When you hear insulin typically you think of blood sugar, the pancreas, or diabetes. Did you know it is in your brain as well? Well, if you didn’t no worries, until recently the brain was classified as an organ without it or just insensitive to insulin. Before we get into the logistics. Let’s review what insulin is exactly.

Insulin, when created in the pancreas is a hormone the allows glucose (aka sugar) to enter your blood stream. While in the brain it actually functions as a neuromodulator that helps neurons exist. According to a review, it is involved in neuronal survival, energy production, gene expression, and synaptic plasticity. As well as the breakdown of glucose as well. Metabolism or breakdown of glucose in the brain has been linked to have effect on how your neurons are able to learn and a persons’ memory.

A study has also showed that in mice neurons contain mRNA of preproinsulin. Which is insulin but in its’ “pre-hormone state”. It was found in all parts of the neuron including synapses. This leads to the synthesis of insulin. Insulin can also enter the brain from systems outside of the CNS. It enters through the BBB (blood brain barrier) by beta pancreatic cells.

So how does all this pertain to Alzheimer’s disease? (AD) Well, the by mistakes in the insulin pathways in the brain. Or a more common term, insulin resistance. Insulin receptors which control the breakdown of glucose in the brain. In turn can regulate of the overall health of neurons. Well, if the transmission of insulin gets wonky or in scientifical terms things like beta amyloid competition. Insulin cannot bind as well, which can lead to neuronal death. Therefore, insulin resistance can increase the pathology of AD.

Not only does insulin play a role in cognitive functions. Studies have also shown that it plays a role in anxiety and depression in the brain. Neuronal-specific insulin receptor knockout (NIRKO) has shown to increase anxiety and depression like symptoms in mice. Research has also shown that insulin can alter body weight and appetite. It can both increase and decrease appetite, which one? Well, it depends on how the insulin got to the brain.  Shockingly it increases appetite when insulin enters the brain peripherally. Synthesized insulin or the insulin made in the brain is what can cause a decrease in appetite and lowers body weight. Below is a little figure that I find helpful to keep track of how insulin plays a role in all parts of our bodies. And how in each part in changes different things for us.

Being that research about insulin in the brain is all new, the possibilities of new findings can lead to remarkable actions we may be able to take to monitor our own health. Insulin in the brain has already been linked to having effects memory, neurological diseases, mental health, and our physical health like appetite and weight. Who knows maybe one day insulin will be something everyone will be familiar with, not just those who have to monitor blood sugar levels. It will be something everyone will want to monitor for themselves to live a long and better quality life.

Alzheimer’s disease and broader dementia are a growing epidemic challenging care for global ageing populations. Characterised as a neurodegenerative disease, Alzheimers involves the degeneration of the brain and a subsequent loss of cognitive function. Memory loss, confusion, and delusion all plague patients with Alzeihmers, and so too, the family and caregivers who care for these individuals. As this disease becomes more prevalent amongst our future ageing population, intriguing research is coming forward on the causes of Alzheimer’s and even some of the ways to prevent it. A review by Ansab Akhtar and Sangeeta Pilkhwal Saw out of Punjab University in Chandigarh, India is presenting some useful insight on the effects of insulin to the brain. 

In order to understand this, however, we must first assess the two largest factors that contribute to the neurodegeneration in Alzheimer’s disease. The first is amyloid-ꞵ plaques. ꞵ-amyloid is a small protein that can misfold and connect with other ꞵ-amyloids to form a plaque-like formation outside of a cell. When this plaque forms, it inhibits the binding of insulin to its receptors in the brain. The second contributor to Alzeimhers important in understanding the effects of insulin are neurofibrillary tangles or NFTs. NFTs arise when Tau proteins become hyperphosphorylated leading to tangle formation in microtubule networks which leads to their collapse. In other words, look at Tau protein as a Jenga block at the very bottom of a tower that resembles the framework of a cell, otherwise known as microtubules. When this block is removed, the microtubule tower falls and so does the cell that it provided a framework for. NFTs are much like the fall of a Jenga tower. 

Insulin is crucial to the action of both amyloid-ꞵ and NFTs. Insulin is responsible for regulating blood sugar throughout the body but it plays a valuable role in protecting the neurons in the brain. The review by Akhtar and Saw provides insight into how the brain developing resistance to insulin is related to the formation of amyloid-ꞵ plaques and NFTs. The first figure placed in the review shows the various ways the insulin signalling pathway can be affected. Many of the molecules inside the cell can contribute to NFT formation internally whilst also allowing amyloid-ꞵ to be produced which can stop insulin signalling all together at its receptor. When there is dysfunction of this insulin pathway, the neurons do not function optimally and often undergo apoptosis, which is programmed cell death. 

Understanding insulin resistance is valuable in understanding Alzheimers and treating it in our future. Processed food products are used by societies across the globe to ensure cheap and abundant food. This abundance, however, has led to metabolic syndrome and an increase in insulin resistant diabetes in our communities. Being one of the largest contributors to these problems, changing our diets should be a starting point. Whole, unprocessed foods take more metabolic effort to digest and minimise the blood sugar spikes we see from processed counterparts. Much like how they slow down digestion, these whole foods also slow down our day to day lives. Taking more time to focus on our diet also allows us to make greater effort towards our physical activity. A healthier society may see less insulin resistance which may be one of the first steps we can make to stopping Alzheimer’s disease in its tracks. 

Ansab Akhtar and Sangeeta Pilkhwal Saw, “Insulin signaling pathway and related molecules: Role in neurodegeneration T and Alzheimer’s disease” Neurochemistry International 135, (2020)

Artstract by Erik Lucken

Introduction

Sleep is such a fundamental part of our lives that it can be easy to overlook all of the benefits of getting a good night of rest. In addition to feeling well-rested and recovered for the next day, sleep allows our body to heal by boosting our immune system, increasing focus and productivity, improving memory consolidation, and many other effects (1). It is clear that these are all great benefits and making sure that we get enough sleep should be a top priority in our lives, but this can be much easier said than done. 

What is Insomnia?

The key to getting a good night of sleep is by having a healthy circadian rhythm, also known as a sleep cycle. In dark conditions, our body begins a chain of chemical reactions that produce melatonin which binds to the melatonin receptor and helps our body relax by reducing nerve activity, which can make it easier to fall asleep (2). When your brain doesn’t produce enough melatonin, not enough can bind to its receptors so your body has a more difficult time knowing when to fall asleep, which also can distort your circadian rhythm which can take days or even longer to repair. It is normal to experience short-term insomnia (up to 3 weeks) at some point in our life, typically a response to stress, but it can also be a side effect of anxiety disorders, trauma, or certain medications.

Figure 1: The Melatonin Receptor

The Neurochemistry of Insomnia

Making sure that enough melatonin is being produced is the main step in fostering a healthy sleep cycle. While still being investigated, calcium is found to regulate the synthesis of melatonin from the amino acid tryptophan. It has been found that the enzymes responsible for these reactions are only affected by lower calcium levels, so they are unable to produce melatonin when calcium levels are too low. The cause of low calcium in terms of sleep is still under investigation. Figure 1 shows the signaling pathway of melatonin. When melatonin binds to the MLT GPCR, it causes Gi to dissociate from the receptor which causes adenylyl cyclase to be inhibited, which prevents cAMP from being produced and this prevents the activation of PKA and CREB downstream. These are all necessary steps to begin falling asleep. When melatonin levels are reduced, this pathway is not activated as much as it should be so cAMP and CREB levels increase when they are not supposed to (2). 

In addition to melatonin, GABA and norepinephrine have been receiving some attention in sleep research. The underlying mechanisms are unknown but it has been consistently shown that in people with insomnia, GABA and norepinephrine levels are decreased, which makes it more difficult to sleep since these substances prevent hyperarousal and hyperexcitation. 

Conclusion

We face different stressors every day and sometimes it can be difficult to fall asleep. Insomnia is a very real thing that can be a result of any number of factors, ultimately leading to a decrease in calcium that is able to be used by enzymes producing melatonin. 

Sources

1. https://www.sclhealth.org/blog/2018/09/the-benefits-of-getting-a-full-night-sleep/
2. https://www.sciencedirect.com/topics/neuroscience/melatonin-2-receptor
3. https://doi.org/10.1016/j.neures.2017.04.011

Neurochemistry is Interdisciplinary

The neurochemistry course is the poster class for interdisciplinary education and makes it so easy to love learning. While offered only to senior neuroscience majors/minors and ACS chemistry majors, the interdisciplinary nature of neuroscience brings together so many perspectives and they all connect on the basis of chemistry. Many in my cohort had double majors or minors in business, nutrition, psychology, biology, chemistry, mathematics, and neuroscience and every discussion, both in-class and virtual, analyzed a very different perspective of our weekly topics. Even on papers that only discussed biochemical signaling, genetics, or biosynthesis, when our class came together, connections were drawn to any field. In particular, many of the discussion topics in our small groups were about applications of the paper and not so much on the actual biochemistry. Neurochemistry sounds like a daunting subject but this interdisciplinarity takes away the fear and allows for us to discuss a complex topic in any way we’d like. There were nights where I found myself falling down the rabbit hole when researching what dreams are, psychedelic drugs, memory disorders, the American housewife drug crisis, etc. all because of what this course instilled in me. 

Neurochemistry is a Liberal Arts Course

The neurochemistry class is exactly what learning at a liberal arts course should look like. To me, a liberal arts education is one that fosters learning from multiple perspectives with people from every demographic. In addition to the interdisciplinary nature of the field, neurochemistry is a strong liberal arts course. I elected to take a PEAK through this course and partnered with the graduating class of social work majors by coordinating a donation drive with ShareHouse, a substance addiction recovery program. This was my first time coordinating an event with anybody, nonetheless an organization. Working on this project, it was clear that neurochemistry and social work students have different ways of thinking. Almost every course I’ve taken at Concordia was in psychology, chemistry, neuroscience, or mathematics so I didn’t have the opportunity to work with many different academic perspectives until this project. 

Learning to Adapt and Overcome

One skill that I have been able to improve on because of this class is my ability to thrive in group work. As I stated earlier, most of my courses here were in STEM and I often worked with people I was very familiar with or who had a similar thinking style so group work wasn’t a challenge for me. Partnering with the social work class in our CAP project, however, was a very different experience. Our team was half neurochemistry, half social work, and finding a successful way to communicate was a difficult task early on. Our initial project proposal was rejected and after reading through it, it was clear that we all understood our agreed-upon plan in a different way. We were able to pinpoint that this was a big issue early on and when we rewrote our proposal, we worked exclusively as a group and found a way to adapt to each other’s thinking and communication styles. When it came time to actually carry out the project, our communication skills and ability to work together as a team were flawless. It is so interesting to look back on this semester and see the drastic improvements we collectively made as a team. Without this course, I wouldn’t have realized that I was only good at communication with like-minded people. I learned that people from different perspectives and backgrounds have different methods of analytical thinking and learning to work with different people absolutely improves my group work abilities. 

What are Anxiolytic Drugs?

Anxiolytics are drugs that act to reduce anxiety. Benzodiazepines are the strongest anxiolytic drugs used commercially but SSRIs and SNRIs, weaker anxiety-reducing drugs, are often prescribed to individuals with both anxiety and depression diagnoses. Benzodiazepines cause strong, immediate anxiety relief and SSRIs/SNRIs are prescribed for long term use and relieve anxiety to a lesser degree

An Overview of Benzodiazepines

Benzodiazepines are very strong anxiolytic drugs with their effects felt immediately. They are commonly not prescribed for more than 1 month at a time unless in more severe situations. These drugs include lorazepam, alprazolam, clonazepam, diazepam, and chlordiazepoxide (marketed as Xanax, Klonopin, Librium, Valium, and Ativan). The side effects of these drugs are dramatic, including memory impairments, sedative effects, impaired judgment, and a higher risk of experiencing depression and suicidal thoughts. These drugs all act in the same way, biochemically and kinetically, but they differ in terms of their potency. Benzodiazepines act by binding to the GABA receptor as allosteric modulators, making it easier for chloride ions to flow into the cell, hyperpolarizing the nerve membrane which leads to widespread inhibitory effects throughout the central nervous system and sedation, including anxiolysis, short term anterograde amnesia, and anti-convulsion (Fig. 1). A common symptom of anxiety is faster breathing and heartbeat, but benzodiazepines reduce these symptoms by decreasing the frequency of certain cardiovascular and respiratory functions (1).

Figure 1: Mechanism of Action of Benzodiazepines

Serotonin and Norepinephrine Reuptake Inhibitors

While benzodiazepines are the strongest drugs designed to treat anxiety, SSRIs and SNRIs have also been found to be effective, particularly in patients with anxiety and depression. These drugs include citalopram, escitalopram, fluoxetine, and sertraline (marketed as Celexa, Lexapro, Prozac, and Zoloft). These substances are weaker than benzodiazepines because they exert their effects on serotonergic synapses, which has a weaker impact on anxiety. These drugs were designed primarily to treat depression but increasing serotonin levels in the synapse can reduce perceived feelings of anxiety. SSRIs bind to the reuptake channel on the presynaptic cell, preventing the released serotonin from being deactivated. Some of the serotonin will bind to the receptor on the postsynaptic cell but once all binding sites are occupied, the remaining molecules will be held in the synapse (2). Normally, these would be taken back to the presynaptic cell but since the SSRI is blocking the channel, the serotonin will stay activated. SSRIs are designed for long-term use. Over time, they modulate the density of serotonin receptors on the postsynaptic cell so it can take weeks before the patient can detect any significant changes. SSRIs are also very different from each other. They differ in their potency, pharmacokinetics, half-life, and binding affinity to the reuptake channel, so it can be difficult to prescribe the most optimal drug. Side effects of these substances include agitation, appetite problems, dizziness, headache, nausea, insomnia, and reduced libido (2). SNRIs involve the same mechanism and relatively the same side effects, but the effects are exerted on noradrenergic neurons by blocking norepinephrine reuptake. 

Figure 2: Mechanism of SSRI’s

Conclusion

Anxiety drugs are very diverse and it can be difficult to know which drug is the best for which person. Benzodiazepines are the strongest, but typically can’t be used for more than a few weeks and have strong side effects by acting on the GABA receptors. SSRIs are weaker than benzodiazepines but still have noticeable effects, but their mechanism involved modulation of the postsynaptic cell, which can take weeks, making them more difficult to prescribe and treat a struggling individual. 

Sources: 

1. https://calgaryguide.ucalgary.ca/benzodiazepine/
2. https://www.registerednursern.com/ssris-antidepressants-nclex-questions/ 
3. https://www.frontiersin.org/articles/10.3389/fpsyt.2014.00005/full