12. Neuroepigenetics of Depression

12. Neuroepigenetics of Depression


“It felt like I was walking through mud all the time. My head was filled with thoughts like, ‘If my friends knew who I really was, they wouldn’t love me.’ Before I was depressed, I could find joy in things so easily. But during my depression, I couldn’t access any of that joy. Now, it wouldn’t produce a feeling in me. If a child smiled at me from a stroller, it might lift me up for a millisecond, but then I’d fall back into darkness.” –  Adapted from a testimonial in the photojournalism project, Humans of New York

Depression, a mood disorder associated with excessive sadness and cognitive dysfunction, is a debilitating mental illness that affects 350 million adults worldwide – more than the population of the entire United States. It can be so debilitating that an individual with depression may be unable to function in daily life, work, and school. In fact, the World Health Organization estimates that depression is the leading cause of disability in the world. While researchers and doctors have made incredible progress in treating depression, around half of patients do not respond to at least one treatment regimen. There is still so much we don’t know about the causes of depression and how it affects the brain in order to develop a nearly 100% effective treatment. Scientists have known for a long time that depression often runs in families. We inherit our genes, or the biological blueprint that tells our bodies how to function, from our parents. Each gene is like a unique recipe in a cookbook that the cells in your body read in order to make a protein, the tiny machines that carry out many important functions in our cells (Listen to Sam’s podcast for more in depth information). There are countless different functions proteins can have – like making up the cell’s structure, making fuel for the cell, and communication of messages between cells. Because our cells have so much work to do, we need a lot of different types of these machine-like proteins – each of which requires a unique recipe to make. This means that our genetic cookbook contains over 20,000 unique recipes in order to instruct our cells to make all the different proteins it needs. However, similar to how many of our mothers or fathers put their own spin on a recipe to make it the “best meatloaf in town,” not everyone’s genetic recipes are exactly the same. Small variations in the recipe cause a slightly different protein to be made, which may affect the way your body works. Imagine how accidentally doubling the amount of salt would affect the food you make – depending on what you are cooking, it may make the dish taste better, sometimes much worse, and sometimes you wouldn’t be able to tell the difference. Some people have tiny differences in certain recipes that call for proteins important for making our brain cells healthy, causing those tiny biological machines to not work as well. As a result, those people become depressed more easily. However, having an “abnormal” recipe doesn’t automatically doom you to become depressed, and having “normal” recipes doesn’t save you from being depressed either. Depression is more than just the effects of “nature,” or biological facts about us we can’t change. Life experiences and the environment also play a key role. People who experience chronic stress, social isolation, and early life adversity tend to be depressed more than those who don’t.   The causes of depression cannot be categorized into just “nature” (differences in genetic recipes) or just “nurture” (life experiences) – it requires a bit of both.

In 2015, depression researchers Gutierrez and Cervilla explored this idea of depression being caused by both our genes and the environment by studying a large sample of people in Spain with depression and depression-like symptoms over a three year period. The researchers looked at each person’s biological cookbook to see if some variations in genetic recipes important for healthy brain functioning seemed to be more common in depressed people over nondepressed people. They also asked the research participants about their significant life experiences and childhood. Their results confirmed what previous researchers had found – certain tweaks in these recipes were associated with an increased likelihood of depression – but they also found something more intriguing – people who had the “depression-sensitive” recipe tweaks, who also experienced emotional or physical abuse as a child, had a nearly threefold increased risk of developing depression when compared to people who only had the “sensitive” gene but no childhood abuse. Furthermore, that risk for developing depression is much larger than the risk associated with just inheriting the “depression-sensitive” recipe or just experiencing abuse. Somehow, experiencing things like abuse and neglect as a child must interact with these genetic recipes in order to make long lasting effects on a person’s brain function. Knowing how environmental factors, especially early life experiences, can lead to real, physical changes in a person’s body to make them more likely to have depression may lead to the development of new treatments, interventions, and compassion to those living with this mental illness.   However, despite the fact that humanity has been plagued with this mental illness for many years, we still do not know the answer to these questions. Until now. Epigenetics, a new and exciting field at the intersection of brain science and genetics, provides new insights on this subject.

Epigenetics looks at how the environment and our life experiences modify the genetic cookbook we inherit from our parents in order to change how often a cell reads certain recipes. If the number of times a cell reads a recipe changes, then the number of proteins it make will changes. Since each protein is designed to have a unique job in the cell, the way the cell works, lives, and grows will change if the proteins’ recipes are read more or less. While scientists initially thought that cells do not change how often they read their set of recipes once they are fully mature, they recently discovered that they can in fact do so in response to our internal and external environment – things like stress, diet, and social interaction can have physical changes on our cells that make them read certain recipes more or less, essentially causing the cells to work differently. Going back to Gutierrez and Cevilla’s research on biological and environmental causes of depression, the stress from childhood abuse could have caused long-lasting physical changes to someone’s brain cells, making them read the recipe for proteins important in keeping the brain cells happy and healthy less often. If they inherited a bad recipe for this protein, and read that recipe less due to the stress from childhood abuse, then they have an even higher chance of being depressed. Thus, epigenetics is this intersection of nature and nurture – how our experiences and environment leads to real, physical changes in our body.

Our body can make the genetic recipes we inherit from our parents harder or easier to read by adding special chemical tags onto the structure of the genes. The cells in our body have to use so many different proteins in order to function, which means that the genetic cookbook is incredibly lengthy. In order to pack it all down into a size that fits in a cell, our genes are neatly wrapped like string around several beads called histones. The looser the genes are wrapped around the histone beads, the easier it is to read, and the more protein machinery is made. Proteins in our cell can add chemical tags on the histone beads that affect the way the gene is wrapped around the histones, making the recipe more or less accessible. These tags do not change the actual ingredients in the recipe – they just make it more or less accessible to the machine that is responsible for reading and making the genetic recipes, like a cook. You can think of these special chemical tags like dog-earing a recipe you like in a cookbook to make it stick out more (more protein is made) or putting a paper clip around its pages, making it harder to open up and read the instructions (less protein is made).

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Genes wrapped compactly around histones, altered by epigenetic tags. Image sourced from: Kenefick, Kari. “Promega Connections.” Promega Connections. Promega, 22 Jan. 2014.

Scientists wanted to see if there was a particular pattern of these dog-ear or paperclip tags around genetic recipes important for proper brain functioning in people with depression. Looking at the genes in brain cells of depressed people, they found multiple genetic recipes that had less dog-ears and more paperclips, making those the genes harder to read, when compared to people who weren’t depressed. There were three major genetic recipes that were harder to read, and therefore the proteins they called for were made less often. The first protein is a chemical messenger, or hormone, that is sent to other brain cells in order to encourage them to grow and work correctly, called BDNF. Low BDNF levels are associated with depression, for reasons that are not fully understood. The protein that receives the BDNF chemical messenger (named TrkB), which tells the cell to grow and work correctly, is also made less in people with depression. You can think of a hormone, like BDNF, as an office memo that is mailed out throughout your body, but only placed in a specific mailbox – the protein that receives the hormone (TrkB). Finally, the third protein, named the glucocorticoid receptor (GR), is the biological mailbox (hormone receptor) that receives your body’s stress hormone, cortisol, allowing your brain cells to recover quicker from the damaging effect of stress. These proteins work together to ensure we have healthy brain cells that can react appropriately to a stressful environment. Once scientists knew which genetic recipes had different patterns of dog-ear and paperclip tags in people with depression, they ran experiments on rats in order to investigate which environments and life experiences can cause similar changes in depression related genetic recipes.

A research study conducted by Szyf and Meaney, two researchers at McGill University, investigated the effects of neglectful mothers of newborn rats on changes in their genetic recipe for the glucocorticoid receptor protein (GR), which helps us quickly recover from stressful situations by receiving the stress hormone signal and then telling your body it is OK to calm down. They separated rat mothers into two different groups – those that displayed a high amount of licking and grooming towards their pups (high caring mothers), and those that showed a small amount of licking and grooming (low caring mothers). What they found in this landmark study was astonishing: the GR recipe in the brain cells of adult rats that were raised in a high maternal care environment had chemical tags added to it that made it significantly easier to read (dog-eared, less paperclips keeping the pages stuck together) than in adult rats raised in low maternal care environments. The brain cells of the rats with high caring mothers made the recipe for the GR gene more often, which should allow them to detect the stress hormone, cortisol, in their body much quicker, allowing a faster recovery from stress.   To test this, the scientists measured the intensity of the adult rats’ reactions to a stressful situation by measuring the levels of the cortisol in their blood after being put in a physical restraint (a very stressful situation for a rat), and found that rats that had more loving mothers when they were pups now had significantly less stress hormones in their blood. Because the gene was easier to read, more GR protein was made, allowing the rats to recover from stress more easily. Even more incredible, an experiment showed that both the chemical tags (paperclips and dog-ears) to the GR recipe and the response to a stressful situation were reversed in pups born to low caring mothers, but were raised by high caring mothers – a beautiful testament to the importance of being a good parent. (You can read more about the epigenetic effects of maternal care in Lizzy and Lisa’s and Erin and Jen’s podcast or essay). When an individual is unable to quickly recover from the negative effects of stress, those effects are more likely to accumulate into depression. Rats raised in low maternal quality environments show more signs of stress-induced learned-helplessness, a way scientists interpret a state of depression in rats by studying their behavior. Essentially, the early life stress associated with lack of proper maternal care causes changes in the baby rat’s genes that persisted through adulthood, causing them to be more susceptible to stress, leading to a higher likelihood of depression.

While Meany and Szyf looked at early maternal care, another pair of researchers experimented with the effect of a different mode of stress on rats – bullying. Tsankova and Nestler, two scientists at the University of Texas Medical Center, put normal, friendly rats in the same cage as an aggressive rat that would bully the friendly rat by biting and scratching it. They put the two rats together for ten minutes every day for ten days. One month later, they compared changes in the genetic recipe for BDNF, a hormone that is sent to other brain cells in order to encourage them to grow and work correctly, between bullied rats and rats who were not bullied, and they found similar results to Meany and Szyf: the bullied mice made less BDNF protein than mice who were placed in a cage by themselves, because their genetic recipe for BDNF had more paperclips and less dog-ear chemical tags, making the recipe much less accessible to read. This caused the neurons to be less healthy and able to communicate with each other. Recent clinical studies found that, similar to rats, a decrease in BDNF protein level in humans is associated with depression, and that antidepressant medications restore BDNF levels back to a normal value. While antidepressant medications are effective for some cases of depression, little is known about the mechanisms through which they work. Tsakanova and Nestler used their findings on stress, epigenetics, and proteins important in the development of depression as an opportunity to explore these mechanisms. Giving antidepressant drugs to the bullied mice after the ten days of bullying reversed the changes made to the their BDNF genes by increasing the amount of dog-ears on the recipe, and decreasing the amount of paperclips, allowing it to be read into the BDNF protein at normal levels so that the cells are happier and healthier. Making more of the BDNF proteins would allow the rats that were bullied to send more of the signal to receptors in the brain cells causing them to grow and function better, leading them to be less likely to develop depression-like symptoms. They also found that the protein that is responsible for removing dog-ear tags on genetic recipes, preventing them from being more accessible, was lower in rats given the antidepressants. Having less of the protein that makes those changes restored the levels of BDNF protein back to normal, as seen in non-depressed rats. The scientists concluded that the antidepressants may work by reversing the epigenetic tags to the BDNF genetic recipe, caused by the bullying, by targeting the protein that makes those changes.

Stressful experiences can cause changes to the amount of paperclip and dog-ear tags to certain genetic recipes, making them wrap more or less around the histone beads. The looser the recipe is wrapped around the beads, the easier it is to read, and therefore the more protein that gets made. As seen in the maternal care experiments, these changes can even last until adulthood. However, the bullying experiments show that certain medications can reverse those long-lasting changes in dog-ear and paperclip tags on depression-related genetic recipes, allowing them to be read at normal levels. These drugs inspire hope of a new, better class of medicines to combat depression. You can learn much more about these medicines in Neha and Sally D’s podcast or essay, and Sally P and Mark C’s podcast or essay. However, we as a society need to be thinking beyond just drug development. Epigenetic research finds physical changes that happen in the brains of people due to environments they cannot always choose or change. If these findings suggest that experience can lead to changes in our gene expression, we must examine how we can fix our current environment to prevent lasting negative effects on people’s mental health. Policies and programs that target bullying, crime, poverty, and other situations and environments that lead to intensely stressful environments need to be implemented to stop the precursors of depression. Finally, we also need to use this research to fight the societal stigma of depression as a sign of weakness, or as something that is fabricated and not a genuine illness. We can share this knowledge to start a dialogue on depression, inspiring us to better understand and be more compassionate to those around us we know to have depression, and to the countless other people we interact with who may or may not.

References

Bun-Hee, L., Kim, Y. “The Roles of BDNF in the Pathophysiology of Major Depression and in Antidepressant Treatment.” Psychiatry Investig. 7.4 (2010): 231-235. Web. 17 April 2015.

“Depression.” World Health Organization. World Health Organization, April 2016. Web. 17 April 2016.

Gutierrez, Blanca, Juan A. Bellon, and Jorge Cervilla. “The Risk for Major Depression Conferred by Childhood Maltreatment Is Multiplied by BDNF and SERT Genetic Vulnerability: A Replication Study.” J Psychiatry Neuroscience 40.3 (2015): 187-96. Web. 16 April 2016

Kenefick, Kari. “Promega Connections.” Promega Connections. Promega, 22 Jan. 2014. Web. 17 Apr. 2016.

Khan, A., et al. “A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression.” PLoS One. 7.7 (2012). Web. 17 April 2015.

Meany, Michael J., and Moshe Szyf. “Reversal of Maternal Programming of Stress Responses in Adult Offspring through Methyl Supplementation: Altering Epigenetic Marking Later in Life.” J. Neuroscience 25.47 (2005): 11045-1054. Web. 16 April 2016.

Sun, H.S., Kennedy, P.J., Nestler, E.J.  “Epigenetics and the Depressed Brain: Role of Histone Acetylation and Methylation.” Neurospychopharmacology Reviews. 38 (2013): 124-137. Web. 17 April 2015.

Tsankova, Nadia M., and Eric J. Nestler. “Sustained Hippocampal Chromatin Regulation in a Mouse Model of Depression and Antidepressant Action.” Nature Neuroscience 9.4 (2006): 519-25. Web. 16 April 2016.

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