Endocannabinoids, retrograde signaling, and learning.

The endocannabinoid system is involved in our ability to learn. Use of medical marijuana, in quantity, is known to reduce short term memory but it may also be helping the body form long term memories. However our natural endocannabinoid system wouldn’t primarily use the equivalent to the euphoria forming THC called anandamide. That is used to reduce nerve cell signaling. It is the non euphoria causing 2AG that is used within our brains to cause stronger nerve cell signals – practice more and the cells are more active in a certain order and that pathway is strengthened so next the cells will fire in that order more easily. (Endocannabinoids Performance through Retrograde Signaling).

More information about nerve signaling between brain cell synapses see Neuroscience, 6th Edition, pages 85-112, 169-189, and 571-593, (1), or summary information and short video explanations are available online for the previous edition: Synaptic Transmission, Synaptic Plasticity, Modification of Brain Circuits as a Result of Experience.

2AG is more similar to the non-euphoric cannabidiol (CBD) that is found in varying amounts in certain strains of medical marijuana. Both 2AG and CBD can activate both the Cannabinoid Receptor 1 and the Cannabinoid Receptor 2. It can have pain relieving and anxiety relieving benefits. (About the Endocannabinoid System)

Phospholipids and cannabinoids can be found in some legally and commonly available foods in addition to medical marijuana or the non-euphoric hemp kernel or hemp seed oil. See this post for more information about the nutrient group and other important nutrients, our bodies need all or most of them on a daily basis: Macro- and Micro-nutrients: Description and Food Sources.

Happy learning!

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

  1. Reference: pp 169-189 “Synaptic Plasticity“, pp 571-593 “Experience-Dependent Plasticity in the Developing Brain“, pp 85-112, “Synaptic Transmission,” Neuroscience, 6th Edition, Editors D. Purves, G.J. Augustine, D. Fitzpatrick, W.C. Hall, A.S. LaMantia, R.D. Mooney, ML. Platt, L.E. White, (Sinauer Associates, Oxford University Press, 2018, New York) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326841/ (Barnes&Noble)

Glymphatic system – yes- sleep helps protect against Alzheimer’s dementia

Following up on Friday’s easy answer day (previous post) – yes, the glymphatic system of the brain does help protect against Alzheimer’s dementia, (7, 8, 14, 17), and sleep, especially one of the deeper stages of sleep (low-delta), is important. (10, 11, 13) Sleeping on your right side may help promote better fluid drainage through the glymphatic system of the brain (sleeping on your right side puts the left side of your body with your heart farther up above the rest of your body, a pillow between your knees and a neck support may also help). (Social media link, reference source: Neurology Reviews, 2) (12) The circulation by the heart can help move fluid through the brain but only indirectly due to the on/off pressure of the arterial pulse. The regular lymphatic system of the body is a drainage system for the brain fluid system but the blood brain barrier prevents direct interaction. Specialized water pumps in some types of brain glial cells help provide circulation within the brain by pumping water in two directions within the second layer of thick membranes that separate the soft brain tissue from the bony skull. (3)(4)(15)(16)

Overall the fluid within the brain does circulate and there is a visible, small, pulsing movement that has been amplified and can be observed in a video: (5). The spread of a dye within the brain can be observed in a different type of brain scan, the fluid diffusion is not rapid taking 24 hours to reach a maximal point, and the movement of the dye was most prevalent (see color chart) near the skull: (6). The glymphatic system as defined as the specialized glial cells with water pump channels is located in the area near the skull. (4) Diffusion of fluid throughout deeper areas of the brain where the blood brain barrier is not found can occur to a small extent through membranes. (9)

Exercise may also help the glymphatic system function better. (18) The lymphatic vessels and lymph nodes in the neck are the initial drainage route for the glymphatic system cleansing of the various fluid filled areas of the brain. Stretching exercises and rhythmic walking type exercise can help move lymphatic fluid from farther areas of the body to the torso and urinary system for eventual excretion.

Small amounts of alcohol – one third of a serving; to moderate – one or two servings per day (too much may not be helpful); may help the detoxification of the brain fluid by mechanisms that are not well understood yet but which seem to involve the glymphatic system. (19, 20) The mechanism may involve the effect of alcohol on GABA receptors, it can activate them which in general would have a calming/inhibitory effect, (23), however GABA receptors also are involved in promoting more production of the water pump Aqaporin 4 channels in neural stem cells within the subependymal zone. (24) The subependymal zone is in the lateral part of the lateral ventricle which is a cerebrospinal fluid filled area near the center of the brain, (27), which is involved in fluid balance and drainage of the glymphatic system. (25) GABA receptors are also involved with flow of chloride ions across membranes (for an inhibitory effect on nerve signaling, (pp 126-131, 1), and affect fluid balance in areas of the brain without the blood brain barrier which makes diffusion of water across the brain membranes more possible. (26)

Alcohol also inhibits the action of the excitatory neurotransmitter glutamate, particularly at the NMDA receptor, (23), which is an excitatory ion channel and also allows calcium to enter the cell where the mineral can activate many functions within the cell. (pp 120-126, 1) If drinking alcohol is not preferred or legal due to age or advised due to pregnancy or possibility of becoming pregnant then GABA (gamma-aminobutyric acid) is available as an over the counter supplement, typically in a form that melts in the mouth to promote more direct absorption. While it is not typically referred to as an amino acid due to its role as a neurotransmitter, it is simply an amino acid, a smaller molecule from which proteins can be formed. The level of GABA a has been found to be reduced in the brains of patients with severe Alzheimer’s Disease and its use as a treatment has been studied, (29), levels in other abnormal brain cells were found to be elevated in a specific area of the brain of patients with Alzheimer’s Disease and treatment to increase transport of GABA has also been studied. (30)

Or sleep, in the form of a short nap, may also help promote GABA. Naps may benefit our health in part because of a beneficial effect on GABA promotion by increased glymphatic action in the brain – twenty minutes of sleep may be adequate. (28)

An overview of the glymphatic system and lifestyle and dietary tactics that might improve its function are described in a video by a nutritionist: (21); and also in a self-help style article by a different person: (22).

Some types of magnesium supplements including magnesium threonate may also help. Magnesium within the brain has many functions including inhibiting the NMDA glutamate receptor which would prevent excess calcium from entering the cell. (pp 120-126, 1)

We tend to hear about neurotransmitters such as serotonin for depression or dopamine and Parkinson’s disease, yet we rarely hear that calcium is the mineral that signals the release of both of those and over one hundred other neurotransmitters that are involved in nerve signals within the brain or throughout the body (page 85, 1.Neuroscience, 6th Ed.). Neurotransmitters include excitatory and inhibitory chemicals and they activate or inhibit the firing of a nerve signal. GABA can be a calming/inhibitory neurotransmitter that may be low when anxiety is a problem. Magnesium is the mineral inside cells which helps control how much calcium will be allowed to enter. Excess calcium can cause excess release of neurotransmitters. Magnesium deficiency can also be involved when anxiety is a symptom.

Adequate fluid is also likely important for adequate cleansing of waste from the brain by the glymphatic system. Problems with edema/swelling in other areas of the body or problems with hypertension may indicate problems with the lymphatic system in general. Moderate exercise helps the muscle power of movement also move extracellular fluid and lymphatic fluid through the lymphatic vessels to lymph nodes to be filtered by blood cells. Waste is removed into blood vessels for later excretion by the kidneys.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326841/Reference: pp 85-112, “Synaptic Transmission,” Neuroscience, 6th Edition, Editors D. Purves, G.J. Augustine, D. Fitzpatrick, W.C. Hall, A.S. LaMantia, R.D. Mooney, ML. Platt, L.E. White, (Sinauer Associates, Oxford University Press, 2018, New York) (Barnes&Noble)
  2. Glymphatic System May Play Key Role in Removing Brain Waste, Neurology Reviews, 2016 October;24(10):13   https://www.mdedge.com/neurologyreviews/article/114150/alzheimers-cognition/glymphatic-system-may-play-key-role-removing
  3. Understanding the Glymphatic System, Neuronline, adapted from the SfN Short Course The Glymphatic System by Nadia Aalling, MSc, Anne Sofie Finmann Munk, BSc, Iben Lundgaard, PhD, and Maiken Nedergaard, MD, DMSc http://neuronline.sfn.org/Articles/Scientific-Research/2018/Understanding-the-Glymphatic-System
  4. Tsutomu Nakada, Ingrid L. Kwee, Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and Cerebrospinal Fluid Circulation in the Brain. The Neuroscientist, May 24, 2018, http://journals.sagepub.com/doi/10.1177/1073858418775027#articleCitationDownloadContainer
  5. Bruce Goldman, The beating brain: A video captures the organ’s rhythmic pulsations. Scope, Stanford Medicine, July 5, 2018, https://scopeblog.stanford.edu/2018/07/05/the-beating-brain-a-video-captures-the-organs-rhythmic-pulsations/?linkId=53912604
  6. Geir Ringstad, Lars M. Valnes, Anders M. Dale, et al., Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight. 2018;3(13):e121537 https://insight.jci.org/articles/view/121537?utm_content=buffer13f62&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer
  7. Brain discovery could block aging’s terrible toll on the mind. University of Virginia Health System, EurekAlert! Science News, July 25, 2018, https://www.eurekalert.org/pub_releases/2018-07/uovh-bdc072518.php
  8. Da Mesquita S., Louveau A., Vaccari A., et al., Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease, Nature, 185,191, Vol 560, Issue 7717, 2018/08/01. https://www.nature.com/articles/s41586-018-0368-8
  9. Albargothy N. J., Johnston D. A., MacGregor‑Sharp M., Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathologica (2018) 136:139–152 https://link.springer.com/epdf/10.1007/s00401-018-1862-7?shared_access_token=oYhOYaeYOAlkFhECIjAc6Pe4RwlQNchNByi7wbcMAY7lrBk-VqU01OilsaKMVR9FXaHRKmFQ1tkD03g-Q04DmsYSxRC_gucPZRYlFW0xfyU2pYNfhmwcokVbMCreuzU3wBLsjKpRasKo-6HXTJLMHNXMqFbaSsQVIB34EgzIUsc%3D
  10. Tamara Bhandari, Lack of Sleep Boosts Levels of Alzheimer’s Proteins, The Source, Washington University in St. Louis, Dec. 27, 2017, https://source.wustl.edu/2017/12/lack-sleep-boosts-levels-alzheimers-proteins/
  11. Yo-El S Ju, Sharon J Ooms, Courtney Sutphen, et al., Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain, Vol 140, Issue 8, 1 August 2017, Pages 2104–2111, Oxford Academic, https://academic.oup.com/brain/article/140/8/2104/3933862
  12. Krista Burns, American Posture Institute: Proper Sleeping Posture for ‘Brain Drain,’ April 5, 2017, https://americanpostureinstitute.com/proper-sleeping-posture-for-brain-drain/
  13. Patricia Farrell, Sleep: Everyone Needs It and So Do You, March 16, 2017, https://www.amazon.com/dp/152061294X
  14. Melanie D. Sweeney, Berislav V. Zlokovic, A lymphatic waste-disposal system implicated in Alzheimer’s disease. July 25, 2018, https://www.nature.com/articles/d41586-018-05763-0?utm_source=twt_na&utm_medium=social&utm_campaign=NNPnature
  15. Nadia Aalling Jessen, Anne Sofie Finmann Munk, Iben Lundgaard, Maiken Nedergaard, The Glymphatic System – A Beginners Guide, Neurochem Res. 2015 Dec; 40(12): 2583–2599. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636982/
  16. Maiken Nedergaard, Steven A. Goldman, Brain Drain, Sci Am. 2016 Mar; 314(3): 44–49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347443/
  17. Rainey-Smith S. R., Mazzucchelli G. N., Villimagne V. L., et al. Genetic Variation in Aquaporin-4 Moderates the Relationship Between Sleep and Brain Aβ-amyloid burden. Translational  Psychiatry, (2018) 8:47 https://www.nature.com/articles/s41398-018-0094-x.epdf?author_access_token=iK09AkugOzYXUjXJCpGfIdRgN0jAjWel9jnR3ZoTv0P4SU0l7P8A1C64dg2xJ-HX7jlpuvyMeHzBYm6I5D0yMRBsx023MtG5Y3KNpj4EoNEqA4ELFuByqeysfTCRKZdGegxohMN9WLBb_S6H0UZYpw%3D%3D
  18. Brown B., Rainey-Smith S. R., Dore V., et al., Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. Journal of Alzheimer’s Disease, vol. 63, no. 4, pp. 1299-1305, May 30, 2018 https://content.iospress.com/articles/journal-of-alzheimers-disease/jad170998
  19. Chloe Chaplain, Drinking wine every day could help prevent Alzheimer’s, experts say. London Evening Standard, June 6, 2018, https://www.standard.co.uk/news/health/drinking-wine-every-day-could-help-prevent-alzheimers-experts-say-a3856646.html
  20. In Wine, There’s Health: Low Levels of Alcohol Good for the Brain. Feb. 2, 2018, University of Rochester Medical Center, https://www.urmc.rochester.edu/news/story/5268/in-wine-theres-health-low-levels-of-alcohol-good-for-the-brain.aspx
  21. Brianna Diorio, Glymphatic System 101, video,August 8, 2018,  https://vimeo.com/283708099?ref=tw-share
  22. Sydney, How To Detox Your Brain By Hacking Your Glymphatic System. A Healthy Body, May 18, 2018, http://www.a-healthy-body.com/how-to-detox-your-brain-by-hacking-your-glymphatic-system/
  23. The Effects of Alcohol on the Brain, The Scripps Research Institute, https://www.scripps.edu/newsandviews/e_20020225/koob2.html
  24. Li Y, Schmidt-Edelkraut U, Poetz F, et al. γ-Aminobutyric A Receptor (GABAAR) Regulates Aquaporin 4 Expression in the Subependymal Zone: RELEVANCE TO NEURAL PRECURSORS AND WATER EXCHANGE. The Journal of Biological Chemistry. 2015;290(7):4343-4355. doi:10.1074/jbc.M114.618686. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326841/ (24)
  25. Plog BA, Nedergaard M. The glymphatic system in CNS health and disease: past, present and future. Annual review of pathology. 2018;13:379-394. doi:10.1146/annurev-pathol-051217-111018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803388/ (25)
  26. Cesetti Tiziana, Ciccolini Francesca, Li Yuting, GABA Not Only a Neurotransmitter: Osmotic Regulation by GABAAR Signaling. Frontiers in Cellular Neuroscience, Vol. 6, 2012, https://www.frontiersin.org/article/10.3389/fncel.2012.00003 DOI=10.3389/fncel.2012.00003 ISSN=1662-5102 (26)
  27. Kazanis I. The subependymal zone neurogenic niche: a beating heart in the centre of the brain: How plastic is adult neurogenesis? Opportunities for therapy and questions to be addressed. Brain. 2009;132(11):2909-2921. doi:10.1093/brain/awp237. (27)
  28. Robert I Henkin, Mona Abdelmeguid, Sleep, glymphatic activation and phantosmia inhibition. The FASEB Journal, Vol 31, No. 1_supplement, April 2017, https://www.fasebj.org/doi/abs/10.1096/fasebj.31.1_supplement.749.4  (28)
  29. Solas M, Puerta E, Ramirez MJ. Treatment Options in Alzheimer’s Disease: The GABA Story., Curr Pharm Des. 2015;21(34):4960-71. https://www.ncbi.nlm.nih.gov/pubmed/26365140 (29)
  30. Zheng Wu, Ziyuan Guo, Marla Gearing, Gong Chen, Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model. Nature Communications, 5,  Article number: 4159 (2014) https://www.nature.com/articles/ncomms5159 (30)

Glymphatic system; easy answer Friday

Friday is the best day of the week for an easy question – so is glymphatic a word? Yes. It is a specialized form of the lymphatic system which exists in the brain to help with fluid flow between areas of the brain and from intracellular areas to the blood vessels. The g is added to refer to fact that glial type of brain cells work in combination with the brain’s lymphatic system – making it the glymphatic system. (pp 844-846, Neuroscience, 6th Ed.)

Slightly more interesting and more difficult easy question/answer – turns out the glymphatic system is most active while we sleep. The brain tissue shrinks quite a bit during sleep allowing easier fluid flow and likely facilitating movement of nutrients to the brain cells and removal of toxins from them. Since exercise and sleep are both linked to better health of myelin – more regeneration/less demyelination – is it likely that the better function of the glymphatic system is involved? — Probably but I have to read more about that idea. I just thought of it and likely others have thought of it before me and written medical papers about it but I only just learned of the glymphatic system today. (I enjoy words and health.)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference: pp 844-846, Neuroscience, 6th Edition, Editors D. Purves, G.J. Augustine, D. Fitzpatrick, W.C. Hall, A.S. LaMantia, R.D. Mooney, ML. Platt, L.E. White, (Sinauer Associates, Oxford University Press, 2018, New York) (Barnes&Noble)