Clogged Synapses: better call the mailman (or have a shut eye)

Sleep is fundamental for our brain.

Our ability to learn and memorize new things profits from sleep; and, sleep loss leads to cognitive impairment that can only be reversed by closing our eyes and sleeping1. The more time we spend awake, and the further we engage with learning activities, the more our brains will demand for sleep. 

The synapse is the structure that allows the neuron (or nerve cell) to pass an electrical or chemical signal to another neuron, or to the end effector cell that produces the action demanded from our brain. Synapses are the foundation of neuronal plasticity, and, in the adult brain, synapses can change their strength and size within minutes or hours in response to a new experience and learning1. Recent research has shown that the need for sleep and synaptic function are strongly linked together.

Sarah B. Noya and her colleagues2 from the Institute of Pharmacology and Toxicology of the University of Zürich (Switzerland) have recently shown that 70% of the synaptic transcripts change during our 24h circadian cycles. The transcripts and proteins related to synaptic signaling, accumulate before the active phase of the bodies and get further cleared out during the day.  In the meantime, proteins that are associated with the body metabolism and translation, accumulate in the synapses just before the resting phase or sleeping time. As such, just before we go to bed, the synapses get congested with protein information from our bodies daily function, that needs to be compartmentalized and processed.

We can imagine the synapses as a clerk’s room filling up with boxes and parcels that need to be deliver to the proper address.

But what is interesting, is the result that comes from another study published at the same time, from Franziska Brüning and her team3 at the Institute of Medical Psychology of the Ludwig Maximilian University of Munich (Germany). This research study shows that sleep deprivation abolishes nearly all of the compartmentalization of these accumulating proteins at the synapses (98%); which means that, without a proper shut eye, the synapses get completely clogged with accumulating “protein-parcels” that don’t get removed. When a chemical or electrical information wants to get through the synapses the next day, it can’t because there’s accumulating protein transcripts that haven’t been properly processed, or phosphorylated. The information gets stalled, due to the congestion at the synapses.

So, next time your brain feels fizzle in the morning, and throughput the day; promise yourself (and your brain) to go to bed early, and have a proper night’s rest!

Compartmentalization of your synapses
Compartmentalization!

References:

1.         Cirelli C and Tononi G. Linking the need to sleep with synaptic function. Science. 2019;366:189-190.

2.         Noya SB, Colameo D, Bruning F, Spinnler A, Mircsof D, Opitz L, Mann M, Tyagarajan SK, Robles MS and Brown SA. The forebrain synaptic transcriptome is organized by clocks but its proteome is driven by sleep. Science. 2019;366.

3.         Bruning F, Noya SB, Bange T, Koutsouli S, Rudolph JD, Tyagarajan SK, Cox J, Mann M, Brown SA and Robles MS. Sleep-wake cycles drive daily dynamics of synaptic phosphorylation. Science. 2019;366.

Stroke or heart infarct?

According to a recent study by Daghlas and colleagues1, compared to sleeping 6 to 9 h/night, short sleepers have a 20% higher risk of having a heart attack; but, if you are a long sleeper (i.e., sleeping >9h/night), than your chances are even worse, because your risk increases to 34%. Even though the researchers don’t know the underlying cause for such susceptibilities, they claim sleeping too much or too little boosts inflammation in the body, which is associated with the development of heart disease. If you have a genetic predisposition for heart disease, this study found that sleeping between 6-9h, actually reduces your risk of having a heart attack by 18%, which is actually very good news, since not only diet and exercise can help you keep your heart healthy. More and more data, supports the evidence that we should consider sleep to be an adjustable and controllable risk factor for our good heath status2.

Speaking of diet, another study published recently in the Journal of the American Heart Association by Hyunju Kim and his team3, showed that healthy plant‐based diets, which are higher in whole grains, fruits, vegetables, nuts, legumes, tea, and coffee, and lower in animal foods, were associated with a lower risk of cardiovascular disease mortality and all‐cause mortality. Of course, they didn’t explore if the quality of plant foods (either healthy plant foods, or less-healthy plant foods) within the “framework of plant‐based diets” would be associated with cardiovascular disease and all‐cause mortality in the general population.

But, what is intriguing is that, another recent study by Tammy Tong and colleagues4, examined the associations of vegetarianism with risks of ischemic heart disease (i.e., coronary artery disease) and stroke. The results of this study showed that vegetarians had 20% higher rates of total stroke than meat eaters – which was equivalent to 3x more cases of stroke over 10 years; and, the associations for stroke did not soothe after adjustments to other disease risk factors. As the authors of the study say, vegetarian and vegan diets have become increasingly popular in recent years, partly due to perceived health benefits, as well as concerns about the environment and animal welfare; but, what the evidence suggests, is that vegetarians might have different disease risks compared with non-vegetarians. The study group of vegetarians and vegans in this cohort had lower circulating levels of several nutrients (e.g., vitamin B12, vitamin D, essential amino acids, and long chain n-3 polyunsaturated fatty acids), and differences in some of these nutritional factors could contribute to the increased stroke risk. Not only that, but a number of studies in Japan5, 6, showed that individuals with very low intake of animal products, also had an increased incidence and mortality from hemorrhagic and total stroke, implying that some factors connected with animal food intake might be protective for stroke. 

Its like Yin and Yang from ancient Chinese philosophy. Rather than opposing, or standing at the sides, our health and life is made of complementary forces that interact to form a dynamic system. It’s all about balance and balancing the sides (and diets).

#Balancing
Balancing life’s way

References:

1.         Daghlas I, Dashti HS, Lane J, Aragam KG, Rutter MK, Saxena R and Vetter C. Sleep Duration and Myocardial Infarction. Journal of the American College of Cardiology. 2019;74:1304-1314.

2.         Tobaldini E, Fiorelli EM, Solbiati M, Costantino G, Nobili L and Montano N. Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. Nat Rev Cardiol. 2019;16:213-224.

3.         Kim H, Caulfield LE, Garcia-Larsen V, Steffen LM, Coresh J and Rebholz CM. Plant-Based Diets Are Associated With a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All-Cause Mortality in a General Population of Middle-Aged Adults. J Am Heart Assoc. 2019;8:e012865.

4.         Tong TYN, Appleby PN, Bradbury KE, Perez-Cornago A, Travis RC, Clarke R and Key TJ. Risks of ischaemic heart disease and stroke in meat eaters, fish eaters, and vegetarians over 18 years of follow-up: results from the prospective EPIC-Oxford study. BMJ. 2019;366:l4897.

5.         Kinjo Y, Beral V, Akiba S, Key T, Mizuno S, Appleby P, Yamaguchi N, Watanabe S and Doll R. Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan. J Epidemiol. 1999;9:268-74.

6.         Sauvaget C, Nagano J, Allen N, Grant EJ and Beral V. Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study. Int J Epidemiol. 2003;32:536-43.

Habenula, the Master of the Brain

The Habenula, is an area of our brains close to the pineal gland, that is involved in pain processing, reproductive behaviour, nutrition, sleep-wake cycles and stress responses, among other things1. A professor I used to know always said the Habenula was the Master of the Brain… and, indeed, recent research has provided evidence that this tiny bundle of nerves is able to produce Dimethyltryptamine (DMT), a psychedelic drug, “cousin” to the famous LySergic acid Diethylamide (LSD). 

DMT is internally bio-synthesized by the enzymes Aromatic-L-Amino acid DeCarboxylase (AADC) and Indolethylamine-N-Methyltransferase (INMT). Dean and colleagues2 were able to identify INMT messenger RNA in human tissues, by using a RNAscope in situ assay system; a highly sensitive technique, which proved for the first time a clear-cut identification of DMT and its enzymes in human brain. 

Outstanding, was the discovery that there was a significant increase of DMT levels in the rat brain after stimulation of experimental cardiac arrest; showing for the first time, that the brain is capable of synthesizing and releasing DMT under stress. 

This ultimately raises the possibility that this phenomenon may also occur in human brains, when we experience situations of extreme stress. The researchers attest that the cardiac arrest-induced increase of DMT may be related to “near-death experiences”, as reported by Timmermann and collegues3. This group recently reported that human subjects given exogenous DMT, experienced “near-death”-like mental states, including the subjective feeling of transcending one’s body and entering an alternative realm, perceiving and communicating with ‘entities’, and themes related to death and dying.

It’s unbelievable that the more we know about how our body and brain functions, the more I realize that our mind is a construction of our organic biological nature.

What we sometimes perceive as a mystical experience is probably just rooted in an organic mechanism that is tricking our minds into a “trip”.

Into the light

References:

1.         Namboodiri VM, Rodriguez-Romaguera J and Stuber GD. The habenula. Curr Biol. 2016;26:R873-R877.

2.         Jon G. Dean TL, Sean Huff, Ben Sheler, Steven A. Barker, Rick J. Strassman, Michael M. Wang & Jimo Borjigin Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain. Scientific Reports. 2019;9.

3.         Timmermann C, Roseman L, Williams L, Erritzoe D, Martial C, Cassol H, Laureys S, Nutt D and Carhart-Harris R. DMT Models the Near-Death Experience. Front Psychol. 2018;9:1424.

Underwater banquet!

Cabal, is a term defined in the Merriam-Webster dictionary, as the contrived scheme of a group of persons secretly united in a plot (as to overturn a government, for example). 

But, if you talk in terms of Biology, cabals are also a series of synergistic venom peptides essential for the capture of prey. One animal venom can be a complex mixture of 10-200+ short chains of amino acids linked by bonds (peptides), working in a concerted mode to regulate physiological function, with very potent and precise molecular targets1.

For example, cone snails, a small venomous marine mollusk that hunts fish and worms, has ~850 species identified, with each expressing many thousands of unique peptides that selectively target a diverse range of voltage- and ligand-gated ion-channels, transporters and G-protein couple receptors2

These tiny wonders of nature have the ability to switch between predatory and defensive venom regimes. For example, if they just want to stunt a predator causing a flaccid paralysis, they will produce venom that has high levels of muscle blockers (motor cabal), and that inhibit sodium channels and nicotinic acetylcholine receptors. But, if in the mean time, they change their minds and intend to eat the prey, they use a combination of peptides that cause a rigid paralysis. This lightning-strike cabal has excitatory peptides that inhibit potassium channels and delay inactivation of sodium channels, causing the prey to lie “dead” until it is happily digested in an underwater banquet.

But, how does the cone snail decide whether it is fear or hunger that it’s “feeling” in that moment?

The simple neuronal circuit of the cone snail shifts from a contented state of inertia, to an active motion, stimulated by internal hunger and an appetite stimulus – just like us, slushing from the couch to the fridge looking for our night prey… The hunting activity of the Conus is then organized by a basic set of behavioral transitions. Once the cone snail detects a fish, through sensory signals, it becomes much more active and moves towards the fish extending its rostrum– a massive funnel formed by the muscular walls of the snail sheath; and, a long, thin trunk extends out in the open, where a harpoon-like tooth shoots out to pierce the skin of the fish3 – imagine if we could actually do the same to that bag of cookies that is lying in the shelve right next to the couch.

The active feeding of the cone snail tends to inhibit the avoidance, and the snail changes to a prevention mood once its appetite is satisfied4

Cone snail
Cone snail

Reference:

1.         Angell Y, Holford M and Moos WH. Building on Success: A Bright Future for Peptide Therapeutics. Protein Pept Lett. 2018;25:1044-1050.

2.         Himaya SWA, Mari F and Lewis RJ. Accelerated proteomic visualization of individual predatory venoms of Conus purpurascens reveals separately evolved predation-evoked venom cabals. Sci Rep. 2018;8:330.

3.         Olivera BM, Seger J, Horvath MP and Fedosov AE. Prey-Capture Strategies of Fish-Hunting Cone Snails: Behavior, Neurobiology and Evolution. Brain Behav Evol. 2015;86:58-74.

4.         Gillette R and Brown JW. The Sea Slug, Pleurobranchaea californica: A Signpost Species in the Evolution of Complex Nervous Systems and Behavior. Integr Comp Biol. 2015;55:1058-69.

Alcohol or Melatonin?

In 1958, in the Yale laboratories, A.B. Lerner and colleagues isolated melatonin from the pineal gland of bovines1. They were surprised that after 40 years of research they had finally found the active component that lightened the frog skin color, inhibiting the darkening effect of the Melanocyte Stimulating Hormone (MSH); hence the name, Melatonin1. Disappointingly, the skin lightening properties of melatonin could not be further demonstrated and the project was abandoned2. In the 90’s, melatonin got back on the coolness charts of science, with Reppert and Weaver calling it “Madness” in a Cell article in 1995. During this time, it was discovered its function in regulating the seasonal and circadian rhythms3, the presence of its specific G-coupled receptors in different tissues4; and, its antioxidant properties5. Since then, melatonin has been widely studied and continues to wonder over its broad range of therapeutic effects. From helping on jet-lag relief6, with insomnia7, being an anti-aging agent8, neuro-protective9, and also, improving cardiovascular diseases10: melatonin-madness continues until today.

Melatonin is widely accepted as a nutritional supplement being prescribed for sleep regulation in jetlag and adult sleep disorders; but in 2011 the U.S.A Food and Drug Administration (FDA), issued a warning to a company selling “relaxation brownies”, stating that the synthetic melatonin used in them hasn’t been proved safe as a food additive. Most commercial products are offered at dosages of 1-3mg of melatonin, which causes a spike of melatonin in the blood, reaching much higher levels than those that are naturally produced in the body somewhere between 50 and 200 pg/mL.

But, why use synthetic melatonin when this molecule is present in appetizing plants, nuts, fruits, meats, beverages and other foods11? The levels of melatonin in foods are much lower than those given as a nutritional supplement; but it has been proven that eating such foods drastically increases the circulating melatonin levels in the range of physiological concentrations, which peak at nighttime12, 13.

Maldonado and colleagues have shown that different types of beers are rich in melatonin; and, the more melatonin they have got, the greater is their alcoholic degree14. No wonder some people claim that beer makes them sleepy. But, Molfino15and I have made the same question: if the volunteers were sleepy, was it because of the melatonin or an alcoholic-mediated effect? So far, there’s still no answer to that question.

But, Garcia-Moreno and Maldonado’s group have shown, that Barley, which is malted and grounded in the early brewing process, and Yeast, during the second fermentation, are the largest contributors to the enrichment of beer with melatonin16. From this, we can deduct that not only beer has melatonin, but whatever drink where fermentation occurs, will also be rich in it. Logically, wine was also found to be a rich source of the Madness-molecule. In fact, beer has around 0,09 ng/mL while wine is up to 129,5 ng/mL11. And again, Rodriguez-Naranjo and colleagues showed that melatonin is formed during the alcoholic fermentation, because it is absent in the grapes and musts17.

 

References:

    1. Lerner ABC, J.D.; Takahashi, Y.; Lee, T.H.; Mori, W. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587.
    2. Jiki Z, Lecour S and Nduhirabandi F. Cardiovascular Benefits of Dietary Melatonin: A Myth or a Reality? Front Physiol. 2018;9:528.
    3. Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod. 1998;3:13-22.
    4. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA and Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A. 1995;92:8734-8.
    5. Hardeland R, Reiter RJ, Poeggeler B and Tan DX. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev. 1993;17:347-57.
    6. Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, Gwini SM, Bartlett DJ, Lockley SW, Lack LC, Grunstein RR, Rajaratnam SMW and Delayed Sleep on Melatonin Study G. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial. PLoS Med. 2018;15:e1002587.
    7. Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG, Espie CA, Garcia-Borreguero D, Gjerstad M, Goncalves M, Hertenstein E, Jansson-Frojmark M, Jennum PJ, Leger D, Nissen C, Parrino L, Paunio T, Pevernagie D, Verbraecken J, Weess HG, Wichniak A, Zavalko I, Arnardottir ES, Deleanu OC, Strazisar B, Zoetmulder M and Spiegelhalder K. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26:675-700.
    8. Day D, Burgess CM and Kircik LH. Assessing the Potential Role for Topical Melatonin in an Antiaging Skin Regimen. J Drugs Dermatol. 2018;17:966-969.
    9. Zhao Z, Lu C, Li T, Wang W, Ye W, Zeng R, Ni L, Lai Z, Wang X and Liu C. The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: in vivo assessment and a randomized controlled trial. J Pineal Res. 2018:e12521.
    10. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, Tu S, Wang D, Li L, Dong JZ, Gao L and Yang HB. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-221.
    11. Meng X, Li Y, Li S, Zhou Y, Gan RY, Xu DP and Li HB. Dietary Sources and Bioactivities of Melatonin. Nutrients. 2017;9.
    12. Sae-Teaw M, Johns J, Johns NP and Subongkot S. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers. J Pineal Res. 2013;55:58-64.
    13. Reiter RJ, Manchester LC and Tan DX. Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood. Nutrition. 2005;21:920-4.
    14. Maldonado MD, Moreno H and Calvo JR. Melatonin present in beer contributes to increase the levels of melatonin and antioxidant capacity of the human serum. Clin Nutr. 2009;28:188-91.
    15. Molfino A, Laviano A and Rossi Fanelli F. Sleep-inducing effect of beer: a melatonin- or alcohol-mediated effect? Clin Nutr. 2010;29:272.
    16. Garcia-Moreno H, Calvo JR and Maldonado MD. High levels of melatonin generated during the brewing process. J Pineal Res. 2013;55:26-30.
    17. Rodriguez-Naranjo MI, Gil-Izquierdo A, Troncoso AM, Cantos-Villar E and Garcia-Parrilla MC. Melatonin is synthesised by yeast during alcoholic fermentation in wines. Food Chem. 2011;126:1608-13.

 

 

Evolution and melatonin

Since life has emerged on Earth, 3.7. billion years ago, the rising and setting of the Sun has been a constant. Whether it was light or dark, it was day or night. Humans, and all other organisms, have evolved with this imposed biological rhythm; and, human physiology was determined by the light/dark cycle.

Every cell in our bodies exhibits a circadian rhythm, a 24h-cycle synchronized to a light/dark pattern. But, how do cells deep inside in our bodies know when it’s dark outside? The answer to that question is Melatonin (N-acetyl-5-methoxytryptamine), the messenger from our brain to communicate to our cells that it is dark. The master clock of the body, the Suprachiasmatic Nucleus (SCN) receives darkness information from the retina and sends it to the brain. From there it provides an input to the Pineal Gland, to produce melatonin. Melatonin secretion increases in the evening, and is stimulated by darkness; whereas light rapidly suppresses melatonin production.

Melatonin is not unique to humans. It is spread through out the animal kingdom, plants, bacteria, and even unicellular organisms have it. There’s no species that has been identified so far that does not contain Melatonin. This expresses the importance of this molecule to life.