantly better when it was collected at night, in darkness. Nighttime exposure to bright artificial light was associated with significantly reduced anti-tumor effect as compared to participants who had no nighttime exposure to bright artificial light.

Immune boosting effect: melatonin receptors have now been identified on immune cells, and higher melatonin levels have been associated with improved immune function.  Melatonin has been shown to help reduce the negative impact of chemotherapy on immune precursor cells in the bone marrow, and has been shown to enhance production of IL-2, IL-6, and IL-12 (messengers involved in immune function). Interestingly, certain white blood cells actually produce melatonin, which suggests it may have a role in signaling between immune cells to coordinate appropriate immune response.  A study evaluating melatonin in HIV patients showed a correlation between low melatonin levels and decreased CD 4 cell count and function. Studies have also shown a higher incidence of autoimmune disease in high latitudes, which suggests a relationship between long nights (less sun exposure) and immune dysfunction. This theory is supported by a study showing higher than normal levels of melatonin in patients with rheumatoid arthritis as compared with healthy individuals.

Depression: melatonin seems to play a role in mental health as well, and numerous studies have demonstrated an association between depression and lower than normal melatonin levels.

Digestion: melatonin is secreted by the enterochromaffin cells of the GI tract in quantities far greater than those in the pineal gland. The enterochromaffin cells are important cells in coordinating certain actions of digestion, such as motility, gastric acid production, bicarbonate, bile, and pancreatic enzyme release. Melatonin production is normally increased after a meal, which stimulates production of acid neutralizing bicarbonate in the small intestine (the contents leaving the stomach have a pH similar to battery acid!).  Patients with duodenal ulcers have been found to have lower than normal melatonin levels. Melatonin also plays an important role in regulating the rate of digestion (motility).

Cardiovascular: low melatonin has been associated with heart disease and heart failure, and higher levels of melatonin have been associated with lower norepinephrine (stress hormone which, in excess, plays an important role in cardiovascular disease).  Higher melatonin levels were also associated with lower and healthier average arterial blood pressure. 

Bone health: melatonin has been shown to help enhance the uptake of calcium in bones. A study in chickens and another in salmon showed that removal of the pineal gland (and thus reduction in melatonin), can induce a disease state which resembles scoliosis in humans.

Reproduction: melatonin plays a role in the production of sex hormones gonadotropin releasing hormone, leutenizing hormone, follicle stimulating hormone, and subsequently the downstream hormones testosterone, estrogen, and progesterone. Sheep which normally reproduce annually can be induced to breed twice per year after pinealectomy, and will also produce more wool. In humans, a study has demonstrated an association between low melatonin levels and precocious puberty.

Conclusion and the third eye:

This photo demonstrates the parietal eye on our very own horned lizard (aka horney toad). The parietal eye is found on many reptiles, and is  actually and externalized photosensitive organ which is directly connected to the pineal gland

Ancient cultures believed in a third eye. In a sense, the retiohypothalamic tract is just that. In fact, the pineal gland forms an external photosensitive organ (eye) on many reptiles and amphibians and some fish, serving the same functions as our own retinohypoothalamic tract. So, in a sense, we do have a third eye, which has regulatory power over every system in our bodies. 

In science, nursing, medicine, faith, and life, I have found two things to be true: (1) that the more I know, the less I know; nothing is as simple as it seems, and (2) everything is one; all systems are in some way connected.

While not a substitute for appropriate medical intervention, outdoor exercise has the potential to provide multisystem benefits. Who doesn’t want to have improved immune, reproductive, musculoskeletal, and digestive function, better sleep, more energy, and guard against cancer, infection, and cardiovascular disease?

For the full review article on melatonin funciton, see Pandi-Perumal et al. (2006). Melatonin: Natures most versatile biological signal? FEBS Journal 273. 2813-2838.