Cobbers on the Brain

With just 3 protons, you could perhaps be excused for thinking there isn’t much to lithium. But it turns out it’s good for a lot more than just batteries. Lithium has been a go-to medication for bipolar disorder for almost half a century, and we’re still figuring out how it works and what it can do.
Lithium’s main role as far as we’re concerned is neuroprotection. It accomplishes this by several avenues. First, it decreases cells’ supplies of inositol by preventing it from recycling old inositol. Normally inositol causes growth cones, areas of neurons which are growing out to form new connections, to collapse. By getting rid of the excess, lithium promoted neural growth and survival. Another way lithium is neuroprotective is that it inhibits a number of signals and pathways that promote apotosis, or programmed cell death, including p53, which has been found to be involved in neurodegeneration due to Alzheimer’s disease and strokes. It’s also proactive, increasing production of BDNF, or brain derived neurotrophic factor. Neurotropic factors are signals produced to promote both survival of neurons and their growth and proliferation. BDNF specifically is known to be part of the mechanism by which some antidepressant and anti anxiety medications work.
Unfortunately, it isn’t all blue skies with lithium. As great an idea as it may seem to start taking a daily bit of lithium just to be safe, lithium isn’t without its drawbacks. It has a low therapeutic index, which means that there isn’t a big difference between the amount that helps you and the amount that hurts you. Without a doctor keeping an eye on you and your dosage, you can reach lithium toxicity pretty easily, and it isn’t fun. Acute toxicity can cause dizziness, seizures, or even coma, and even trickier is chronic toxicity when you take just a bit too much each day and it builds up. That can cause muscle tremors, kidney failure, and psychosis. So as lovely a metal as lithium is, it’s still yet another medication to be careful with.

Wow, it is hard to believe that it is already the end of fall semester senior year. Where did the time go? Well that means it is time to reflect on my “capstone” experience in neurochemistry with one final blog post.
 
Going into this class, there was a lot of “hype” from students. By the time that senior year rolls around, most of us know each other and the professor. Some students were anxious about the experience because neuroscience was out of comfort zone. Other students, like myself, were extremely excited for this class because it really digs into the mechanisms and how neuroscience happens through signal transduction. I was excited to take this class as I am finishing my neuroscience minor. I was also excited about this class because it is taught in a unique way compared to the typical lecture, memorize, and regurgitate for an exam. In this capstone course, the students are considered coinvestigators with the professor. No one knows every detail about the topics that are being discussed so everyone is responsible for diving into the research in order to teach the rest of the class.
 
The class was structured in a way that the responsibility was on the students. Each week, an article would be assigned relating to a signaling pathway, usually related to a neurological disease or condition. On Mondays, our class would come having read the article and then we would discuss what was still on clear. The class would make a list of topics that we wanted more information about and then we would assign each member of the class to a topic. Each person was responsible for researching that topic by Wednesday and preparing a mini presentation (short and sweet!) about the main points of the topic in relation to the article we read. On Wednesdays, we would present our mini presentation topics through a process similar to “speed dating.” Each pair would have five or six minutes to tell each other about the high points of their topic and try to make connections. It was definitely entertaining to watch! After gaining information for the Wednesday speeding dating session, our class would reconvene on Friday to have a group discussion.  The focus of the group discussion was not to hash out the fine details of the mechanism usually; instead, we discussed what it meant in the bigger picture. How would this impact society? Does this information really change anything that we are doing now in terms of treatment? Do people need to know this information? After each week’s discussion, we were asked to write a blog post to share what we learned with the general public and explain what we think other people need to know. This was definitely a new experience for me but I think it was good to push us to write for an audience that we don’t usually address. The public needs to know about the important (and cool) research that is going in neuroscience so the information needs to be accessible. Being able to write and communicate with a diverse audience is an important skill. The public service announcement project was also a creative way to show application of the information we learned. Neurochemistry allowed us take science and apply it to the real world, which takes Concordia’s mission statement of being responsibly engaged in the world (BREW) to heart.
 
The other part of the class that was different and facilitated learning was the exam style. For each of the two exams, there was an in-class portion and a take-home portion. In class, we were given essentials points from a mystery article and we were asked to weave them together in order to form a working hypothesis. After the in-class portion, we were given the actual article and allowed to assess the hypothesis we have previously proposed. I think the exams in this class are my favorite exams I have taken in college. There is no cramming for this type of exam, it a reflection of the skills that you have developed through active participation. The exams also challenge students to make connections, use logic, and think critically.  I also think that the way the exams were structured it takes a lot of the pressure off so students can focus on learning for the sake of learning, instead always trying to earn an A. The exams were a great way to shift the focus to learning and enforce important skills.
 
Overall, I think that neurochemistry embraces Concordia’s goals of liberal learning. It turned the typical class structure on its head and pushed the students to take the next step in our educations. It was a new level of innovation, rigor and risk for everyone involved; we had to sink or swim together and I think we all say that we gained more than factual knowledge from this class.. There should be more classes that encourage students to participate and then share the information with the world. Neurochemistry was the perfect way to cap off my undergraduate experience here at Concordia College.

When I was 15 my sister had an accident while sledding and suffered a concussion. Visiting her in the hospital was a rather surreal experience, with her failing with recognize me one minute then trying to hold a conversation about Russia the next. I could tell there was something unusual going on, but I didn’t have any inkling of all the things going on inside her brain at that moment. Of course I knew that getting hit too hard in the head was a bad thing, your brain could slosh around and there was no possible way that could be a positive thing, but it turns out that in the wake of a concussion there is a flurry of activity down at the molecular level.
The worst part of the story is that when you get a concussion, your brain gets leaky. It’s about as bad as it sounds. Your brain normally generates the electrical impulses it uses to function by swapping tiny concentrations of ions across cell membranes. After a concussion, the leaky cells let those ions out when they shouldn’t, resulting in random electrical pulses going all over the place. The neurons’ ion pumps go into overtime to try and get things under control, which uses up a lot of energy. Unfortunately the concussion also disrupts your cells’ normal energy generation, so instead of using oxygen as normal, they try to use anaerobic metabolism. This generates large amounts of lactate, which can shift the local pH. Among other things, this can make your cells even leakier. Eventually your brain can cope, but in the meantime you get headaches, confusion, and vomiting.
And the coping takes time. More time, in fact, than it takes for you to feel better. It can take over a month for things to get back to normal, and if there are any head injuries in that time, the effects can be catastrophic. It can result in second impact syndrome, in which the already damaged brain swells dramatically. This can be disabling or even fatal. In the absence of second impact syndrome damage can still be compounded, with enough damage resulting in chronic traumatic encephalopathy. In the past this was called dementia pugilistica or punch drunk syndrome, as it was commonly seen in boxers. CTE is a progressive neurodegenerative condition, resulting in brain atrophy, with symptoms and neuropathology similar to Alzheimer’s disease, including amyloid beta plaques and tau protein deposition.
While there’s no chance we could get our athletes off the field, we need to be aware of the dangers and what can be done to protect them. New rules are being put into place which help prevent some of the riskier maneuvers, and advanced helmets are being developed which minimize the force transferred to the athlete’s brain. At the risk of sounding rather older than my years, it’s good to have fun but there’s no reason we can’t be safe while we do it.

Continuing a trend of unlikely players, the paper “Targeting dysregulation of brain iron homeostasis in Parkinsons’ disease by iron chelators” tells us the story of how too much metal can mess up our brain. Now, iron is an important part of our diet. It’s the most important part of our blood, helps us bulk up on muscle, but unfortunately it’s a bit too easy to get too much of it in our brains. See, most of the time our bodies maintain what’s called homeostasis. Basically it means each part of our body works to keep the right levels of the right stuff in the right place. When that goes awry, we get problems. In this case, problems with iron homeostasis in the brain. Normally it’s used for everything from neurotransmission to DNA synthesis, but as we age it accumulates. In Parkinson’s disease, the major issue is that neurons in the region called the substantia nigra die off. Coincidentally, the substantia nigra of Parkinson’s patients tends to have elevated levels of iron. It takes on some abnormal electrical states as well, which generates free radicals and cause the misfolding of a protein called alpha synuclein, which is known to be involved in Parkinson’s.
So now that we’ve laid out a nice big problem, what do we have for solutions? They’re called chelators, and they’re substances that can bind metal ions in a way that makes it easier for our bodies to get rid of them. A major source of good iron chelators is green tea. It’s full of catechins, which are molecules with a lot of carbon rings that allow them to surround ions like iron so the normal homeostasis mechanisms can sweep it away.

Like I expect most people would, I used to think that insulin was just something for diabetes. As a biology major I suppose I knew that it regulates how your body uses the sugars in your blood and built up energy reserves, but that was supposed to be it. Well yet again Neurochemistry went and ruined what I thought I knew. It turns out that insulin also has quite a few other roles, especially in the brain. Insulin and its cousin, insulin-like growth factor-1, are key players in neural development and survival. But great power and great responsibility, right? This means when they’re messed up they don’t just cause diabetes. Apparently they can also be involved in Alzheimer’s.
Their role in neural growth and survival make them important for making and keeping memories, so that’s fairly straightforward, but insulin is also important because it decreases inflammatory responses in our brains. And of all the places we want to avoid too much inflammation, the squishy organ in an enclosed space is probably at the top of the list. Not only that, but inflammation can interfere with the normal cleaning out of your brain so you can’t get rid of, for example, amyloid beta- a major player in Alzheimer’s. That’s in addition to your neurons lacking energy without insulin telling them how to eat, subjecting them to oxidative and mitochondrial stress—basically, burning themselves out—and both too much or too little insulin giving you hyperphosphorylated tau protein, another Alzheimer’s contributor. So your brain starts getting too big for its britches, your neurons are busy dying instead of keeping your memories like they’re supposed to, and why? Apparently due to insulin resistance, the same problem we have with diabetes. But on the bright side, we’ve got a little better view into Alzheimer’s disease, and one more way we might be able to treat it.

Dopamine is one of the few neurotransmitters that most people have probably heard of. It’s the ‘reward chemical’, the one that makes us feel good when we reach a goal or do something we enjoy, right? Well, it’s a bit more complicated than that. Okay, a lot more complicated.
While dopamine does have a lot to do with pleasure and reward, it has many other effects depending on where in the brain we’re releasing it and what receptors it’s binding to. It’s involved in attention, hormones, and motor control, and its dysfunction is part of conditions from schizophrenia to Parkinson’s disease.
In the article “Beyond cAMP: the regulation of Akt and GSK3 by Dopamine Receptors”, the authors take a look at D2 dopamine receptors and how they affect a signaling pathway called the Akt/GSK3 pathway in the hopes that it might give a better idea of how to deal with dopamine-related conditions. This pathway is especially important for that work because among other things, it affects the entire outlook of the cell- how it will do its job, whether it needs to move, or replicate, or self-destruct. When dopamine binds to D2 receptors, they inhibit Akt, and Akt normally inhibits GSK3, that means GSK3 can go to work.
This is important to treating dopamine conditions because the drugs we have now are kind of like hammers when we need tweezers. For example, in bipolar disorder and schizophrenia, when dopamine has too much of an effect, we inhibit dopamine, and in Parkinson’s, when there’s too little dopamine signaling going on, we add more dopamine. Sounds easy enough, but remember the part about dopamine doing a lot of stuff? Unfortunately when there’s a problem it’s usually not with all of it. There’s too little or too much in a specific area of the brain, and when we try to act too broadly we can sort of fix the local problem, but globally we’re causing nasty side effects. Luckily research into the Akt/GSK3 pathway has given us some better targets to shoot for. For example, people with schizophrenia have too much dopamine *signaling*, but it’s not really dopamine’s fault. They have too little Akt, which means dopamine can overpower it too easily. So drugs targeting Akt instead of dopamine should fix the problem without mucking everything else up. Hopefully in the near future, this research will bear fruit in the form of ‘tweezers’—medication that does what we want, and nothing else.

In all honesty, before this class started I was secretly a little terrified for it. Now, that doesn’t mean I wasn’t excited about it too–I knew basically everyone in the class and really enjoyed the professor, so I was excited about those aspects. Prior to this class I had very little (and I mean VERY little) neuro experience, therein laid my terror. In retrospect, that terror was completely unwarranted, and as the weeks went by I became increasingly shocked at how much I was learning. The premise of the class was to initially (in the first few weeks) gain a general knowledge of neurological processes, e.g. receptor types and basic pathway mechanisms. As the class progressed the goal was to utilize those original tools to help decipher scientific papers about neurological disorders. This whole process was amalgamated with the use of individual presentations and group discussions in order to instill and solidify the information we were learning.

The learning aspect of this class was unique, and something I had never experienced before. Starting the first day we decided that instead of a normal classroom setup with rows of desks, we wanted to be in a circle, which Dr. Mach promptly termed “The Nest.” This allowed us to have a more open style of face-to-face communication in the class. The first few weeks, while we explored the pertinent background information, the class was loosely structured like any normal class: we would be assigned papers to read about the receptors or pathways and sets of questions to answer that would further our understanding, and then we would briefly lecture about and discuss the topic in The Nest. When we started delving into the papers about neurological disorders, the class started veering from traditional learning. The learning in this class was very self-lead. We were assigned to read articles about disorders, followed with a class discussion about all of the topics we did not understand. We would then, as a class, get to choose what to explore in greater detail. It would be our responsibility to pick a topic, research it, and present in some fashion the next class day. To wrap up the paper and solidify what we learned, the week would end with group discussions. These discussions served not only to retouch on the nitty gritty mechanisms, but to broaden the topic and look at the societal implications and big picture. The latter often led to some very engaging discussions in which we would delve into societal issues and the steps necessary to solve problems–this added a more global aspect to the class and really connected the field to other areas.

The writing component of this class was as well a completely different experience than I was familiar with. Writing papers was unheard of, instead blog posts were the medium for our written assignments. The goal of the blogs was to relay the information we learned that week to the general public, and in a way that was understandable to someone who isn’t a scientist. This was a very interesting exercise, as usually when writing for a science class you try and write everything very concise and to the point. For the blogs we had to transform the science into a readable and understandable text from which people could learn something. This approach required that we actually understand the science enough to rewrite it in a completely different way, which was an extremely effective way of learning and reinforcing topics from class.

In all, I was extremely pleased with my capstone experience as a whole. This class enabled me to think deeper about topics I was not overly familiar with, and feel more comfortable with subject matter. I was able to understand the material and form it into a new medium in which others could learn from. Additionally, this class was simply fun on a basic level; my peers were a blast to be in class with, and Dr. Mach was a co-learner, rather than someone talking at us for 70 minutes straight. It is classes like this one that remind me how lucky I am to be at Concordia, fully immersed in the academic world.

When I first signed up for Neurochemistry I really had no idea what the class was going to be like. At first I assumed it was going to be somewhat similar to the other chemistry classes I have taken at Concordia, but then I heard a little more about it from a peer. The class was going to be more discussion based, where we spend time reading recent articles and discuss them with our class. I was apprehensive at first, as science is something that I feel as though I am better at simply “doing” than “discussing.” Despite this, throughout this semester I have learned that discussing science is maybe the most important aspect. What’s the point of learning anything if you can’t make sense of what it really means and share that with others?
Even if I don’t remember any of the science-y details from this semester, I can walk away knowing I learned something much more valuable. I learned the importance of preparation. I learned that you can’t be scared to voice what you don’t understand. About halfway through the semester, our class realized that something wasn’t quite right. We were all so quiet on the days we should be the loudest. Mondays were our day to come in after reading an article and share with the class what parts we did not understand. Our class faced multiple issues with this. One was that many did not take the time to really read the article. These articles were somewhat short, but very dense. In order to really understand what was going on, and thus be able to ask questions, you had to spend hours reading just a few pages. Many of us did not take the time to do this. On top of that, even when we did read and did have questions, many of those in our class were timid on sharing our questions in class. I think a lot of us were nervous of what others might think of us, afraid that we weren’t “smart” enough. What most of us didn’t realize was that most of the class felt the exact same way. Through this class I learned that if you truly try your best in preparation (in any subject), then no question is a dumb question.
After discussing what we did not understand from the article on Mondays, we were all sent away with something to research. After some digging, we came back on Wednesdays, and were to teach our classmates what we learned. This put us in a position that no other class at Concordia has done for me. Once a week, we were the teachers. Our professor did nothing different from us on these days. This challenged our entire class, making us realize the importance of teaching and how helpful it is in really understanding a topic yourself. After learning from each other, we spent our Friday class periods simply discussing. Sometimes discussing the science, but mostly discussing that week’s topic at large, and what it meant for the world that we live in.
Concordia College loves its catchphrase, BREW (Becoming Responsibly Engaged in the World.) This class was a huge help in preparing us to BREW after graduation. Looking especially at science classes, it is easy to get lost in the content and not understand how the material affects our lives at large. By looking at topics such as obesity, Alzheimer’s, Diabetes, Autism, ALS, and concussions, we were able to not only decipher the science behind these topics, but what this science means for our lives. What can we do to help prevent these diseases? How can we help people who already have them? Is there hope for the future? Not only learning about these disease, but figuring out how we can help, seems to hit at the very definition of BREW. This class helped me realize how science can change our bodies and our world, and through this even helped me narrow my options for a future career.