Veni, Vidi, Vici
The search for a better understanding of life begins here.
2023 started where 2022 left off with the continuation of my final year project (FYP). I had to stack four 4000 modules along side my FYP. It was tough but I endured, securing three A's and 2 B+. I graduated with a CAP of 4.11/5.0, not the best that I could have done.
Sometimes I ask myself why did I only start to do well in year 3 at NUS. Then I realised, it was the year I fell in love with neurobiology. Learning about action potentials, resting membrane potentials and neurophysiology just resonated with me so well. I only realised then how much I truly loved physiology. All of our cells are encapsulated by a cell membrane. Every process in and out of the cell depends on the state of our cell membrane for without it, the cell perishes. Yet, receptors and channels are the cell's only passage into and out of the external environment. That made me think about our boundaries in life. Like the cell's membrane, we are encapsulated by our character, skills and experience yet so much more potential lies ahead with we are willing to break open into our external environment. I've always wanted to teach. I made 2023 the year I started to teach and communicate science to actual students. Trust me, it was tough. I was so blessed to have my first student in July. He was a primary 6 kid with an extensive knowledge about phenomena beyond his syllabus. He reminded me of myself when I was younger, reading encyclopaedias and watching the discovery channel, when my friends were reading magazines and comics. My second assignment was tough. I met students who were unwilling to open up to science, holding their convictions so tightly. Nevertheless, I persisted and completed my assignment. I started private teaching in August. A young 17 year old girl at the bottom of her class with a GPA of 1.40/4. Her mother, a doctor, had forced her into studying nutrition in a bid to be a part of the industry. I was hired in the middle of her semester and had to try my best to bring her up from failure to a passing grade in 3 weeks. She was clearly disinterested in human anatomy and physiology and had no reason to be interested either - she did not get to choose. I could empathise with her. When I was her age, I had a false sense of belief that maybe I was always meant to pursue medicine - I got through to the interviews but failed terribly. My naive 20 year old mindset was inadequate to face the challenges at that time. I did not pass the interview and I did not make my parents proud that their son could have been a doctor. The dream is long dead. I still am very well-versed with medicine categories and symptoms but they only serve to remind me of what could have been. I did not pursue medicine again because I dread reliving everything again - the hopes people had in me, the nights I spent worrying about my application status while being constantly encouraged that I would definitely get in. Okay, I shall not digress further. Either way, this student of mine gradually developed a great mindset in understanding human anatomy and physiology. I would not dare say that I am a great teacher but I am certain she made the effort to study. I employed the tricks I learnt as a neurobiology student and my understanding of memory mechanisms. We did spaced learning with constant repetitions of the content. When I left her home on my last day, I was relieved because I have had a part in her educational life, exposing her to the wonders of biology. I am still expecting her final results - if she passes, she would not have to retake the module and she would be free to go overseas for holiday. If she doesn't, I am still certain she will persist and be even more well-equipped for the content. I am reinvigorated every time I meet my goals and achieve my level of satisfaction in teaching science. My current assignment is a primary 6 boy, who is already bright in his own right. Refining his knowledge of scientific concepts and breaking up misconceptions in his weaker topics continues to drive my passion for communicating science. I was recently offered the PhD program for my work at the learning and memory lab at NUS School of Medicine but I was not offered the scholarship. My professor has not been forthcoming with his intentions both financially and academically. Therefore, I have not made the decision yet on whether to accept the offer. It is a tough decision but I cannot leave all my eggs in one basket. I applied for a medical writing position at a reputable company recently but I think I messed up on the application. Perhaps I was too excited or hasty to submit my application. I did not properly check that the autofill boxes filled my name in reverse. I did not address my cover letter following the proper standards of the industry. I can only hope my content suffices and they see through my mistakes. I am still learning as I go. These mistakes will never carry on, but they have to occur first for me to be conscious about it. But that is life. All in all, 2023 has been a great year so far. One filled with challenges, celebration and convictions. Thefriendlyscientist is still finding his place in the world and his saga will definitely continue.
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PART I In 2021, over 537 million adults were reported to suffer from diabetes mellitus. This number is projected to increase to well over 750 million by 2045 if it remains unaddressed. Another whopping 541 million adults are pre-diabetic, on their way to join this long list of diabetic patients. This has severe implications as more people are suffering from chronic and secondary diseases that accompany diabetes mellitus. A staggering estimate of USD 966 billion was pumped into diabetes-related healthcare expenditure in 2021, a huge increase from USD 300 billion in 2006. We commonly use the word “diabetic” when we describe someone with persistently high blood glucose levels or chronic hyperglycemia (hyper-: high, glyc-: glucose, -emia: presence in blood). However, the word “diabetes” stems from the Greek diabainein or “to flow through” and does not give us much information about the condition of a person. Therefore, we must be clear when we characterize diabetes patients. To be more accurate, the term we should all use is diabetes mellitus – mellītus, Latin for “sweet”. Together, diabetes mellitus refers to something sweet flowing through. This quickly describes hyperglycemia in diabetic patients as "sweet" blood flows throughout the entire body. There are several types of diabetes mellitus (DM),
One key point to note is that T2DM is a progressive condition with multiple checkpoints before becoming a severe condition. These checkpoints do not mean that we have leeway before becoming serious as they are accompanied by other comorbidities that can greatly hasten the progression and affect our quality of life. Summary: Diabetes mellitus (DM) affects an alarming number of people in the world and weighs a heavy economic burden on governments and healthcare systems. There are several types of DM that affect people. 90% of DM cases are T2DM. T2DM is a progressive condition that increase our risk of several secondary diseases that affect our quality of life. PART II We will be diving deep into a potentially revolutionary drug that seems to be a more sustainable way of treating and slowing T2DM progression. First, we have to understand the mechanism of T2DM and how it affects patients’ quality of life. T2DM has both genetic and lifestyle-mediated components. It was found that a majority of T2DM patients have T2DM parents. Corrective lifestyle interventions have been heavily promoted by governments to combat T2DM cases through the years. However, it is still our choice to take these corrective measures at the end of the day. How does the body digest and absorb sugars? Everyone knows that a person suffering from T2DM has persistently high blood glucose. We often associate T2DM patients with amputations, loss of sight and ants surrounding a toilet after use. Have you ever wondered why? When we consume starch (complex sugars) from food, they are broken down first in the mouth by salivary amylase (an enzyme that breaks down sugar) before being further broken down by several other enzymes in the small intestines into glucose (a simple sugar). Glucose is first absorbed by the small intestines and then blood capillaries that circulate glucose around the body via the cardiovascular system. This forms our general supply chain for glucose demand around the body as all our cells require glucose for energy! How does T2DM cause problems for patients? As complex sugars are broken down into glucose, it sends a signal to our pancreas to produce insulin. Insulin serves as signaling molecules for all our cells to be ready to absorb glucose from the blood. You can think of insulin as a key card granting glucose access to our cells. In T2DM, our cells no longer respond to insulin as efficiently as before – insulin resistance! Glucose remains idle in our blood and does not get completely absorbed by our cells! In the long run, chronic hyperglycemia causes glucose to coat proteins and fat in our blood, resulting in damage to blood vessels in certain areas of our body. At first, the pancreas tries to compensate this resistance by producing even more insulin. If no proper measures are taken to support this, eventually even the pancreas would fail and the cells producing insulin would die. The progression of T2DM has officially transitioned into a more severe condition, requiring patients to frequently inject insulin, just like T1DM patients. T2DM can be simply characterized by insulin resistance and therefore hyperglycemia. Interestingly and maybe paradoxically, hyperglycemia can both be the result and cause of insulin resistance. If the damage occurs in the retina, we observe blurred vision or blindness in these patients as blood is no longer sufficiently supplied to the light-sensing cells of our eyes. If damage occurs in the nerves our limbs, especially our legs, we would not be able to feel if we had cuts on our feet. This means that if we stepped on a sharp pin, we would not feel it and/or take any measures to remove the pin. Left untreated, this wound would be at a higher risk of infection and gangrene, likely leading to an emergency amputation to stop the infectious spread. What about ants in the toilet? Normally, only a small amount of glucose is found in urine. However, chronic hyperglycemia affects the kidney's filtration efficiency and capacity for glucose reabsorption over time. This causes a lot of glucose to “leak” out into urine, leading to “sweet urine”. Summary: T2DM is a progressive condition that has a genetic and environmental component. T2DM is characterized by chronic hyperglycemia due to insulin resistance. T2DM increases the risk of debilitating conditions that affect the quality of life of patients. PART III Chronic obesity is a public health concern as it increases the risk of insulin resistance, cardiovascular diseases and liver-related diseases. It also affects mobility and therefore the ability of these people to work and care for themselves. This results in social and economic complications as family members have to care for these immobile patients, many even quitting their jobs to do it full-time. Recall that chronic hyperglycemia is both the cause and effect of insulin resistance. What if there was a way to reduce our intake of food such that we do not put ourselves in deeper risk of T2DM and obesity? Semaglutide is a glucagon-like peptide-1 (GLP1) analog recently approved for use in lowering blood glucose levels in adult T2DM patients by the Food & Drug Administration (FDA). Once we understand what GLP1 does in our bodies, we can fully appreciate how revolutionary this is. Glucagon-like peptide-1 (GLP1) What is glucagon anyway? Let’s break it down and compare with insulin. Insulin and glucagon are both part of a feedback system to ensure our blood glucose levels are balanced. Glucagon raises blood glucose by using up our stored glucose (glycogen) and fatty acids by decreasing fatty acid synthesis. Both glucose and fatty acids can be used as energy sources to keep us running. This is what happens when we are in a starving state, our body literally eats itself up as it tries to use up stored energy like stored sugars and fatty tissue!
GLP1 is also produced by the body and behaves somewhat similar to glucagon but not exactly the same. Glucagon raises blood glucose while GLP1 reduces blood glucose by promoting insulin release. Let’s look at some of its functions.
The list goes on, but one thing is for sure. It seems… too good to be true. We must preface that these functions of GLP1 are mostly associative and not completely known to result in these effects. One thing to note is that although GLP1 is made in our bodies, they are released at low levels (picomolar) and only rise 2-3x when we consume food. Some food groups like fat, protein and dietary fibre were shown to promote GLP1 secretion. Since Semaglutide is a GLP1 analog, it should affect similar targets of GLP1! Let’s take a look. Semaglutide A double-blinded, randomized controlled phase 3 clinical trial conducted in 2018 showed that administration of 2.4mg Semaglutide once a week for 68 weeks resulted in almost 15% reduction in body weight for the diabetic experimental group vs the non-diabetic control group (-2.4%). Further body scans revealed that the experimental group also lost a significant amount of total body fat compared to the controls. Interestingly, controls still lost weight but at a lower rate. This could open up a new market for weight loss therapies but more has to be done to validate these effects. Inevitably, all drugs come with some safety risk and adverse effects. The majority of adverse events were gut motility-related complications like diarrhea, vomiting, headache and gastrointestinal disorders. Only a handful of patients suffered from hypoglycemia (very low blood glucose). This is a great thing as most anti-diabetic drugs (e.g., sulfonylureas, biguanides) leave patients with severe hypoglycemia and thus at risk of loss of consciousness, seizures and even death. Summary: Semaglutide is a glucagon-like peptide-1 analog that has promising drug efficacy in controlling blood glucose and weight gain in obese T2DM patients. It is a promising tool for weight loss programs but more work has to be done. Semaglutide safely reduces blood glucose levels but carries with it some risk of negative gut-related symptoms. So, is Semaglutide a great alternative for treating T2DM? The answer, as with many new drugs, remains uncertain until more work is done. Being FDA-approved is only one step towards understanding the power and risk of Semaglutide. There are still many years of post-market surveillance and diligent adverse drug reporting (pharmacovigilance) to account for before we can truly put our faith in Semaglutide. Until then, this is your friendly scientist signing off! References Barnes, A. S. (2011). The Epidemic of Obesity and Diabetes. Texas Heart Institute Journal, 38(2), 142–144. Goyal, R., & Jialal, I. (2023). Type 2 Diabetes. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK513253/ Klein, B. E., Klein, R., Moss, S. E., & Cruickshanks, K. J. (1996). Parental history of diabetes in a population-based study. Diabetes Care, 19(8), 827–830. https://doi.org/10.2337/diacare.19.8.827 Mahapatra, M. K., Karuppasamy, M., & Sahoo, B. M. (2022). Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Reviews in Endocrine & Metabolic Disorders, 23(3), 521–539. https://doi.org/10.1007/s11154-021-09699-1 Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., & Kushner, R. F. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 384(11), 989–1002. https://doi.org/10.1056/NEJMoa2032183 Stick your dominant arm out with its palm side facing down. Now, with your non-dominant hand, locate (with your index finger) the centre of your dominant palm in one try. Most of us will get this right 100% of the time - I mean, who doesn't know where their body parts are? Take for example, how do you know where to scratch when you feel an itch? How does your brain know that that body part is there?
Enter, proprioception or the ability for your brain to know where its limbs are, how to aim and how to move. Why is the sensing of movement important? First, we have to look at what happens if it goes wrong, because in order to know how things work we first have to know what happens if they don't! The cerebellum ("little brain") is the main control centre in the brain for the coordination of voluntary muscle activity, equilibrium (balance) and muscle tonus (a steady state of partial muscle contraction in order for movement/posture). It's key to note that the cerebellum itself does not initiate muscle movement - that part is initiated by the primary motor cortex and the premotor cortex in the frontal lobe of the brain. Therefore, if the cerebellum is damaged due to injuries like stroke or head trauma, patients would tend to have uncoordinated movement or ataxia - picture someone needing to use the bathroom really badly while doing a weird walk. Now, in order for our cerebellum to coordinate such movements, it needs to receive information from the senses - one of it is proprioception and a copy of the request sent down from the primary motor cortex to skeletal muscles (muscles that we love to build). With these information, the cerebellum can integrate and regulate muscle tonus and motor activity unconsciously - imagine having to think about how to move your limbs every time you walk! It'll be a terrible waste of conscious effort! Case Study #1 A retail manager, Sam, got into a car accident in which he suffered multiple injuries to his skull and brain. During his post-accident rehabilitation, doctors noticed he had an abnormal sense of balance and posture - something a lot of us take for granted. Sit up straight! His doctor suspected cerebellar damage and sent him for multiple lab tests and MRI scans. These tests confirmed her suspicions and she diagnosed Sam with truncal cerebellar ataxia. Let's break these words down.
So now that we have a sense of what it would be like if we have a damaged cerebellum, let's focus on proprioception. Often known as the sixth sense, proprioception is the sense of self-initiated movement, amount of force produced and body position relative to space. As I've mentioned above, it is important for our cerebellum to process these information in order to initiate smooth motion. Perform a wiping motion and observe how elegant your arm moves. A damaged cerebellum would result in a myriad of problems,
How does the brain receive this information? What form does this information take? In an ingenious stroke of evolution, our muscles, joints and tendons are FILLED with mechanosensitive neurons. As the name suggests, these neurons are responsible for sensitive in detecting changes in muscle tension, joint position and load, and reporting it to the central nervous system (brain + spinal cord) for processing. There are 2 pathways for proprioception,
The names of these pathways are not important, but the key idea you need to get from this is that we are incredibly constructed in a way that almost all senses have established pathways to the brain for processing and the initiating of a subsequent reaction. This can also be seen in amputees who have lost their limbs. Some amputees experience what is known as phantom pain - the feeling of pain in the now non-existent amputated limb. But how? It is because, although the limb is gone, what's left of these established pathways are still present and sending information to the brain as per normal. The brain is so plastic (malleable) that it is able to redirect information from the body (whether it's still around or not) to another part of the brain - although most of the time it's at random, producing strange experiences like phantom pain. I hope this week's post has invigorated you to go out and move! Appreciate your body and its ability to move without a second thought, fluidly and in complete coordination. No one truly has two left feet! Stay safe and curious! Case Study Information: https://www.physio-pedia.com/Cerebellar_Ataxia_-_A_Case_Study While there is no clear evidence supporting the existence of ghosts, ghouls and spirits, there are studies that suggest that ghost sightings are merely auditory-mediated hallucinations and pareidolia (perceiving meaning in meaningless stimuli). It turns out that frequencies of sound (between 0.1 to 20Hz) below the range of human auditory awareness can cause hallucinations. These sounds is known as infrasound or the aptly named "haunted frequency".
Vic Tandy recounts in "The Ghost in the Machine", published in the Journal of the Society of Psychical Research in 1998, of how he and his colleagues experienced creepy hauntings at their laboratory. I would like to caution that this journal publishes research related to the world of parapsychology and should be read with an open mind - although I am not much of a believer in the mystics, I do believe that we should give people a chance to share their ideas despite not having training or professional experience in their fields of interest. At first, Vic dismissed any claims of a haunting in his lab until he had an experience himself. One night, he saw a white misty apparition from the corner of his eye and at that point, he broke out in cold sweat with fear clouding up his clarity. However, after mustering up the courage to confront the apparition, it vanished. Coincidentally, as he was fixing his fencing sword for an upcoming competition the next day, he observed that his blade started to vibrate while it was clamped on a bench vice. Being a trained engineer, he connected the dots that the blade was only capable of vibrating as it was likely receiving sound energy at a rate/frequency close to its own resonant frequency. Resonant frequencies are frequencies of sound that resonate/oscillate much stronger as it approaches the natural frequency of whatever it is acting on - take for example how some opera singers are able to break wine glasses with their voice. They are producing sounds that match the natural frequency of the wine glass at a high amplitude (what we call "volume"), causing the molecules that make up that glass oscillate at an even higher amplitude or vibration. This strong vibration produces structural strain that causes it to eventually break. Likewise, humans also have a natural resonant frequency (about 5Hz for whole body and 19Hz for ocular (eye) resonant frequency). This flipped a switch in Vic's head because if sounds below human perception can cause things to move on their own, what makes us so sure that our bodies are not subjected to strong vibrations caused by resonant frequencies in our surrounding environment? Vic peered deeper into this lab, looking for machines and electronics that may produce sub-threshold sound frequencies. He finally found the root of the ghostly sightings in his lab - a newly-installed fan in the room where most of the hauntings were sighted. He realised that the room happened to be built in such a way that sound was constantly folding back on itself into a standing wave - this makes sound waves peaks higher and troughs deeper! The frequency? 19Hz. This suggested to him that perhaps there is something about infrasound waves and hallucinations. Further studies found out that experiencing infrasound may lead to difficulty breathing, visual and auditory hallucinations as these reinforced sound waves were resonating with our organs. As you may know, the retinas in our eyes receive and transmit light into electrical signals that travel to the back of our brain - the Primary Visual Cortex. In this area, these electrical signals are processed and shared with other association areas across our brain. Therefore, if our retinas are affected by resonance, it could possibly lead to erroneous signals being sent to the primary visual cortex and perceived as objects that may not even be real, say blurred vision or even hallucinations. It was shown to also produce a sense of dread in people - "I don't feel so good", "this place doesn't feel right", etc.. Realise that most haunting happen in hospitals? Can you guess what hospitals mainly operate with? Machines like medical devices that produce a plethora of sound frequencies - lots of them. However, as we love to find meaning in things, we often correlate a place of death as a place of hauntings, unknown to the fact that perhaps the explanation is much more simpler and direct. Even low-levels of carbon monoxide poisoning can produce difficulty breathing, dizziness, a sense of dread, visual and auditory hallucinations in people. It was even noted that some seemingly haunted places were also sites within a field of infrared sound - some even 200 times stronger in volume - although we are unable to hear them due to the limitations of human biology (human audible range is about 20-20kHz)! It was noted that when these sounds were silenced, the hauntings also seemed to disappear. Just because we are unable to hear these sounds doesn't mean that they do not exist! Well, the paranormal aficionados would likely say the same for not being able to see ghosts. Touché... While I am not discounting your experiences with the paranormal, I would like to open your mind to the possibility that our experiences may not be as reliable as we think! Perhaps this world isn't as spooky as we think and we shouldn't always accept that odd experiences are undeniable facts that prove the existence of the paranormal. It is possible that the cultures of old likely experienced similar inaudible infrasounds and/or chemical leaks that produced vivid hallucinations. Perhaps they incorporated their experiences into legends and mythology because they were unable to explain these occurrences! Well, spooky or not, you decide! Stay safe and curious! Sources How Can a Voice Break Glass?. (2022). Retrieved 9 July 2022, from https://wonderopolis.org/wonder/how-can-a-voice-break-glass Segall, J. (2022). The Haunted Frequency - Higgs Centre for Theoretical Physics. Retrieved 9 July 2022, from https://higgs.ph.ed.ac.uk/outreach/higgshalloween-2021/haunted-frequency Tandy, V. (2022). The Ghost in the Machine. Retrieved 9 July 2022, from http://www.richardwiseman.com/resources/ghost-in-machine.pdf After a week of intense training, I have learnt so much (although there is always more to learn) about field electrophysiology setup and about my area of work - Hippocampal CA2 neurons.
Let's first talk about field electrophysiology. As you may know, our neurons communicate through ionic charge (e.g., the flow of cations (e.g., Na+) and anions (e.g., Cl-)) in an electrical-chemical-electrical fashion. The chemical aspect of this communication comes in the form of neurotransmitters like dopamine, serotonin, acetylcholine, to name a few notable ones. When neuron A wants to talk to neuron B, an action potential must first be initiated by the cell body (soma). This charge is summated at the axon initial segment and axon hillock (sort of like a form-up point before entering a battlefield) before the decision to fire an action potential is initiated. This action potential is what we normally recognise as the "firing" of neurons. The action potential then travels along the axon of neuron A, only to terminate at the axon terminal. This surge of ionic charge is a signal to the axon terminal to open calcium channels found there, thereby depolarising the axon terminal membrane (think of depolarisation as a trigger to open/close membrane-bound ion channels). This sudden influx of calcium ions kickstarts a cascade of cellular machinery to release little vesicles (packages) containing neurotransmitters - what type? well, that depends on what type of neurotransmitter neuron A expresses. These neurotransmitters are released into a sort of passageway most people would know as the synaptic cleft. For the sake of terminology, the area where the axon of neuron A meets a dendritic spine from neuron B is known as a synapse. The space in-between this synapse is known as the synaptic cleft. Neuron A (being the neuron before the synaptic cleft) is known as the presynaptic neuron while neuron B, the postsynaptic neuron. Now, these neurotransmitters can bind to their cognate channels along neuron B, allowing an influx of ions - depending on the population of ion channels on neuron B's dendritic spine membrane. This, again, produces an ionic current due to the flow of ions through the channel, causing neuron B's membrane to depolarise. As you can tell by now, this process is highly regulated based on the electrical state of neurons. Neurons talk (crosstalk) with many other cell types in our bodies to relay information or even feedback information to the brain regarding the state of the body - as you would probably imagine, damaged neurons/nerves will therefore have detrimental effects on the human body as a whole. So now that you have an idea about how neurons function in general, we can talk about field electrophysiology. The "field" in field electrophysiology relates to how we are recording the collective activity of a population of neurons and not single neurons. Electrophysiology can be explained as the study of the electrical properties of biological organisms - it is not only used in neuroscience but cardiology as well! My area of research is involved in looking at Hippocampal CA2 neurons - a population of neurons in the cornu ammonis area in the Hippocampal proper. The hippocampus, otherwise known as Hippocampal formation, is made up of several areas - Hippocampal proper, dentate gyrus, subiculum and entorhinal cortex. The most famous/well-known circuit in the hippocampus is the trisynaptic circuit, whereby afferent inputs ("coming inwards") are picked up via the entorhinal cortex and are passed into the dentate gyrus via the perforant path that "cuts through" the hippocampus. This information is passed from the dentate gyrus to the CA3 and then CA1 area via mossy fibres and Schaffer's collaterals respectively. 4 areas of concern synapsing with each other via 3 distinct synapses = trisynaptic circuit. As you can tell, the CA2 was not even mentioned above - although in recent times, there is a growing establishment of a disynaptic circuit that revolves around the entorhinal cortex, CA2 and CA1. Used to be, the CA2 was seen as a just transitionary area of CA1 and CA3 - although generally, the CA2 area is involved in processing social memory and motivation. Disruptions in the CA2 area was shown to increase interaction time between mice who had previously met, as if it's their first time meeting each other every time. However, with modern technology and analytical equipment, we are able to distinguish certain genes selectively expressed in CA2 neurons - namely RGS14, a protein suggested to be the reason why CA2 neurons are highly resistant to plasticity at the Schaffer's Collateral-CA2 synapse. This is awkward because most neurons in the hippocampus are highly plastic (the ability to change their synaptic connectivity and function). However, dendrites found more distal (away) from the CA2 cell bodies are highly plastic - Entorhinal Cortex Layer 2-CA2 synapses at the stratum lacunosum moleculare (SLM). There is still so much more to learn about the CA2 area, especially how certain neurotransmitters like Acetylcholine can actually 'prime' CA2 synapses before a weak tetanization to create long-lasting potentiation (Benoy et al., 2021). For now, I haven't really been given a direct project objective but I have been training and familiarising myself with the maintenance and operation of the field electrophysiology setup. I have also been trying to locate CA2 neurons, entorhinal cortex-CA2 and Schaffer's collateral-CA2 areas through familarizing myself with how these signals should look. I also tried eliciting early-LTP (short-lasting potentiation of neurons) and late-LTP (long-lasting potentiation of neurons, >3hrs) in these synapses. However, I have been unsuccessful in producing good results. I believe that with time and more experience with the setup will allow me to be more efficient. Eventually. With that, this closes another stressful yet exciting week! Stay safe and curious! Benoy, A., Bin Ibrahim, M., Behnisch, T., & Sajikumar, S. (2021). Metaplastic Reinforcement of Long-Term Potentiation in Hippocampal Area CA2 by Cholinergic Receptor Activation. The Journal Of Neuroscience, 41(44), 9082-9098. https://doi.org/10.1523/jneurosci.2885-20.2021 In 1949, Donald Hebb famously introduced his postulate in his book "The Organization of Behavior" - what is now known as Hebb's Postulate - that "neurons that fire together, wire together". This co-activation is what we believe happens when memories are first created. For one, we know that a majority of neurons in the brain can no longer divide or make copies of themselves after embryonic development - except in the dentate gyrus of the hippocampus and cells in the subventricular zone that continually produce adult neural stem cells. Another notable area is in the olfactory epithelium that lines our nasal cavity allowing us to have the sense of smell. Imagine if our neurons divided every time we make a new memory, our heads would most likely run out of space and explode! Therefore, we have to look deeper into structures that is iconic and unique to neurons.
Synapses are little bulbous connections that form communication links between neurons. It is estimated that the human brain is made up of around 86 billion neurons, that would give us about over a quadrillion possible synapses - imagine the potential for storage space and connectivity! To simplify this, let's break it down. Neurons are specialised cells that form part of the brain - a majority of rest are sort of housekeeping cells that ensure that neurons have a comfortable environment to sustain their functions. Each neuron has dendrites (so called input sensors) and an axon (output projectors). Dendrites branch out like little roots and they link up with axons from other neurons in order to receive information. These little roots contain bulbous synapses that act as transmission points or like a mailbox. Now that you are familiar with dendrites, axons and synapses, we can finally talk about how synapses are truly the places where memories are stored due to their immense quantity and complexity. So, neurons that fire together, wire together. In neuroscience, a competing theory of how memories are sustained for long periods of time revolve around long-term potentiation (LTP). This is because neurons communicate via an electrical-chemical-electrical method. Long-term potentiation just means that activated neurons ("fired") sustain a long period of electrical stimulation that signals to its own nucleus (sort of like the HQ of the cell) to kickstart a whole cascade of processes that enables its continual connection with whichever cell initiated the firing/potential in the first place. This continual connection lies in structural and functional changes in the synapse - therefore, LTP is a process that strengthens connectivity between neurons. Remember how I mentioned that association with other events tend to create stronger memories? Memories are not physical objects in the brain that can be stored and retrieved like your hard drive. Memory is the probability that the same circuit/network of neurons activated upon the first exposure to a stimulus is activated again based on another related stimulus. This probability is further tilted in the favour of "remembering", only if you strengthen it with repetition, associated events or emotions. Let's take your name for example. How do you know your name? "My parents gave me that name.". Alright, I think I've set the bar too low. But have you ever wondered how you remembered that? Perhaps, it was your first day of school and your parents were frantically making sure you remember your name and how to spell it by repeating it over and over again. The excitement or anxiety of your first day at school plus the constant barrage from your parents greatly strengthened your image or memory of your name. So think of this, every time someone asked you about your first of school, you seem to remember the flow of things - parents nagging at you on whether your remembered your name and how to spell it, how you thought your teacher called out your name when they didn't, how embarrassing that must have felt and so on... These related events are then associated with the memory of your name and the events that occurred on your first day of school. Neurons that fire together, wire together. Oh how we have come full circle... Okay, but repetition works too. How come? If you activate the same circuits over and over again, they also tend to sustain LTP. However, the caveat is that without persistent rehearsal, you would probably forget your memorisation in a few weeks or months depending on the context. An additional factor is sufficient sleep since most of memory consolidation occur during our periods of shuteye. Therefore, burning the midnight oil might be doing more harm than you think as it also opens the floodgates to a multitude of cardiovascular and metabolic diseases that can also affect neural function! Try to remember all these words in sequence in 10 seconds, Hairdryer Potato Landyard Yarn Geometry Animals Jargon Nut Unless you have photographic memory or employed the use of memory exercises to remember all the words, you probably only remembered the first two or three words and the last. Why is that so? What did you do constantly when you tried to remember the sequence of words? You kept repeating the first word again and again in order to start the sequence. How about the last word? Well, just so happens that the last word is the most recent word you remembered due to its place on the list - give or take another minute and you might forget it all together. There you go, I have proven today that memory is the probability of a network of neuronal firing - otherwise known as an engram - in the brain that occurs when you are relating it another event. This likelihood can be strengthened by emotional content, context and repetition. I did not go deep into the two different phases of LTP as it may only complicate the general understanding of memory consolidation into long-term memory. Stay safe and curious! Ever wondered why and how you remember things? Simple things like your own name, your home address, your favourite past time or food?
While I cannot provide you with a definite answer, there are several concepts that bring to light the core of memory formation and recall. Firstly, how is it possible that we remember significant events yet are oblivious to everyday routine? While the answer to this question seems like a no-brainer. "Of course you remember significant events! It's so... significant!", you might be shouting to the screen as you read the previous paragraph. But what is significance? Memories are more strongly consolidated in the presence of emotional arousal and even fear. To understand what is significant, we have to also look at what is insignificant. Daily routine is a good example of insignificance because we tend to just "go with the flow", incorporating "muscle memory" (although that itself is seemingly a part of procedural memory - like how you still remember how to ride a bike after years of not riding) into our everyday lives. Take for example, having a cake after a long day of work. If I had asked you what cake you had a day after, you probably would remember quite clearly since it was so recent. But if I asked you again a month later, you probably would not even remember having cake a month ago. However, if it was your 21st birthday and you had specially ordered a three-tiered strawberry cake with sparkler candles, it is highly likely that you would still remember it months or even years into the future. This is because of associativity - we associated the basic memory of the cake we had with its flavour (if it was a remarkable tasting cake), the people present at our birthday, the venue you celebrated your birthday at, the feeling you had when you cut the cake and when you received gifts. These additional events strengthen memory, especially if they provide some form of sensory arousal - smell, taste, sight, touch, hearing and proprioception (otherwise known as spatial awareness of your body - perhaps someone dunked your head right into the cake). In another simpler example, something insignificant would be how you are able to sleep every night without being bothered by the traffic outside. This form of habituation occurs because you have the same stimulation at the same time of the day/night - therefore, your brain works to ignore it. But you will always remember your first night living in that home and how you initially couldn't sleep! Amazing, isn't it? However, negative emotions can also strengthen memory - consciously and unconsciously. When was the first time you got scared? Perhaps, at a cinema while watching a horror film when you were 5 years old. You may not remember the exact scenes where the jump scares appeared but you do remember that horror movies tend to make you jumpy and afraid of going to the toilet at night. This "trauma" can also strengthen memory - fear memory. It associates objects or experiences that were similar to your initial exposure to that horror film. Perhaps, in the film the jump scare came out as the protagonist was walking through a dark alley. If that scene was extremely impactful or if you happen to chance upon a dark hallway or alley, you might feel a sense of fear - a tingling of anxiety as you question yourself on whether you should continue to walk through less you might get jumped or see something you shouldn't. However, under normal circumstances, we would forget these triggers and go on with our lives as time passes. Unfortunately, for those who have experienced real and impactful trauma, even with time, a simple reference to said traumatic event may cause them to trigger the same circuits in their brains when they were first exposed to the traumatic event. For example, war veterans hearing firecrackers during Chinese New Year may experience heightened anxiety and fear as they unconsciously/consciously associate the same sound as gunfire during their time of service as their brains activated the same connective circuits that were first created during the time a friend was lost in a firefight or when they thought they were really going to die. This is known as post traumatic stress disorder (PTSD) and it is not limited to war veterans, even victims of domestic abuse and/or sexual assault tend to develop PTSD. "Why have fear memory in the first place?", you might ask. Well, we aren't certain but fear memory does have beneficial purposes. Imagine that your ape ancestors accidentally stumbled into a lion's den while hunting. A pride of lions may have chased them out or even killed members of their tribes. Fear memory is advantageous for them to remember the location of the den and how they felt when they were in the face of imminent danger (the same system (sympathetic nervous system) used for fight-or-flight are then pre-activated as it anticipates danger), causing them to run away as far as they can from said lion's den if they were to chance upon it again. As with everything, too much of anything can become a bad thing - developing into stress disorders and depression as a result of overstimulation of the sympathetic nervous system even in the absence of a real threat. This post is just a brief overview of memory - the good and the not so good. However, we should learn to appreciate our brain as it makes so many decisions everyday to protect us from external threats and deciding which memories are worth keeping or throwing out. Stay safe and curious! Around December last year, I thought I had accidentally deleted the entire blog while tidying up its format. Thankfully, 2021 me did not press "Publish" and everything that I had thought were lost were still present online. With this, I have decided to continue thefriendlyscientist and document my Final Year Project (FYP) journey at NUS. I am attached to Prof Sajikumar's Laboratory, under Dr. Yee Song. I am hopeful and look forward to their tutelage. This would help me decide if I do want to pursue a higher education - PhD.
I would be looking into how memories are consolidated upon acute restraint stress. My first step is to test our protocols using theta burst stimulation (to emulate physiological brain theta waves) in the ventral hippocampus (vCA1). I will continue to bust myths and superstitions as my former self had intended for this website. Stay safe and curious! A beverage most people thoroughly enjoy is alcohol or rather ethanol (we will use these terms interchangeably throughout this article). Every alcoholic beverage comes with an alcohol percentage label. This labelling or alcohol percentage proof, as it is known, has been used since the 1500's, allowing the British Government to charge higher tax for beverages containing high levels of alcohol. Well, even after the levies have been lifted, these labels still exist on the bottles of our favourite alcoholic beverages - perhaps to remind us how much we truly appreciate the power of confidence it brings. Let's talk about alcohol and how it is metabolised in our bodies.
Consuming Alcohol You must be wondering why do we get drunk really easily when we drink on an empty stomach. Well, it's as simple as you think it is. When our stomachs are empty, there is nothing for the alcohol to get absorbed into and it will quickly get absorbed by our small intestines to enter our bloodstream. Alcohol has a stimulatory and depressive effect on our central nervous system, the former makes you extremely confident and excited while the latter makes you feel down and moody. These effects may result in long-term neurological complications especially in reducing neuroplasticity - the ability for the nerves in our brains to make new connections and prune unnecessary ones . Journey to the Liver Once alcohol reaches our liver, it is picked up by liver cells that quickly metabolises it because alcohol is seen as a poison in our system. Our livers are, after all, the most efficient detoxifying organ in bodies - so don't be wasting your money on "detox teas" or "detox pads". Drugs and toxic materials are mostly detoxified in our liver and kidneys before we excrete them out so that we do not risk circulating and introducing these toxic chemicals to the rest of the body. Liver cells express specialised enzymes to break down alcohol, namely - Alcohol Dehydrogenase (ADH) and Aldehyde Dehydrogenase (ALDH2). Alcohol Dehydrogenase breaks down alcohol by first converting ethanol into acetaldehyde - a very toxic chemical. This toxin is quickly converted into a much less harmful chemical known as acetate by Aldehyde Dehydrogenase 2. Acetate (a ketone body) can be shuffled out of the liver into the brain (especially when you are hypoglycaemic) and other organs to be used as an alternate fuel source. Alcohol and Medication Other enzymes like Catalase and Cytochrome P450 can also convert ethanol into acetaldehyde, however they come with a few setbacks. Cytochrome P450 is also used by the liver to break down drugs like paracetamol/acetaminophen. This should ring some bells in some of you. Remember how you've heard from someone that you should not mix alcohol with any drug, whether recreational or therapeutic? When we consume alcohol and drugs, the alcohol in our liver will force the breakdown of drugs like paracetamol to enter the Cytochrome P450 pathway as opposed to its intended and safer pathway. This shunting of paracetamol into a different pathway causes it to be converted into a more toxic chemical that can severely damage the liver. This toxic chemical is usually neutralised by an antioxidant known as glutathione. However, the worst part is that because alcohol has a higher priority in being metabolised, glutathione levels will be severely depleted to meet the needs of alcohol breakdown. This causes the toxic chemical to build up causing liver failure, and as I mentioned above, the liver is our most potent detoxifying organ so if it fails we will most certainly die. However, if you are quick to remember this article when you accidentally mix alcohol and prescription medication in future, be sure to immediately check yourself into the nearest hospital. They would usually treat you with N-acetyl-cysteine (NAC) to help replenish the depleted glutathione in your liver. We often ask ourselves, "What is life? Why do we live? What is our purpose?"
These questions do not mean that we are ignorant or poignant to living. We didn't even get the choice to exist, did we? We just simply became because our parents conceived us. If you find yourself asking these questions, it proves that you have acknowledged your stake in life and what you plan to do with it. It shows that you have the beginnings of an examined life according to Socrates. What is life? It is often difficult to draw the line between a living and non-living thing. In biology, we consider a living thing only if it achieves all these 7 criteria, 1. Order - organised structures and organ/organelle (little organs) systems 2. Response to the environmental stimuli - like not touching a hot stovetop... 3. Reproduction 4. Growth & Development 5. Regulation - operating pathways (blood circulation, waste excretion, etc.) 6. Homeostasis - maintaining a system of physiological order (temperature control, etc.) 7. Energy processing - making use of the food we provide to our bodies This makes viruses non-living things since most of them do not meet multiple criteria on that list. Viruses rely on host organisms to reproduce and propagate through an environment. They do not necessarily have organelles or even grow. The most "growth" they achieve cannot be credited as their own but a chance mutation by our dear friend, natural selection. They do not have any means of regulating themselves nor process any forms of energy. It is as if they are inanimate objects with a biological purpose - to hijack and host and make more of itself. Recall how evolution probably doesn't care about the organism? DNA just wants to replicate and preserve its own existence according to natural selective pressures - although "want" is not the best word to use since it is complicated to define the intentions of "inanimate objects". Perhaps viruses were once free-floating DNA that happened to be absorbed by a protein shell, that was beneficial at that time and just stuck with it as its own form of self-preservation. Why do we live? Unfortunately, I cannot give you a definite answer for this because no one can really answer it. Well, I can provide you with a possible biological explanation! Because natural selection has propelled us to. In order for DNA to replicate, it requires a whole system of proteins and enzymes to function. The system itself needs energy to function - that's where metabolism comes in. Our cells generate energy from the food we eat, in turn this energy is used for daily housekeeping and cell replication - all to preserve DNA and well... to keep you alive. DNA uses us as their "host organism" to feel hungry and stay out of trouble in order to remain alive. You can kind of think of DNA as our true puppet masters always conjuring up the next plan to keep us alive and reproductive. We live because DNA desires to preserve itself. If we die before we reproduce, our genetic lineage ends there. This is why we have urges to eat, sleep, keep healthy and avoid danger. These urges originate from hormones released from the brain telling the entire unit to survive and produce the best quality of reproductive cells - sperm and egg. Even fear is an evolutionary ability gained back in the day. Imagine not having fear, we would be charging straight into enemy territory or even jumping off unsurvivable cliffs. Without fear, we would not have strong motivations to make difficult decisions. Then again, we are the the result our DNA and our DNA defines our basic state. What is our purpose? Well... our purpose is to live. It's inevitable for us to die one day, so why not live life to the fullest? Living to the fullest is obviously subjective, everyone has their own perspective and goals in life. Our biological purpose is to survive and reproduce. However, because we are considered lifeforms capable of higher-order learning and thinking, we have moved past that stage in evolution to pursue higher goals. Unfortunately or fortunately, some of us have regressed to our ancestral ape behaviour - desiring to be alphas and competing with rival tribes through cunning and devious schemes (office politics *cough* *cough*). These are not entirely terrible traits since a society without leadership and direction leads to monotony and sluggish economies. Perhaps there is another form of selection at work? Ultimately, the purpose of life is what we deem it to be. The meaning of life according to thefriendlyscientist I believe that life has no true purpose apart from being at the mercy of DNA's journey towards immortality. We are born to reproduce and then return to the ground as life as ordained. That doesn't mean we have to live life under oppression from "treacherous DNA" or fear that there is nothing after death. We can define the meaning of life according to our own dreams and goals. We didn't complain before we were born, what makes you think we will after we die? I really hope I haven't cause anyone to have an existential crisis after this post. I feel that these are important and difficult questions to ask ourselves. Having a simple life and being ignorant to things outside of our comfort zone is great but is that truly a life worth living? There is more to life than living because we have evolve past the need for DNA's propagation. Look at couples who have decided to not reproduce or people who chose to remain single? It's proof that we have achieved a state of life outside the confines of genetically-driven urges. Natural selection is no longer our driver but sexual selection and culture - the ability to choose our mate or even remain single. I hope this gives you some form of comfort from what we have discussed today! If you have any thoughts or opinions that are different from mine, do share them in the comments! What is your definition on the meaning of life and its purpose? Let me know in the comments! |
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