Degenerative protein aggregates: a whole body view

A few weeks ago, Vivian wrote a post about prion disease, discussing how understanding the mechanisms of Kuru could help us design treatments for other neurodegenerative disorders characterized by protein aggregations. The accumulation of protein as a pathological process has also been investigted outside the brain. Aging and degeneration are complex system-wide phenomena and studies like the one by Demontis and Perrimon (2011) show that by looking outside the brain we can unveil new whole-body regulatory mechanisms for neurodegeneration.

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What does cocaine do in the brain?

Not all drugs can completely change who we are. Cocaine is one of the few with this power. Like many other psychoactive drugs, cocaine was first used as an anesthetic, but its potential effect on one’s mind and will was soon discovered and overshadowed its original usage. Cocaine’s power does not lie within the molecule itself, but rather in its interaction with the brain’s reward system (see a previous TBT post for the discovery of this system).

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The winter blues: Is it all in your head?

“February is my favorite month.” said no one living in Boston ever. The short days, cold temperatures, and repetitive snow really throw a dagger (presumably made of ice) into good times. I tend to think of Dec-Feb as my hibernating months; I am more lethargic, less motivated, and my fiancé and labmates can vouch for the fact that I am slightly more irritable than the good natured loving person I always am in better weather.  I’ve come to attribute my noticeable seasonal downswing to Seasonal Affective Disorder, or SAD (an acronym that ironically makes me quite happy), a self-diagnosis I probably made from seeing a commercial. Being the curious graduate student that I am I decided to do a little research on the subject and see what I could learn—really trying to go above and beyond what pharmaceutical advertising taught me.

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The neuroscience behind mindfulness

Mindfulness is currently a very hot topic. It seems like every health website, magazine and newspaper is touting the benefits of meditation and yoga practices. Wired posted an article on how meditation can calm the anxious mind and help one manage emotions, Shape magazine relays that meditation can provide greater pain relief than morphine, while many other articles convey that mindfulness will help with weight loss, sleep, disordered eating, and even addiction. Amidst all of the articles promoting mindfulness we also see the backlash—a New York Times op-ed from October 2015 calls for us to take a step back and remember that mindfulness has not been proven to be the panacea to our society.  Personally, as a stressed out graduate student, I wonder if a mindfulness practice would increase my happiness and well-being, and as a neuroscientist I wonder what is true and how does it work, so I recently attended a lecture on the topic given by Dr. Sara Lazar, who works at Harvard Medical School and Mass General Hospital as a leading neuroscientist in the field of meditation.

Dr. Lazar started her “Neural Mechanisms of Mindfulness” lecture with the basics. She defined stress as wanting or expecting things to be different than they actually are, and offered the simple idea that the key to reducing stress is to understand and accept things as they actually are. This acceptance involves making your expectations realistic, acknowledging the imperfection of situations, and finally, knowing that right now in this very moment everything is okay. The last point is indeed, what mindfulness meditation is. Noting that there are many types of mindfulness techniques, Dr. Lazar clarified what she means by mindfulness meditation, telling us it is the practice conscious awareness of the moment—accomplished by focusing on your breath and on the primary sensations you are experiencing, without any judgement of those sensations. The above points show a logical reasoning for why mindfulness meditation could help reduce stress, but what is the neurological evidence? How can scientists prove that one mental behavior is changing your state of mind?

The Lazar research group tackled this question by recruiting people who had never meditated before and splitting them up into two groups: one experimental group had an 8 week mindfulness meditation intervention, and the other control group did not. The 8 week experimental group had a weekly meditation class and a recommended 40 minutes a day of meditation while the control group did not go through the mindfulness classes or meditate at all; thus the study aimed to measure meditation specific effects. The design of this experiment was crucial because (as is the case with any scientific study) without a control group for comparison it is near impossible to make any conclusions about how the experimental conditions are affecting the experimental . At the end of the 8 weeks, the team studied the differences in amount of gray matter within the brains of each person by using fMRI neuroimaging techniques. The participants’ brains were imaged before and after the 8 week duration of the experiment. The results showed that people who practiced mindfulness mediation (but not the control group) had increased their gray matter (compared to their own baseline) in four different regions:  the posterior cingulate (associated with mind-wandering and self-relevance), left hippocampus (important for learning and memory), temporo parietal junction (helps with perspective taking, empathy and compassion), and pons (aids in communication between brain stem and cortex as well as sleep ).  These areas are varied in function (hence the links to explore for yourself!) but to generalize, it appears that meditation is changing the brain in places that are important for focus, empathy and compassion, and emotional regulation. The researchers also reported decreased amgydala gray matter; a brain region associated with fear and perceived stress. [side note: increase in gray matter means an increase in cell body size or dendrite arborization and vice versa for decrease, so it is not a perfect measurement of increasing the function of the area but rather an indirect indication that the area may be more active]  What is solid about this study is that it correlates change in brain structure with the reports from the participants in the study. The group who underwent mindfulness training reported decreased stress, anxiety, mind-wandering and insomnia, as well as increased quality of life as compared to those who did not practice meditation. To make the correlation a little stronger, the researchers also measured cortisol, a stress hormone, and found decreased levels of cortisol within the participants who underwent mindfulness meditation intervention.

holzel

Beyond this initial study,1 Dr. Lazar’s lab has continued to elucidate the neural mechanisms behind self-reported effects of mindfulness mediation. Their group has found that mindfulness meditation decreases bipolar2 and general anxiety disorder symptoms3, and have proposed that increased gray matter in the pons may be the area underlying reports of increased psychological well-being4. This correlation of brain regions with participant self-reporting, using proper controls and a consistent method of mindfulness mediation, really seems to be a good way to begin to understand how we can use our minds to help heal our own minds. The stressed graduate student part of me is convinced enough to give mindfulness mediation a try, and the neuroscientist part of me is excited to see what further investigation tells us as the field continues to ask how quieting our thoughts can alter our brains and even our bodies5.

Dr. Lazar stressed in her lecture that meditation should really be learned properly, as it can be very hard for us to change our state of minds. Meditation is not simply sitting in silence, but is instead a “state of open, nonjudgmental, and nondiscursive attention to the contents of consciousness, whether pleasant or unpleasant”6.If you want to give mediation a try, here is a list of answers to frequently asked questions put together by the Lazar Lab and this is another cool blog post by Sam Harris on various forms of meditation with some tips on how to get started.

Citations

  1. Holzel, B. et al. Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Res. 191, 36-43 (2011).
  2. Stange, JP et al. Mindfulness-based cognitive therapy for bipolar disorder: effects on cognitive functioning. J Psychiatry Pract. 6, 410-419 (2011).
  3. Holzel, B. et al. Neural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness training. Neuroimage Clin. 2, 448-58 (2013).
  4. Singleton, O. et al. Change in Brainstem Gray Matter Concentration Following a Mindfulness-Based Intervention is Correlated with Improvement in Psychological Well-Being. Front Hum Neurosci. 8, 33. (2014).
  5. https://www.theconnection.tv/sara-lazar-ph-d/
  6. https://www.samharris.org/blog/item/how-to-meditate

 

 

Love to tan? Blame Coco Chanel & your skin cells.

Coco Chanel, 1920 Sometime in the summer of 1923, a forty-year-old French woman named Gabrielle returned from a holiday cruise in the French Riveria with a sunburn. I imagine this must have been a common occurrence, and surely would have gone unnoticed except for one thing: Gabrielle was actually known as Coco. As in Coco Chanel. The fashion icon’s newly bronzed skin became an instant trend among her fans that subsequently catalyzed a widespread obsession with sun-tanning.

No disrespect to the immense influence of Coco Chanel (apparently she is also credited with freeing women from the suffocating corset), but her sunburn was particularly timely. Not only was the Victorian-era aesthetic reverence for pale skin already fading, but sun exposure was just recently being heralded as the new ‘cure-all’ for a wide variety of diseases and illnesses. So it’s easy to understand the enthusiasm with which people embraced sun-tanning. Good for your health and fashionable - when does that ever happen?

Fast-forward almost a hundred years, however, and our understanding of sun exposure has changed drastically. UV light is a major risk for all types of skin cancer. Shockingly, one study estimated that a higher percentage of people develop skin cancer from repeated indoor tanning than lung cancer from smoking1. That is insane. Yet despite an increased awareness of the link between UV-exposure and skin cancer, sun-tanning persists as an immensely popular pastime for millions of Americans. Continuing to behave a certain way despite knowing there are negative consequences is a hallmark of addiction. Could the obsession with sun-tanning be more serious than an aesthetic adoration for tanned skin? Could it be that UV light somehow directly impinges on the brain’s reward system to induce a biological addiction akin to drugs of abuse?

In the last decade, more and more evidence suggests this is indeed the case. Many UV seekers - those who repeatedly and persistently suntan outdoors and in tanning salons - meet the standard diagnosis requirements for a substance-related disorder. And just like you can’t trick a cocaine addict with baking soda, you can’t trick a tanning addict with UV-free light - they can tell the difference2. What’s even more striking is that sun-tanning isn’t just analogous to substance abuse, it appears like it is substance abuse: specifically, opioid addiction. Opioids as in heroin and prescription painkillers. If given an opioid blocker during UV exposure, some tanning addicts go into withdrawal, suggesting that addiction to UV light is really an addiction to opioids3,4.

Evidently there are no opioid molecules hiding in UV light. So the most straightforward hypothesis is that UV light is somehow triggering the body to produce its own endogenous opioids which ultimately increase dopamine release in the brain to engender reward and addiction. Now figuring out if and how that actually happens is much harder to do in humans, but a recent study using mice showed that exposing mice to UV light (they actually shaved the fur off to maximize skin exposure) increased blood levels of beta-endorphin5. Beta-endorphin is an endogenous opioid most famous for its incredible capacity to act as an analgesic when released following a physical trauma (‘shock’) and for producing euphoric feelings during exercise (‘runner’s high’). It interacts with the same protein that morphine, heroin, and all opioid prescription painkillers bind - the mu-opioid receptor.

It turns out that when cells in the outermost layer of your skin (keratinocytes) are exposed to UV light, a signaling cascade is initiated that results in the production and secretion of beta-endorphin5. The beta-endorphin then diffuses into the blood where it circulates throughout the body, including the brain. Once it gets in the brain - well, then the rest of the story is familiar. Like other opioids that the brain produces, beta-endorphin is known to increase dopamine release to trigger feelings of reward and reinforce behaviors; in excess, this is exactly what causes addiction.

While all the evidence appears to support UV-induced beta-endorphin release as the cause of sun-tanning addiction, the case isn’t fully closed. No study has directly shown that mice repeatedly exposed to UV light will continue to seek it out in the face of negative consequences - a key feature when defining addiction in humans. Thus, it remains to be known whether people really become addicted to UV-induced beta-endorphin release, or if instead it’s just one component of UV-light addiction.

As with all studies done in model organisms, we must be cautious when applying the results found in mice to humans. In particular, one difference between mice and humans seems a little mystifying with respect to studying sun-exposure: mice are nocturnal. So it’s perhaps quite reasonable to postulate that mice evolved specific mechanisms to ensure enough sun exposure to be healthy (i.e. get enough vitamin D), and that humans would not need such a mechanism since we are awake during the day. It would be interesting to compare UV-induced beta-endorphin release in nocturnal and diurnal animals to see if the phenomenon is conserved.

Regardless of this wrinkle, I think it’s safe to strongly suspect UV-light as an addictive substance, and as such should be treated with the same cautiousness and respect as we do other substances of abuse. So while it might have been the celebrity sway of Coco Chanel that started an industry of sun-tanning, its continued persistence despite the discovery of UV light’s carcinogenic properties likely has something more to do with our evolutionarily ancient fondness for opioids rather than just cultural aesthetics.

References

  1. Wehner, M. R. et al. International prevalence of indoor tanning: a systematic review and meta-analysis. JAMA dermatology 150, 390–400 (2014).
  1. Feldman, S. R. et al. Ultraviolet exposure is a reinforcing stimulus in frequent indoor tanners. J. Am. Acad. Dermatol. 51, 45–51 (2004).
  1. Kaur, M., Liguori, A., Fleischer, A. B. & Feldman, S. R. Side effects of naltrexone observed in frequent tanners: could frequent tanners have ultraviolet-induced high opioid levels? J. Am. Acad. Dermatol. 52, 916 (2005).
  1. Kaur, M. et al. Induction of withdrawal-like symptoms in a small randomized, controlled trial of opioid blockade in frequent tanners. J. Am. Acad. Dermatol. 54, 709–11 (2006).
  1. Fell, G. L., Robinson, K. C., Mao, J., Woolf, C. J. & Fisher, D. E. Skin β-endorphin mediates addiction to UV light. Cell 157, 1527–34 (2014).