Wednesday, January 6, 2016

It’s An Exercise Resolution

Biology concepts – exercise, stress, aging, mood, neurotransmitters, monoamines, endocannabinoids, endorphins, blood brain barrier

Exercise is a common New Year’s resolution. You want to
test yourself and gain in body and soul what comes from
accomplishing physical tasks. However, there is such a
thing as biting off more than you can chew. Make small
goals and add length and intensity slowly, so you can
always feel you are improving.
It’s New Year’s resolution time! Last year we talked about how difficult your brain makes it to change a habit and we gave you some strategies to help you succeed. But succeed at what? It’s time to decide on a resolution.

Two of the most popular resolutions are to lose weight and to exercise more. These two can be linked, although they don’t have to be – you could just starve yourself. I don’t think anyone should make a resolution to starve this year, so let’s look in more depth at exercise as a good habit.

There are two major questions to be answered as to a “getting fit” resolution. The first is obvious – why would more exercise be good for me? We all know about how expending more energy than you take in will help you control your weight. So that’s an easy one.

Exercise also helps your health by building muscle, improving flexibility, increasing bone density, and improving both cardiac and pulmonary function. All these changes result in reduced susceptibility to diseases, especially diseases of life style, like diabetes, cardiovascular disease, cancer, and metabolic syndrome.

Those benefits were obvious, but you probably know so more. Exercise may hurt – but it also makes you feel good. Intense physical activity is a powerful mood enhancer, while at the same time reducing the effects of stress on your body. We all know folks who go for a run or go lift when they are stressed. It really does work.

Linked to de-stressing you in the short term is exercise’s effect on reducing the results of stress long term. This kind of stress means time, oxidation, wear and tear, as well as mental stress – basically, aging. Even at a cellular level, exercise may work to impede the signs of aging.

A 2010 study divided stressed women into two groups, those that began exercising and those that did not. After just a three-day exercise period, the population that began exercising showed fewer signs of aging in sample cells taken. Maybe wearing yourself out will let you wear yourself out for many more years.

People, well most people, are happier after they exercise.
Stress relief is a major contributor, I recommend that
anytime things are getting on your nerves, go out for a
brisk walk or get on your bike. The sense of
accomplishment also contributes to making you happier,
but there is so much more.

Unrelated to simply wearing you out, physical activity improves your sleep. This is so true that doctors now prescribe exercise to those suffering from insomnia. We’ll talk more about this in a couple of weeks.

The benefit you may not think of is …….thinking. Exercise actually improves cognitive (from Latin = to know or recognize) function and memory. Your brain may not be a muscle, but it definitely benefits from increasing your physical activity. This will be our subject for next week, just in time for the all the kids to have a new weapon in their arsenal for good grades.

Now for the second question about exercise, and it’s a doozie. How does exercise accomplish all these wonderful things? The effects of exercise on your physical body comes mostly from your innate ability to react to stressors. More work required from muscles results in muscles growing bigger and stronger to meet the demand. This includes your heart –it’s a muscle. No, for these biology stories, let’s focus on the mechanisms at work that affords exercise the ability to affect your brain. It’ll blow your mind.

Today let’s talk about how exercise actually makes your brain – and the rest of you, happier.

The monoamines dopamine and serotonin are intimately
involved in several mental disorders. You can see that
decreases in one lead to different problems than losses of
the other, but when they are both down, you get
depression and a will to eat more. Eating is another, not
so healthy, way of feeling happier.
The major players are neurotransmitters (NTs) and other molecules that can alter brain activity. Things like dopamine, serotonin, and norepinephrine are NTs; endocannabinoids and endorphins work to block negative inputs.

Levels of dopamine, serotonin and sometimes norepinephrine neurotransmitter are reduced in many patients with clinical depression. Each of these NTs is produced from single aromatic (meaning they have a ring structure) amino acids. Serotonin is produced from tryptophan, dopamine is produced from tyrosine, and norepinephrine is made from dopamine.

As such, they are called monoamines (mono = one and amine = amino group from an amino acid). They react with millions of brain cells to induce feelings of happiness and well-being. Having too little leads to depression or other psychiatric problems.

Depression is often treated with drugs called monoamine oxidase inhibitors, since the enzyme monoamine oxidase is responsible for degrading the monoamine NTs once they have been released from neuron to stimulate the next neuron. Less degradation means more activity, so using these drugs is like increasing the serotonin, dopamine, and norepinephrine levels in the brain.

Exercise increases serotonin in the brain, so you feel better about the world and your place in it. The increased brain serotonin may come from blood, a single study showed a decrease in blood serotonin after exercise. On the other hand, maybe exercise increases production of serotonin in the brain. Maybe it’s both.

Dopamine isn’t left out when it comes to exercise. Physical activity increases calcium (Ca2+) flow to brain, which is necessary for dopamine production. But just as serotonin can be increased in more than one way, so can dopamine activity. Published results show that moderate exercise increases the number of dopamine receptors on neurons, so more good feeling is possible.

So dopamine and serotonin are increased by exercise and make you happy. How about just decreasing any signals that make you less happy? This is the second major effect of exercise; it decreases pain and stress. This occurs through release of two other types of compounds – endocannabinoids and endorphins.

Cancer and AIDS lead to a wasting syndrome call cachexia.
Here is Robin Gibb after he was diagnosed with advanced
liver cancer. There is loss of fat and muscle as the body
tries to burn anything for fuel. These diseases destroy
appetite and mood, so cannabinoids (marijuana) can be
prescribed to elevate both. Exercise would also help by
stimulating endocannabinoids.
Endocannabionoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-GT) are made from arachidonic acid; they are eicosanoid lipids, and are still another function of the lipids. Endocannabinoids are very similar to phytocannabionoids in cannabis (marijuana); they both act on the same receptors to increase appetite, elevate mood, increase immune activity, and decrease memory. This is why cannabis is used for MS and cancer patients.

A study from 2011 shows that blood endocannabinoids, especially AEA, go up after intense exercise. This increase stimulates production of brain derived neutrophic factor (BDNF) in the brain. BDNF and serotonin have a reciprocal effect; each raises the level of the other (see picture below). BDNF also stimulates neurogenesis (more on this in 2 weeks) which can be important in mood, since 50% of female depressives are seen to have a smaller than normal hypothalamus. The effect of AEA after exercise on long term mood and outlook takes just long enough for neurogenesis to begin.

Endocannabinoids also reduce nociceptive (noci = unpleasant) inputs, so your pain tolerance goes up with exercise. A 2013 study showed that exercise-induced increases in endocannabinoids increased rats tolerance for nociceptive stimuli, either by mechanical means or through heat. This is similar to how endorphins mimic opioids (like morphine) to create analgesia.

Brain derived neurotropic factor (BDNF) plays a central role
in depression. With increased stress you get more cortisol (a
glucocrticoid) which drives down BDNF and this increases
neuron die back and loss. This is why some people have a
reduced hypothalamus during depression. On the right, you
can see the loop by which increased BDNF drives serotonin
production and serotonin then drives BDNF production. Your
brain wants you to be happy.

Endorphins (endo = internal, and orphine is from morphine) are produced in the pituitary and released into the bloodstream. They interact with opioid receptors on neurons to induce analgesia (an = no, and gesia = feeling), just like morphine. Endorphins are released in times of stress or pain in body – you know, like when you try running a few miles.

Together, endocannabinoids and endorphins reduce pain and this improves mood. Runner’s high, that feeling of euphoria that is supposed to come from long intense exercise, is reported to come from endorphin release after glycogen stores have been depleted (out of immediate energy). However, the high, if you ever feel it, might actually come from reducing the stress and pain inputs. In this environment, the increased serotonin and dopamine can have bigger "be happy" effects.

This is all a great theory, but there’s one problem. The blood brain barrier (BBB) doesn’t let much of what’s in the blood into the brain. In most of the body, the junctions between the cells that make of the blood vessels are a little leaky. Many large and electrically charged molecules can get through them into the tissue. This would be bad for the brain, since many bad molecules can be in the blood as well, toxins and such. The BBB is an evolution-produced guard for our big brain.

The blood brain barrier keeps potentially damaging
molecules out of the brain tissue. On the left you see a
typical vessel, with loose junctions between the
endothelial cells that line the vessel. On the right is a
vessel in the brain. It has tight junctions to greatly reduce
the passage of molecules, and is surrounded by the ends
of astrocytes (helper cells in the brain) which also
provide another layer of protection. The only way
anything of size is getting through is to have a
dedicated transporter.
The BBB comes from the physical connections between blood vessel cells being very tight (hence the name tight junctions). Basically, unless you are small and can simply diffuse through the endothelial cells or you have a specific transporter – you ain’t gettin’ in.

How could serotonin endocannabinoids or endorphins in the blood, or calcium for dopamine production have effects on your brain if they can’t get in?

There are two answers. 1) Endocannabinoids and endorphins have some of their effects outside the brain. There are receptors for them in the peripheral system, where the painful stimuli might occur. This would work well for preventing pain and noxious stimulus inputs from getting to the brains.

Bikram hot yoga takes you through many poses for
stretching and stress relief. The sessions take place in a
105˚F room that is also humidified. You sweat like a
dog, if dogs sweat a lot. This increased heat may help
loosen the blood brain barrier so mood altering
molecules can enter, but the vast majority of mood
enhancement takes intense cardiovascular activity,
something not provided by the average yoga class.
2) It seems that exercise temporarily increases the permeability of the BBB, so serotonin from blood, Ca, endocannabinoids, endorphins, even blood levels of BDNF can get to the brain and help you be happy. As proof, a brain protein was found in the blood after exercise in a 2013 study, indicating the BBB was disrupted.

The increased permeability may come from exercise-stimulates angiogenesis (angio = blood vessel, and genesis = birth). New blood vessels are built, but new vessels are leakier. It may also be that exercise produces heat, and studies have shown that heat in the brain makes the BBB leakier. This may be why hot yoga participants seem so happy afterward – ask them ‘cause I’m not trying it.

Next week, how exercise helps you to sleep better. And it isn’t from just wearing you out. Believe it or not, your immune system is involved!

For a good resource on the structures of the brain, see Open College's Interactive Brain map.

Galdino G, Romero TR, Silva JF, Aguiar DC, de Paula AM, Cruz JS, Parrella C, Piscitelli F, Duarte ID, Di Marzo V, & Perez AC (2013). The endocannabinoid system mediates aerobic exercise-induced antinociception in rats. Neuropharmacology, 77C, 313-324 PMID: 24148812

Koh SX, & Lee JK (2013). S100B as a Marker for Brain Damage and Blood-Brain Barrier Disruption Following Exercise. Sports medicine (Auckland, N.Z.) PMID: 24194479

Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V, & Meeusen R (2012). Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression. Psychoneuroendocrinology, 37 (6), 844-51 PMID: 22029953

Vučković MG, Li Q, Fisher B, Nacca A, Leahy RM, Walsh JP, Mukherjee J, Williams C, Jakowec MW, Petzinger GM. (2010). Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [¹⁸F]fallypride. Movement Disorders, 25 (16), 2777-2784 DOI: 10.1002/mds.23407

Puterman E, Lin J, Blackburn E, O'Donovan A, Adler N, & Epel E (2010). The power of exercise: buffering the effect of chronic stress on telomere length. PloS one, 5 (5) PMID: 20520771

For more information or classroom activities, see:

Monoamine neurotransmitters –

Exercise and mood –

Blood brain barrier –

Endocannabinoids –

Endorphins -