Week 10- Linking It All Together

Hey everyone! Seriously can’t believe this quarter is about over. We discussed a variety of topics within the past 10 weeks and not too surprisingly they all seem to intertwine. Here’s our attempt to put the pieces together and review why what is happening below our necks is closely related to our brain health and vice versa.

Insulin

A peptide hormone responsible for regulating glucose uptake… but really, it’s so much more. We know that today that dysfunctional insulin leads to decreased cerebral glucose metabolism, increased inflammation, increased oxidative stress, decreased neurogenesis, and decreased neuronal repair. It has been shown over and over again to be upregulated during learning and task acquisition in animals — it is a crucial player in induction stage long term potentiation. Healthy peripheral insulin activity during development is important for proper hypothalamic neurocircuitry development and, as such, is part of a positive loop: peripheral insulin determines central insulin concentration, that concentration affects neural development and that neural development modulates activity of pancreatic beta cells through vagal activity. Ultimately, we see that plays a critical role in regulating carefully-tuned environments, both centrally and in the periphery.

Metabolic Disturbances and Neuropsychiatric Disorders

By this time we all know a lot about the implications of Insulin resistance, diabetes, and obesity and their effects on our bodies. (if not refer back to our past blog posts;)) Yet, the big mystery throughout our class was how our peripheral connected to our central functioning. For instance, how would one’s diet have implications on brain health, and are there any shared mechanisms tying these things together? Evidence reveals that there is a connection between metabolic disturbances (such as experienced in the peripheral body) and neuropsychiatric disorders (such as depression or even Alzheimer’s disease). The big focus as of now is on Insulin, which does come as a surprise since it has only been thought to exist in the brain within the past decade! To simplify, Insulin is involved in various processes such as maintaining neurons, forming new connections, modulating neurons and with overall functioning of the brain via insulin receptors.

Neuropsychiatric Disorders

There is nothing comical about having a neuropsychiatric disorder- such as depression, schizophrenia, or bipolar disorder. But what is it really and what is happening with one’s brain?

“Neuropsychiatric diseases, such as schizophrenia, depression and autism, are a huge burden on society, impairing the health of those effected, as well as their ability to learn and to work” (NatureInsight)

It would be terrible to be considered a “burden on society”, but despite those perceptions, many don’t actually understand what those patients are dealing with. One group this past week, the squints, had us go through a mental exercise imagining some of the symptoms experienced by patients with Schizophrenia. Patients with neuropsychiatric disorders experience actual changes to their brain functions and chemistry, and some experience symptoms of memory loss, paranoia, or extreme sadness. In attempting to treat these various symptoms, maybe the key lies with insulin in the brain.

Where is the link?

We’ve been given information over the past 10 weeks about the interconnections between our metabolism and the functioning of our brains. But what are the actual mechanisms behind this, and how can disruptions in metabolic processes impact the health of our brains? Though this research is incredibly new and there is still much to be discovered, we have some hints. For example, let’s take a look at Alzheimer’s disease: a neurodegenerative disease affecting millions of Americans. Recent estimates have indicated the disease may rank third in most deaths in the US. Despite these dire statistics, there is no known cure or prevention for the disease.

However, recent studies point to insulin signaling as a possible mechanism. In a normal brain, insulin binding to its receptor causes a signaling cascade having many effects. In this pathway, IRS-1 activates PI3K, which then activates AKT, which inhibits GSK3B. This is important because GSK3B phosphorylates tau. And why do we care about tau? Well, one of the neuropathological hallmarks of Alzheimer’s disease is the hyperphosphorylation of tau forming neurofibrillary tangles in the brain. So when inflammatory pathways such as the JNK pathway become activated, the normal insulin signaling pathway is disrupted. Now, instead of activating PI3K, IRS-1 inhibits it, causing a chain reaction which leads to AKT no longer inhibiting GSK3B. Now tau becomes hyperphosphorylated, causing neurofibrillary tangles. A small, but clear physiological link between insulin and Alzheimer’s disease!

This is just one instance of how a small disruption in the insulin signaling pathway can lead to something as serious as neurofibrillary tangles in the brain.
On the left, the normal insulin signaling pathway. On the right, the hyperphosphorylation of tau caused by the activation of JNK.

The Big Picture

The overall lesson from this class is: don’t eat crappy food- or basically the American diet- if you want to maintain a healthy brain throughout life. It’s rough and I definitely questioned myself many times as I indulged in a shake or bowl of ice cream on my cheat days. Strong evidence shows that we basically are what we eat, and that one’s diet strongly influences brain function. With this in mind (pun intended), insulin seems to be a promising target for changing how we treat neurological and psychiatric disorders. As seen in patients with neuropsychiatric or neurodegenerative diseases, many also report co-occuring metabolic disturbances. (I should probably cut out the oreo cookies- but you should really try them with peanut butter, it’s life changing…)

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