Taken from http://cdn.theatlantic.com/static/mt/assets/jamesfallows/ObesityMap2.jpg
During the week of November 10th, we discussed a rather controversial article about obesity and the possibility that it could be caused by disease-like factors. Many people view obesity as the result of choice though it is well-known that some people have a higher metabolism than others and can maintain a healthy weight without much work. Recent research has shown that many neurological factors are involved in development of obesity. First is the decreased sensitivity to leptin at its receptors along with some insulin resistance as seen in type 2 diabetes mellitus. Together, these two problems create a dysfunctional appetite which is not curbed when a person should feel full, and also irregular glucose metabolism, which can lead to many neurodegenerative paths similar to Alzheimer’s disease. Studies have shown that maternal high-fat diet before pregnancy maintained through breast feeding leads to increased lipid peroxidation (a precursor to neurodegeneration) and lowered production of cells in the hippocampus, an area of the brain associated with formation of long-term memory. High-fat diet also leads to inflammatory factors that are associated with memory impairment. Obesity, as defined by body mass index, is not actually necessary to have some of these neurological markers. Healthy people who have high-carbohydrate and high-fat diets are also susceptible to memory deficits seen in obese patients. Simply having a high-fructose diet has been shown to increase lipid peroxidation and decrease insulin effects on its receptor. Thus, the human body is subject to dietary effects on cognition from conception until death. There is some evidence, however, that weight loss can stimulate some cognitive improvement, though the mechanisms behind this have yet to be explored fully. Sleep also plays a role in the cognitive deficits of obesity as circadian rhythm alteration can elicit memory deficits in some individuals and further weight gain, causing an unfortunate positive feedback loop. Weight gain may also be associated with declining activation of the reward circuit in the brain, which also happens in chronic drug abuse.
The discussion and topics covered in class reminded me of a similar discussion in my Drugs and Behavior class concerning addiction. I feel like as a society we are so ready to place blame on an individual’s character rather than fully examining the situation each person is in. We label obese people as lazy and unmotivated without knowing their diet as a child or their socioeconomic status. Socioeconomic status plays a huge role in what foods are available to people. Processed, cheap foods are readily available for working-class individuals while wholesome foods necessary for a balanced diet not only cost a lot more, but take longer to prepare. With the demands of education and work, maintaining a healthy diet for oneself is difficult and even harder when working multiple jobs to support a family. The view of obesity and addiction as diseases is a double-edged sword. While it does remove some stigma from the two conditions, it also eliminates some sense of personal responsibility. Those with either of these controversial conditions must also realize that personal volition can help improve one’s life, though the path to recovery may well be bumpier than the path to disease.
Just a Hit by a Grunge Band?
What a normal 90’s kid thinks after he/she hears the “Lithium”
What a 90’s kid in neurochemistry thinks when he/she hears “Lithium”
During the week of November 3rd, we reviewed an article concerning the efficacy of lithium in neurological diseases. As much of the public is aware, lithium has been used in the treatment of bipolar disorder for decades. When patients suffering from Major Depressive Disorder are unresponsive to all other popular treatments, lithium is actually one of the first “alternative” treatments considered. Lithium’s mood-altering effects come from its ability to inhibit GSK3. GSK3 activates serotonin autoreceptors, which prevent serotonergic action by facilitating its reuptake into the neuron. GSK3 is involved in many other pathways, especially those involved in neurodegeneration. Because of its actions on the normal constituents of a common pathway, lithium has been studied and shown to be effective in many other disorders and diseases. Lithium has also been shown to be neuroprotective when given as pretreatment before stroke through its prevention of excitotoxicity. After stroke, lithium treatment can even have benefits due to its ability to induce transcription and proliferation, leading to neuronal recovery. In Parkinson’s, lithium has been shown prevent apoptotic (programmed) cell death. In Huntington’s disease, lithium treatment prevents excitotoxicity and increases the expression of neuroprotective factors leading to improved mood and also some improvement in motor function. Lithium has also been effective in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) for similar reasons, though it is most effective when supplemented with antioxidants as oxidative stress has been implicated in ALS onset. Lithium has been shown to be effective in slowing the progression of multiple sclerosis (MS) by reducing inflammatory responses. Lithium’s neuroprotective role in MS was shown to be greatest when used before the disease’s onset. Lithium even has been shown to curb alcohol-induced degeneration in utero and greatly diminishes the symptoms of fetal alcohol syndrome; this protection was even seen when lithium was administered after alcohol consumption. Lithium can also be used to counteract some of the adverse effects of antipsychotics without decreasing their efficacy. Lithium also has been shown to be effective in preventing the hyper-phosphorylation of tau proteins and amyloid-β aggregation.
As we can plainly see, lithium has numerous benefits in neurological treatment and also can be used to prevent many adverse effects. On paper, it appears to be a neuroprotective wonder-drug. Why is the public not taking lithium supplements? In the lab, lithium also shows promise; clinical trials are another story. Some studies show great effect, while others are inconclusive at best. Also, a simple WebMD search shows that side effects include nausea, diarrhea, dizziness, muscle weakness, and fatigue. There also are some potential interactions with many commonly-prescribed and over-the-counter medications. Members of the general public should not jump to conclusions and buy lithium supplements with a 30-day supply in one pill like they do with vitamin C. Because of its many routes of action, lithium has the potential to cause a slew of adverse effects if not dosed properly. When used to treat bipolar disorder, lithium levels are monitored very carefully to prevent toxicity. As human studies on neurodegeneration attenuation show conflicting results, more research should be done with consistent methods and longitudinal designs to evaluate the long-term efficacy of lithium treatment in degenerative diseases.
What are we really learning about in college?
Before beginning my capstone experience in Neurochemistry, I was very curious as to how this would be different from any other class. I imagined all of the chemistry behind what I learned in my previous neuroscience courses would clarify everything, and it would all suddenly make sense. As the semester progressed, I realized that some of the things I hadn’t understood before were indeed starting to make more sense, but it became more and more apparent that I would never get to the point where I would truly feel as if I fully understood everything. Now, as the semester comes to a close, I realize that in many ways, this is part of the beauty of science: though we will continue to constantly try and learn more, there will still always be more to discover, just as there will always be more I myself can learn. The way we learned in this course was very different than anything I’ve ever experienced in any of my other classes, and seems to be very appropriate given that my classmates and I will all be leaving Concordia perhaps sooner than we fully appreciate, and it will start to fall upon us more and more to take responsibility for our own learning. In this class, we didn’t sit and listen to a lecture during every class period, but instead we looked at articles regarding recent research in neurochemistry, and then worked as a class to dissect and look for the aspects of the article we didn’t understand. We would then seek out more information, and bring it to class to share with everyone else, and finally at the end of the week, we would sit and discuss the article and some of its implications. It seems as if this is a much more realistic way of learning information than sitting in a classroom, and this experience gave us a much more realistic picture of how we must continue to be life-long learners.
To be totally honest, I don’t know whether I will remember in five years what Akt does and all of the different pathways it can impact, but some of the broader themes of the course are ones I will surely carry with me. We learned many different things about obesity, endocannabinoids and marijuana, Alzheimer’s, Parkinson’s disease, and concussions. Several things struck me as we studied these diseases and their related neurochemical mechanisms. First of all, the mechanism for any one of these diseases is by no means simple. We usually would study one or two aspects of it as they pertained to the article we were looking at that week, and then through our research as we tried to understand the article better, found several other pathways that might also play a role, or contribute in some form. Secondly, I came to understand how much public opinion can do to mask the science behind certain things. I am speaking with endocannabinoids and marijuana in mind, as I discovered that there are certainly substantial potential medical benefits that may be a result of the use of cannabis, and these benefits had previously seemed almost mythical to me and simply an argument people used as they were trying to legalize marijuana. I also learned about how important some small changes we make in our lives can make a huge difference. From drinking a cup of green tea every so often to working to develop better diet and exercise habits, the smaller changes can make a huge difference in both the future health of both yourself and your children. It has become apparent that there is no wonder-drug, and that side-effects are sometimes unavoidable when you are trying to treat one thing without throwing other systems out of balance. It suddenly makes a lot more sense why we spend so much time trying to learn more about disease and develop a treatment for it, but often are still unable to find a perfect solution. This class has taught me to think critically about a lot of things that I might have taken at face value before, and overall, has taught me to be more inquisitive about the world around me, which is perhaps one of the most useful things I can take away from a course.
ALS… Making Progress Towards Understanding
Amytrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig’s disease, is a disease which appears in adults and affects motor neurons. There are two different forms, of which sporadic ALS is by far the most common. It now appears that an imbalance of calcium could play a huge role in the pathogenesis of ALS. A variety of proteins and transport mechanisms exist to ensure that the appropriate levels of calcium are in various cellular organelles, namely the endoplasmic reticulum, which is important in modifying proteins as they are produced, and the mitochondria, which is important in energy production for the cell. When inappropriate levels of calcium are in the endoplasmic reticulum, ER stress occurs and a mechanism called the unfolded protein response is activated in response. In ALS, too much calcium is taken out of the ER and put in the mitochondria, and so proteins are not folded properly in the endoplasmic reticulum, and the increased levels in the mitochondria can have a variety of detrimental effects such as defects in energy metabolism, the generation of reactive oxygen species (which are not good things to have around, and are part of the reason it is so good for us to consume things high in antioxidants like green tea), and the activation of apoptosis (which ultimately means cell death). As a result of these abnormalities in motor neurons, the motor neurons die, and we see ALS. The reason only motor neurons are affected in ALS is due to a certain kind of receptor motor neurons have called an AMPA receptor. When the neurotransmitter glutamate is released, it binds to AMPA and allows calcium into the cell and throws everything out of balance. AMPA receptors on the motor neurons of those with ALS lack a certain component which results in more calcium being allowed into the cell.
There are a number of different molecules and mechanisms that also play a role in regulating calcium levels in the cell, and thus provide targets for treating ALS. Of course, as always, we must add in the caveat that it is much more complicated than it appears at first glance to actually treat this, as we don’t want to affect other pathways that use the same molecules and/or mechanisms. As ALS affects motor neurons, it should come as no surprise that these molecules also play a large role in things like muscle contraction, and so we have to be careful to not harm that by going too far with modifying the levels of all of these molecules in the body.
There is also the issue that it is currently somewhat unknown whether misfolded proteins are misfolded because the motor neurons have degenerated, or if the motor neurons degenerate because the proteins are misfolded. There are many things that remain to be known about this, but at least we are starting to make good headway in starting to learn what exactly is going on in the spinal cord of patients with ALS.
Overcoming the Complexity of Autism to Find Treatments
The incidence of autism has been rising dramatically in recent years, and as a society, we must sit and wonder, is there anything we can do to stop it? We recently learned more about how autism is thought to occur, and discovered that autism may occur as a result of nerve cells in our brains failing to connect to the proper targets, and thus the so-called “wiring” in the brain of someone with autism isn’t in quite the right order. It is encouraging to learn, however, that some people (between 3 and 25%) diagnosed with autism will eventually “grow out of it,” and will no longer exhibit the behaviors necessary for an autism diagnosis.
In addition to synaptic dysfunction, it is believed that there is abnormal signaling in the neurons of the basal forebrain that are related to acetylcholine. The levels of brain-derived neurotrophic factor are also very elevated in people with autism. Acetylcholine acts as an anti-inflammatory neurotransmitter in many cases, and so with its dysfunction, there are also some abnormal amounts of inflammation seen in those with autism.
It seems that polyunsaturated fatty acids might play a big role in helping to limit some of the negative effects of autism. They can help inhibit the production of cytokines, which will lead to inflammation, and may also contribute to the formation of the appropriate synapses which are absent in autism. They will also help contribute to neuronal survival. Unfortunately, the levels of polyunsaturated fatty acids are lowered in autism, but if we can effectively supplement these or reversing this pathology, we might have a chance to try and limit the effects of autism that we see. It might also be helpful to help supplement brain-derived neurotrophic factor. Yet another thing that might be helpful in limiting the effects of autism involves making sure nitric oxide levels are neither too high nor too low, as both situations can have adverse effects due to nitric oxides role as a neurotransmitter, but also due to its toxicity at higher levels.
Whether you understood anything I just told you or not, you can probably take away one important message. The pathogenesis of autism is quite complex, and something that will likely take much more research if we are to ever have any hope of developing effective treatments or finding some sort of cure. We did find one promising medication through our study of this article, but whether it is truly effective appears to be something that still needs to be investigated in more depth. This article was yet another reminder of how complex some of these neurological conditions are, and that often there is no easy answer in the treatment of many of these. Though we can investigate many different avenues for many of these conditions, truly finding solutions becomes much more complex because we need to make sure we aren’t affecting other systems adversely when we try and bring things from the diseased state to the normal state. Indeed, drug development is a very complex process.
Spinning Out of Control
I don’t know about you, but I’ve never spent a lot of time contemplating the brain’s role in the development of obesity. I, like I’m sure many others, have always thought about obesity somewhere along these lines: “Well, people like to eat, and they just have to control themselves… Some people are just more or less motivated to do this than others.” Of course, this inner monologue usually had more context than I’ve introduced this with, and that context usually served to make the series of thoughts much more relevant and usually more serious. I never stopped to consider that perhaps obesity, like many other things, is part of a vicious cycle, where one struggles to get off the train after he or she initially gets on.
There are two main types of neurons that are important in the regulation of appetite, and that subsequently appear to be quite important in the development of obesity. POMC neurons, when activated, will essentially send the signal that you are full, and that you don’t need to eat any more. One of the main molecules that is involved in sending this signal is called CART. On the other side of things, ACMP neurons send the signal that you are hungry, and that you should eat. This is done largely through the actions of neuropeptide Y, or NPY. Maintaining the proper balance of activation of these neurons is very important in maintaining proper nutrition levels. It is very interesting to note that when you eat and what you eat can alter the signaling in these neurons. For instance, what is usually considered to be an unhealthy diet will deactivate the “don’t eat” POMC neurons and activate the “eat” ACMP neurons. As a result, when one starts to eat unhealthily, it is perpetuated by a desire to continue to overeat.
To me, this starts to raise questions about the role of free will in obesity and other diseases of the brain. We can become somewhat addicted to food in a similar manner as things we consider more to be “drugs,” and as we learn more and more about the many facets of addiction, we find that although free will is never completely absent, it may become harder and harder to summon as the hole which is dug gets deeper and deeper. It is hard to think of obesity this way, as it is something that so many people suffer with, and oftentimes it is truly difficult to get back on the right path. The problem is not helped by the fact that the cheapest food around is the most unhealthy. If a family is struggling with money, eating salads may not necessarily be at the top of their priority list. As a result, people may become trapped not only by the neurological basis of overeating or poor nutrition but also by the socio-economical trap of not being able to eat healthy foods on a regular basis, and thus the situation often quickly spirals out of control.
Lithium: Still a little sketchy…
Sometimes, it’s amazing (and a little bit terrifying) to think about how little we know about a medication before it hits the market and is given to patients. Of course, the medication has gone through rigorous trials to ensure that it is both effective in treating the targeted disease, and that it is safe to be taken, but the exact mechanism often remains a mystery for a long time, and we may still be working on figuring it out. For example, lithium has been used to effectively treat bipolar disorder for over fifty years, but we still don’t know every detail regarding how this happens.
We do know that it plays a role in providing protection for neurons, and also that it aids in providing trophic support, which means that it helps to provide the nutrients that the neuron needs to function properly. Two major mechanisms are at play in lithium’s actions. Lithium blocks the actions of glycogen synthase kinase-3 and kick-starts the actions of brain-derived neurotrophic factor. It also regulates the amount of calcium which can freely enter the neuron, which is a good thing as in some cases, calcium can cause the cell to undergo apoptosis, or programmed cell death. Lastly, lithium will lower levels of something called 1,4,5-trisphosphate by blocking the thing that helps to produce these, called phosphoinositol phosphatases. This stops the cell from inducing autophagy, which is another mechanism by which the cell might destroy itself.
The applications of lithiums effects seemed nearly limitless while we were discussing this paper in class. It can help to limit the adverse effects of diseases ranging from stroke to Huntington’s disease, and everything inbetween, including amytrophic lateral sclerosis (otherwise known as Lou Gehrig’s disease), fragile X syndrome, Alzheimer’s disease, and Parkinson’s disease. In fact, as we were studying lithium, it began to seem as if there was nothing it couldn’t do. We began to ask ourselves why we weren’t taking lithium as a regular supplement, and it only became apparent after a little research that though lithium has many beneficial effects in treating disease, it also isn’t necessarily something we want floating around in our bodies at extremely high concentrations. As we reached this realization that there is certainly too much of a good thing, I began to think about how easily the public conscious is swayed by information like this in the same way that we were.
I recently saw a post by a friend on Facebook cautioning everyone against vaccines, and as I clicked on the link to see what so-called evidence lay behind this proclamation, I realized how any of us can be easily swayed by information that we are presented with, especially when we aren’t familiar enough with the content to know what the right questions to ask even are. If we take a little time to familiarize ourselves with the topic broadly, we can start to see where the holes in the logic are. I’m not saying that we have to know everything about every single topic—to say such a thing and believe that this is a real possibility seems almost ignorant—but knowing enough to figure out what questions to ask and then exploring those is certainly the first step. All those years ago when it was discovered that lithium was beneficial in treating bipolar disorder, the researchers certainly did not know everything about it. Even today, we are still discovering more every day. However, they learned enough to figure out what the right questions to ask were in both the short and long term. First, is it safe and effective to use in treating bipolar disorder, and then later, how does it work and what else might it be used for? I think this skill of learning to ask the right questions is one that we all (myself included) undervalue, but is one that can be extremely helpful in gaining a clearer picture of the topic at hand.
Liberal Arts, the Brain, and My Capstone Experience
One of the biggest reasons I chose Concordia College was the fact that it is a liberal arts college. Contrary to my stepdad’s belief that a liberal arts college turns its students into left-wingers, Concordia College prompts its students with the challenge to become responsibly engaged in the world. This is done over a period of four years where students cultivate a love for learning, develop foundational skills and transferable intellectual capacities, gain an understanding of disciplinary, interdisciplinary and intercultural perspectives, and nurture an examined cultural, ethical, physical, and spiritual self-understanding. Although students chooses a major in which they focus their studies, they must also complete the core curriculum. The core curriculum draws from diverse departments, allowing students to gain a well-rounded education. A major element of a Concordia education is the capstone course, which aims to draw together all of Concordia’s learning goals into one course. I chose Neurochemistry as my capstone course, and it did not disappoint.
As a biology major and chemistry minor, I am use to the traditional lecture-style course in which material is learned for quizzes and exams. Neurochemistry was not like this. Although there was some lecture early on in the class in order to gain the necessary knowledge for the rest of the class, the course was largely discussion based. Right off the bat we were told that we would get out of this class exactly what we put into it. We wouldn’t be tested on specific knowledge, so it would be our responsibility to be informed on each topic. Each week we would read a paper, discuss what we didn’t understand, research and present on these topics, and finally discuss the topic with a wider focus. While it was important to gain a full understanding of the paper and the disorder we were discussing, I came to understand that it was just as important to put it in a wider context and discuss the political, social, and economic implications. As a science major, I found it initially difficult to look beyond the science and consider a topic in a wider context. Throughout the course of the semester, however, this grew to be one of my favorite aspects of the class. In following the framework of a liberal arts education, neurochemistry allowed us to take an interdisciplinary approach to topics we may not have in the past.
Although the course was largely unconventional, we did still take exams. However, these exams were very different from any other I had taken. We were given a deconstructed version of a scientific paper upon which we were supposed to formulate a hypothesis. This hypothesis had to be based upon the science presented to us and explain the events that were noted. In addition, there was a take home portion of the exam in which we were given the full article and asked to critique the hypothesis we had formulated during the in class portion of the exam. I personally loved this style of exam as it forced us to not only think critically, but gave us the opportunity to learn from and correct any mistakes we had made.
Neurochemistry has proven to be one of my favorite courses I have taken while at Concordia. For me, the hallmark of a good class is one in which I am able to learn just as much about myself as I do about the material of the course. While learning about signaling of the brain, molecular pathways, and neurodegenerative diseases, I was also able to gain a greater sense of appreciation of lifelong learning, collaboration, and interdisciplinary work. More importantly, I was able to break outside of my often narrow focus of scientific topics and consider them in a broader scope. While I am thankful for the knowledge I have gained in this course, I am even more thankful for the fact that I have grown as a student and as an individual.
ALS: A Tough Disease to Swallow
Imagine this:
You are a 45 year old individual. You are married and have school-aged kids. You have a successful career in which you have found fulfillment. Overall, you’re a pretty healthy individual. Generally, you are happy. However, you’ve recently been experiencing muscle weakness and the occasional muscle spasm. After a couple of weeks you finally decide to get it checked out. With a few tests, the doctor calls to give you the news: you have been diagnosed with amyotrophic lateral sclerosis (ALS) with a prognosis of 3-5 years. In a moment your life has become infinitely more complicated. You must consider how to manage this disease as well as what steps you will need to take to provide for your family after you are gone.
While this may seem dramatized, it is likely all too true for many individuals suffering from ALS. ALS is a neurodegenerative disease that is characterized by the progressive loss of motor neurons. This disease is popularly known as Lou Gehrig’s disease. Approximately 20,000-30,000 individuals in the United States have ALS with 5,000 being diagnosed annually. The disease typically has a fast progression with a mean survival time of 3-5 years. Symptoms progress from localized muscle weakness, fatigue, slurred words, poor balance and a weak muscle group to the loss of function of most voluntary muscles, requiring assistance in breathing and the use of a feeding tube. There is currently little to be done to treat ALS. When patients are diagnosed they are encouraged to gain a reasonable amount of weight as fat reserves will be able to provide energy as the disease progresses. Currently, riluzole is the only pharmaceutical approved for the treatment of ALS. It works by decreasing calcium influx and indirectly blocks the stimulation of glutamate receptors. It has been shown to extend the life expectancy by 3-5 months and delays the need for a tracheostomy or ventilator dependence. With few treatment options, care for ALS patients is primarily aimed at providing comfort and independence.
Although we do not yet understand the mechanism behind ALS, we do know that disturbances in calcium homeostasis and protein folding are essential features of neurodegeneration. Because of this, folding proteins are a hopeful target for pharmacological treatment of ALS. The ultimate goal is to stabilize the folding of proteins and prevent their aggregation. Currently, there are two ways in which scientists hope to modulate ER stress that leads to improper folding of proteins. One approach aims to inhibit the ER stress pathway, ultimately preventing cell death. The second method aims to induce the unfolded protein response with the hope that proteins will be able to be properly folded. Although these methods work in two very different ways, both hope to correct noted problems associated with ALS. Our lack of knowledge on the pathology of ALS highlights the need for research on this disease. With a better understanding of the disease there is hope to provide better care to those who suffer from it.
What does Calcium have to do with ALS?
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that affects around nearly 22,600 Americans at any one time. Due to degeneration of motor neurons, muscle weakness is the main symptom of the disease. Motion in muscles is lost, spasms may occur, speech is affected, and eventually the respiratory system gives out. Usually with a late onset of somewhere between 55 and 65, those diagnosed with ALS have an average lifespan of 3-5 years after diagnosis. While the cause of ALS remains somewhat a mystery, it is known that there is a hereditary factor, with the disease known to run in families. Calcium has recently been found to play an important role in ALS.
The article our class focused on this week is titled “Calcium-dependent protein folding in amyotrophic lateral sclerosis.” Protein misfolding in cells can lead to neurodegeneration. Calcium levels regulate folding proteins which are responsible for correct protein folding. Calcium homeostasis is disturbed in those with ALS and this causes higher levels of misfolded proteins. It is clear that disruption in calcium homeostasis is a problem, but researchers are still not positive that misfolded proteins are leading to neurodegeneration. Much research still needs to be done in this area before finding the cause or the cure for ALS.
The interesting thing about ALS is that it doesn’t affect cognitive abilities nearly as much as physical abilities. Our class had a very interesting discussion about the difference between declining physically but not mentally, versus declining more mentally than physically. This is such a difficult question that I don’t think anyone has a simple answer to. Would you rather have your body physically disabled and not be able to speak well and know what’s going on the whole time? Or would you rather lose it mentally before you can watch your body basically fall apart? Not that anyone can choose the outcome of this, it sparks interesting discussion.
In the end, this article did not come up with a cure for ALS, nor is there really anything we can do in our daily lives to prevent the disease. Of course eating healthy and getting exercise can never hurt. There is still a lot of research to be done in terms of ALS. The research presented in this article is leading researchers in a good direction and hopefully one day we will know much more on ALS and can help those who suffer.