Simulating the Mini-Universe in Your Head

by Joel Stevens

What do you think about when you day-dream? I mean really day dream. Those moments where you are
really deep into your own little world.  Those moments where for a few brief minutes you forget about appointments, parking tickets, homework, reports, car payments, taxes, global warming, job security, the economy, the tea party; those moments where you just drift into existential bliss and tune out the societal noise.

What do you think about?  Maybe you think about yourself and ask what makes you you? Why am I here, why are we all here? In those moments, however do you ever wonder or just sit in awe of the 3 pound organ in your head that allows you to tune out the noise and ask such deep questions?  Do you ever wonder how the human brain works?

As crazy as it sounds, this is still the central question of neuroscience today.  Which, may appear to be surprising to some, seeing as it is one of the most well funded disciplines in all of biology.  However, you really have to take into account the enormous mind-boggling (no pun intended) complexity of the human brain! It is made up of millions of individual neurons all connected with one another by TRILLIONS, yes that's right, trillions of synapses (the small gaps between two interacting neurons).  We have known since the 1950's how individual neurons initiate signals and send them to another neuron. We also have a pretty good idea how the brain performs simple motor tasks such as grabbing a pencil or interpreting sensory information such as someone poking you with said pencil, known as neural circuits. Where it gets really messy and complicated is when we start to investigate things such as decisions making, problem solving, and the big one consciousness. How would we even begin to start doing this?

Well whenever scientists try to investigate something that is to complicated to observe in the field or in a lab setting, we try the next best thing we develop computer simulations, or mathematical models, to create the closest thing we can to reality inside a computer.  This has been done for years, in fact one of the pioneers of computer science Alan Turing goal was to ''build the brain'' and ended up building a computer.  As you might have guessed the mathematics must be extremely complicated in order to program a simulation of a human brain, and you are right! Enter the crazy, complicated field of computational neuroscience.

Even though the idea to simulate the brain using computers has been around for almost 60 years, what has just become available is the computational power to actually perform such tasks.  First, though I just want to briefly give a crash course in how to approach modeling.

There is a trade-off when developing mathematical models or computer simulations, because you want to make it as realistic as possible, otherwise your results could be shaken off as unrealistic.  However, the more variables and dimensions you add to a model, the more complicated the mathematics gets, i.e. the more moving parts there, are and the greater the chance something could go wrong. My graduate adviser goes by the rule that a great model will follow the 80-20 rule, meaning that you cannot account for 100% of the things going on in a system, so you only want to account for 20% of the most important variables.

And this is where neurosciences have struggled, because as I said before, the human brain is IMMENSELY complicated. Some scientists believe that simulations must also account for the genes being expressed in each neuron as well as individual ion channels in each of the millions of individual neurons on top of the trillions of precise connections.  Brain hurt so far? Don't worry so does mine, but stick with me here! What really is going to impress you though is that recently computational power has reached the point in which we can actually do this!

This is heavy stuff, here's probably what your brain is feeling

And the power is pretty intense, these are not your standard laptops used to roam Facebook. These are massive super computers, filled with bull testosterone (well not really, but they're pretty intense). To put it into perspective your laptop that you are reading this on has most likely 2 or 4 core processors, processors are the part of your computer that does actual computations, i.e. the brain of your laptop.  One of the super computer simulation called Blue Brain developed by Henry Markham in Switzerland uses 16,384 total processing cores which are able to simulate the physiological activity of 100 million neurons and 500 million synapses, all while taking into account ion channels dynamics and neural network morphology. This particular model is considered to be one of the most complicated to date, and has been given the 1 billion euro prize by the Human Brain Project.  However, due to the sheer detail and size taken into account in its development, the model has come under some scrutiny for being too complicated, and most likely will require even more advanced computer technology, available in approximately 10 years.

Not all computational models have the detailed approach as Blue Brain. Researchers at the University of Waterloo in 2012 developed a brain model called Spaun which simulates a much smaller scale than Blue Brain, still 2.5 million neurons.  The most interesting thing about this simulation is that it was designed to perform cognitive tasks, while others like blue brain simulate more of the actual physiological connections of an entire brain.  Spaun has the ability to do simple tasks such as look at a set of numbers, remember, and then repeat the numbers back by writing them on a piece of paper, and other tasks similar to ones on basic intelligence tests. Pretty cool eh? The big breakthrough, and in my opinion the most intriguing finding, was Spaun's limitations.

Unlike most computers that just evaluate millions of possible decisions in milliseconds and then finding the best answer (think chess playing supercomputers), Spaun instead paused; it hesitated before giving an answer! It actually thought! To me that sparks a certain sense of fear that one day simulations like this may become self aware and destroy all of mankind! It also sparks some extreme interest and hope that these models become increasingly more accurate.

And I have no doubt that they certainly will! It is just going to require a lot more knowledge of neural connectivity in the brain, as well as you guessed it more computational power.  Which ultimately is the limiting factor, as always, when it comes to really complicated models such as these.  One day however, I have no doubt that we will have cell phones with human-like AI like operating systems, similar to one in the recent Spike Jonze's movie Her, hopefully minus the awkward dating your phone phenomena.  All AI thoughts and/or concerns aside, realistic computer simulation of the human brain will contribute greatly to understand how exactly the human mind works as a whole, as well as, aid in solving diseases in which our minds' machinery goes haywire; such as Alzheimer's, depression, and even schizophrenia. As well as aiding in understanding how we can perform abstract processes such as what problem solving, creativity, and create/store memories. Most importantly however, these models could very well hold the key to understanding the process that gives our species the ability to ponder its own existence.  So keep at it computational neuroscientists!  Math/computer/biology nerds are rooting for you! 

A heavy blog like this requires some heavy music! Enjoy some mind bending music the next time you ponder your own existence!  

References

1.)  Eliasmith, C. and O. Trujillo. 2014. The use and abuse of large-scale brain models.Current Opinion of Neurobiology 25:1-6.

2.) Eliasmith, C., T.C. Stewart, X. Choo, T. Bekolay, T. DeWolf, Y. Tang, and D. Rasmussen. 2012. A large-scale model of the functioning brain. Science 338:1202-1205.

3.) Markram, H. 2006. The blue brain project. Nature Reviews: Neuroscience 7:153-160

4.) Stewart, T.C., F.X. Choo, C. Eliasmith. Spaun: a percption-cognition-action model using spiking neurons

http://www.gizmag.com/brain-computer-simulation/25349/

http://phenomena.nationalgeographic.com/2013/02/14/will-we-ever-simulate-the-brain/

Images
http://www.titaniumteddybear.net/wp-content/uploads/2010/09/lolwut-jurassic-face-thread.jpg
http://www.quickmeme.com/img/1c/1cba02b056944308e72401de0acbf9dbb471aad66deea493613a633be13ab92d.jpg
http://www.troll.me/images/ancient-aliens-guy/computers-how-do-they-work-thumb.jpg
http://www.artificialbrains.com/images/blue-brain-project/blue-gene-p-architecture.png
http://images.scholarpedia.org/w/images/8/86/Encyclopedia_of_computational_neuroscience.gif

What makes a genius?

by: Emily Smith

You can't tell from the bowl cut and missing front teeth, but I was once mistaken for a child prodigy.

Growing up, my parents always played a classical music recording when we were eating dinner. One of the more frequent choices was Mozart, so I associated most classical pieces with his name. One night, my family went to a friend's house for dinner. The hosts opened the door and as we walk inside, I hear the familiar sound of a classical orchestra. Without skipping a beat, 4-year-old me says "ah, Mozart!" The hosts were flabbergasted--I happened to be right! They asked my parents if I was some kind of musical genius. My parents laughed, I would have guessed Mozart regardless of what had been playing…

Play this while you're reading to elevate your level of classiness!

My brush with almost-greatness made me wonder, what would the brain of a true genius look like? Was Mozart hard-wired to compose awesome orchestral pieces? Was Einstein destined to confuse physicists everywhere with his Theory of Relativity? Was DaVinci's brain tinkered so he could be the father of invention? How are young teenagers going to college????

Nolan Gould, a.k.a. Luke from Modern Family, is 15 and is taking college courses. Can you taste the irony?

According to Haier and colleagues (2004), individuals having more gray matter in certain Brodmann areas (BA) tend to have a higher IQ.  Hmm…let's take this apart so us "non-geniuses" can understand this phenomenon:

What is gray matter?
Gray matter is the part of your brain that houses all the cell bodies and axon terminals to form synapses, thus allowing signal transduction through chemical (neurotransmitters) and electrical (action potentials) signals. The white matter houses the neural axons, which allow regions of gray matter to communicate.

Basic structure of neurons and how they communicate

What are the "Brodmann areas?"

 The Brodmann areas are simply a way to map and describe the brain's functions. When your brain receives information, it generally moves from the back of the brain to the front. The frontal lobe is responsible for higher thinking and planning (characteristic of modern humans).

So what does this mean?
Basically, it is the physical structure of the brain and not necessarily any chemical change that leads to intelligence of astronomical proportions. For example, Einstein's brain has been analyzed by several labs since his death in 1955. Diamond and colleagues (1985) postulated that there might be differences between the neuron:glia ratio in Einstein's brain. The study concluded, however, that Einstein's neuron:glia ratio in the overall brain was not significantly different from the "control" population (Diamond et al., 1985). Witelson et al. (1999) described differences between Einstein's brain and an otherwise equal male control brain, finding enlarged parietal lobes (~15% wider than the control!) and a complete absence of the parietal operculum (try saying that 5 times fast…). Specifically, the inferior (left) parietal lobe was larger than average; this part of the brain is responsible for mathematical thought and visuospatial cognition (Witelson et al. 1999), leading some researchers to believe the unique brain structure was a large part of Einstein's brilliance.

Figure 2 from Witelson et al. 1999 visualizes the differences between Einstein and a "normal" male human

Furthermore, Shaw et al. (2006) suggests that it is not merely presence (or absence, as the case may be) of brain structures or gray matter, but the path of development that is the most important predictor of intelligence. They found that children with higher intelligence had high cortical plasticity. In essence, the gray matter in their cortexes expanded very quickly in early childhood and rapidly thinned during adolescence, indicating a dynamic system (Shaw et al., 2006). Though this does not fully explain the complex mechanisms involved in determining intelligence, it is a telling story for the importance of early development in children.

Figure 2 from Shaw et al. 2006 shows changes in cortical thickness as it relates to developmental age of different brain regions important for intelligence

What about savants? 
A savant is defined as a person with serious cognitive impairment (either developmental or acquired) who also has a so-called "island of genius," or incredible skills that invariably involve massive memory (Treffert, 2009). Generally, savants have fine-tuned abilities in memory, drawing, music, calculating, reading, and several others (Bolte and Poustka, 2004). Treffert (2009) focused on describing the brain of Raymond Babbit, better known as "Rain Man." He is an autistic savant that is missing the corpus callosum, or the partition between the left and right brain, that allows him to quickly skim and retain information from two pages at once (Treffert, 2009). It appears as though brain structure may play an important role in this class of "genius" as well, though there are many disagreements about whether savants can really be considered geniuses.

Us "non-geniuses" can't read a book with each eye on a different page…I'm going cross-eyed just trying to imagine it!

According to Treffert (2009), 1 in 10 people with autism have at least some sign of savant-like behaviors. Some groups have suggested that testosterone "poisons" the left hemisphere of the prenatal brain and the right hemisphere must make up for this loss (Bolte and Poustka, 2004). According to an informational website posted by Dr. Dave Hiles (2001), prodigious savants (such as Derek Paravicini, below) are defined as people whose brilliance is stellar not only in contrast to the disability, but would be a spectacular feat in a non-disabled individual.

Check out this awesome "60 Minutes" video about one of the more recently famous savants, Derek Paravicini:

So in essence, brain structure and course of development seem to be key for predicting genius-level IQ. There is still much to be figured out about geniuses and savants, but these discoveries could lead to a higher level of understanding of the modern human brain.

Though music might not be my calling, maybe listening to Mozart in my early years has primed my brain for science. Maybe, just maybe, I'll just become the next Nobel Prize-winning biologist!

 ;)

References
1. Bolte, S., and F. Poustka. 2004. Comparing the intelligence profiles of savant and non savant individuals with autistic disorder. Intelligence 32: 121-131.
2. Diamond, M. C., A. B. Scheibel, G. M. Murphy, Jr. and T. Harvey. 1985. On the brain of a scientist: Albert Einstein. Experimental Neurology 88: 198-204.
3. Haier, R. J., R. E. Jung, R. A. Yeo, K. Head and M. T. Alkire. 2004. Structural brain variation and general intelligence. NeuroImage 25: 425-433.
4. Shaw, P., D. Greenstein, J. Lerch, L. Clasen, R. Lenroot, N. Gogtay, A. Evans, J. Rapoport and J. Giedd. 2006. Intellectual ability and cortical development in children and adolescents. Nature 440: 676-679.
5. Treffert, D. A. 2009. The savant syndrome: an extraordinary condition. A synopsis: past, present, future. Philosophical Transactions of the Royal Society B 364: 1351-1357.
6. Witelson, S. F., D. L. Kigar and T. Harvey. 1999. The exceptional brain of Albert Einstein. The Lancet 353: 2149-2153.


Links
http://24.media.tumblr.com/tumblr_m606xsXwTl1qk6wc3o1_250.gif
http://www.umich.edu/~cogneuro/jpg/Brodmann.html
http://www.indiana.edu/~p1013447/dictionary/greywhit.htm
http://25.media.tumblr.com/tumblr_mbp8h0jyyw1qzpwi0o1_500.gif
http://www.youtube.com/watch?v=Ak2jxmhCH1M
http://bio1152.nicerweb.com/Locked/media/ch48/48_05NeuronStructure.jpg
http://www.psy.dmu.ac.uk/drhiles/Savant%20Syndrome.htm
http://www.youtube.com/watch?v=cbqjxmTNivQ
http://www.youtube.com/watch?v=Rb0UmrCXxVA

Did you taste the purple coming from that song? Synesthesia is a mind boggler.

Seeing sounds and tasting colors

By: Michael Spelman

Alright, alright, take a deep breath and get ready for a trip through what could be described as the brainchild of Hunter S. Thompson, Dr. Suess and Salvador Dali after they all got together for a party that would have put to shame the entire decade of the 1960s. 

But first some background. The concept of perception, be it taste, smell, sound, touch or sight, has been a prominent focus of philosophical experimentation since Plato and Aristotle first asked "Why?". In Plato's Allegory of the Cave, it is posited that the ideas we form from sensations we experience, our perceptions, are more important in generating "reality" than the things eliciting the sensation in the first place. Essentially, reality is based more more in how we perceive things, than the things themselves. But what happens when the mechanisms of our perception get mixed up? How would one's concept of reality be affected? I will delve into that soon, but first let's overview some of the mechanisms behind sensation and perception.

Chemoreception, Mechanoreception, and Photoreception:

Our five senses (seeing, hearing, smelling, feeling, and tasting) result from the stimulation of certain types of sensory receptors in our bodies. Mechanoreceptors in our skin and our inner ears are activated by signals such as pressure that cause a physical or mechanical change in sensory neurons. This physical change is communicated to the brain by way of an electrical signal and is perceived as touch or sound, respectively. Chemoreceptors on our tongues and in our nose communicate with the brain in a similar manner, but in response to the presence of some combination of chemicals. These chemical combinations result in the perception of various tastes and smells. My personal favorite sense, sight, comes from photons of light entering our eyes and being transduced, or changed, into an electrical signal that is communicated to our brains. This is such a gross oversimplification it hurts my Biopsychology bachelor's degree, but it will suffice for now.

Alright, so the question that should be on your minds at this point is "if all of our senses get to the brain by way of these electrical signals, then how are they perceived as different from each other?" The answer lies in the complexity of our brain. The image here shows a schematic representation of our thalamus, the brain region responsible for organizing incoming sensations and sending the information to the appropriate cortical region for further processing (Krettek and Price, 1977). 

Wait, what? What is a cortical region? The cortex is the outermost portion of our brains, essentially the part that anyone would see and say "oh, thats a brain!". Each portion of the cortex is responsible for a specific set of functions, as shown in the image below. For instance, the rear-most portion of the cortex is known as the occipital lobe and is responsible for interpreting visual inputs and telling our brains what we are seeing. There is a dedicated brain area for interpreting each of the five senses after being relayed by the thalamus. 

As you might be thinking, the incoming signals to the thalamus, and subsequently to the cortex are awfully close to one another. And since they are all electrical inputs, couldn't the brain occasionally make a mistake or let one signal go to the wrong area of the brain? Surprisingly, our brain is remarkably efficient in getting messages where they need to go and rarely makes mistakes (unlike the U.S. postal service, am I right?). However when things go wrong things can get real weird, real quick.

Synesthesia, LSD, and Contemporary Art 

When the brain makes mistakes in interpreting incoming signals that are not due to normal aging processes, psychological conditions such as behavioral and mood disorders, and schizophrenia can occur. However, it doesn't always result in such devastating conditions. Synesthesia is one such condition that could, in theory, actually be really friggin cool. 

Synesthesia is defined as the involuntary physical experience of a cross-modal association (Cytowic, 1995). In layman's terms, it means that experiencing one sense, simultaneously activates another sense. For instance, seeing sounds, or hearing colors, or tasting geometric shapes. It may seem like something out of a science fiction book, but it is actually a diagnosable psychological condition that is estimated to occur in 1 in 2,000 people (Martino and Marks, 2001). Though, synesthesia is not found in the Diagnostic and Statistics Manual of Mental Disorders because it does not generally interfere with daily life, and synesthetes generally enjoy their added sensory perceptions (Jensen, 2007). Martino and Marks described that synesthesia can be either strong or weak; strong synesthesia refers to the full experience of a sensation not related to the modality being experienced, whereas weak synesthesia encompasses such experiences as seeing colors when reading words or numbers. 

I know, I know, you're thinking to yourself "how could this possibly happen, and how can I get in on this action?" Well, as with any other psychological disorder, it is largely unknown how synesthesia comes about. According to Grossenbacher and Lovelace (2001), synesthesia is thought to have a genetic basis and is thought to be inherited according to X-linked dominant patterns. There are a number of theories on the physical basis of synesthesia. The one that seemed most reasonable and worth mentioning was that of Local Crossactivation (Hubbard and Ramachandran, 2005). Essentially, neurons existing in brain areas connecting the sensory input from a certain modality to the brain region that interprets it actually send unusual connections to brain areas involved in perceiving other senses: basically the brain of synesthesetes (people who have synesthesia) have extra wiring that usually is not present in the brain. A large amount of research has supported this theory using neuroimaging techniques such as diffusion-tensor imaging (DTI) and functional magnetic resonance imaging (fMRI).

It has also been hypothesized that there are three classifications of synesthetes. The first type of synesthete experiences strong synesthesia from an early age and is classified as a developmental synesthete. The second is considered an acquired synesthete, and the condition can arise later in life as a result of injury. Now for the part Mr. Thompson was an expert on. The third type of synesthete is an induced synesthete, and their experience of synesthesia results from the ingestion of hallucinogenic substances such as LSD or mescaline (by no means am I promoting the recreational use of such compounds, but as a result of my undergraduate studies I find the subject totally fascinating). 

Although it is likely the quickest way to induce synesthesia, drugs are far from the only thing that can evoke the experience of multiple senses at the same time. In fact, we experience synesthesia on a regular basis (to a much milder extent). Reading a fiction novel for example can stimulate our imagination so much so that we create a visual representation of the most minor details from the story. Advertisers and cinematographers regularly generate imagery that is meant to evoke and stimulate emotions. Music videos such as this Blockhead video, directly pair sound with visual effects to create a really awesome video (and this song/artist is just the bees knees overall).

My favorite part

Now for the REAL trippy philosophical stuff. As a Neurologist, Dr. Richard Cytowic has extensively studied perception and synesthesia, interviewing patients and documenting various case studies. From his experiences he has expanded on the hypothesis of "form constants". Such form constants are what Cytowic and Dr. Heinrich Kluver describe as the four basic types of hallucinatory constants. These include gratings and honeycombs, cobwebs, tunnels and cones, and spirals. 

What do these form constants have to do with synesthesia? Kluver proposed that the experience of form constants is due to some fundamental aspect of visual perception. Amazingly, the visual cortex is mapped in such a way that the perception of these shapes correlates to a sweeping activation of neurons responding to individual line orientations, similar to when we perceive a moving object! (more on visuospatial mapping here) Now get this. The likely reason that these hallucinatory forms are "constant" is due to the presence of the Golden Ratio in nature, and our brains innate propensity to process it. While only a theory, the golden ratio has been posited as the mathematical explanation of perceived beauty, and patterns in nature. So much so that some little-known artists such as Leonardo DaVinci and Salvador Dali prominently planned paintings around this golden ratio. The band Tool has even made this awesome song lyrically centered on it (and paired some cool imagery with it too). 

Now, if you'd please humor me while I do some philosophizing of my own. What if, because the incoming information from the outside world (such as a vibrating photon of light entering our eyes, or vibrating molecules of air on our skin or eardrums, or vibrating chemoreceptor channel enzymes in response to chemical binding) is so similar across modalities, it could be considered abnormal NOT to experience synesthesia? What if we were meant to experience more than one sense at a time, and synesthesia as a trait was evolutionarily selected for? Think about THAT.

Bibliography:

Cytowic, R.E. 1995. Synesthesia: Phenomenology and neuropsychology. PSYCHE 2(10).

Grossenbacher, P.G., and C.T. Lovelace. 2001. Mechanisms of synesthesia: cognitive and physiological constraints. TRENDS in Cognitive Sciences 5:36-41.

Hubbard, E.M., and V.S. Ramachandran. 2005. Neurocognitive mechanisms of synesthesia. Neuron 408:509-520.

Jensen, A. 2007. Synesthesia. Lethbridge Undergraduate Research Journal 2(1).

Krettek, J. E. and Price, J. L. (1977), The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J. Comp. Neurol. 171:157–191.

Martino, G., and L.E. Marks. 2001. Synesthesia: Strong and weak. Current Directions in Psychological Science 10:61-65.

Parts of the brain thalamus of anatomy. (2012). Retrieved from http://www.rudyard.org/parts-of-the-brain-thalamus/

Sanderson, K. J. (1971), The projection of the visual field to the lateral geniculate and medial interlaminar nuclei in the cat. J. Comp. Neurol. 143:101–117. 

Ramachandran, V.S., and E.M. Hubbard. 2003. Hearing colors, tasting shapes. Scientific American 288:52-59.

Don't Worry, Be Happy. Or Just Try Not to Stress Out too Much

Don't Worry, Be Happy. Or Just Try Not to Stress Out too Much...

By: Joshua Mier

Now this is a song everyone has heard, or at least the face is of someone that we all can recognize. The message Mr. Marley so elegantly declares is also relatively straightforward: "Don't worry about a thing, because every little thing is going to be alright." You say those lines and you can already hear the jingle in your head. So then it seems a simple enough rule to follow right? Well, unfortunately we all know that life isn't always this simple. If we wanted to, we could make an laundry list of all the things that make life difficult, like for instance....Ha! Gotcha, why the hell would anyone want to read that, right? Believe me, my goal here is not to be Jamaican ya crazy:

Did he just throw in both a Cool Runnings and Winter Olympic's Gag?

However, I think everyone can agree that sometimes life just slaps us in the face to let us know we're awake: work continues to pile up, deadlines aren't being met, relationships not panning out the way we had planned. All these negative sentiments can effectively accumulate to the point of anxiety, or the sensation that we all love to loathe: Stress...

This emotion can easily resonate throughout the body: the heart begins to race, your muscles start to twitch, your ventilation rate spikes and it feels as if every neuron in your body is firing all at once. So then have you ever wondered:

1. What is stress exactly and how or what's causing these feelings in the first place? 
2. What effects does stress have on the body, what parts of the body are effected?
3. How do these biological reactions effect overall short or long term health?

Here, I will attempt to answer these questions. But first, I would like to open with a brief quatrain from Walter D. Writle's famous poem "Thinking:"

If you think you are beaten, you are.

If you think you dare not, you don't.

If you like to win, but think you can't.

It's almost certain you won't.

This may seem a little pessimistic, but it's message is clear in being aware of your thoughts. This will make more sense at the conclusion (but please don't cheat and skip to the end!)

I) What is Stress and how does it manifest throughout the body?

First off, stress is a notoriously hard to define for biologists since it covers such a broad spectrum. However, in this instance, we are talking about the physiological stressed strait. That is:

• Any environmental factor that:
• Disturbs the normal adaptive responses or
• Causes disrupts normal physiological functioning to a point where chance of survival is reduced.

Notice: That this definition uses environmental factor. Which makes sense for animals (e.g., temperature, salinity, pH, a big ass predator...)

The normal physiological state is the point when a organism is at homeostasis (your body is basically saying "it's all good."). Stress is an environmental stimulus that causes a disturbance in homeostasis.

So now we know what environmental factors trigger the stress, what exactly is it triggering...

• Stress triggers hormonal pathways! 

Hormones are "chemical messengers" that are secreted by endocrine gland cells that travel through the bloodstream to exert their effects on distant target cells. Only cells that retain the receptor will elicit the response.

In the stress response (Oh CRAP, it's not all good bro) environmental stimuli activate endocrine pathways that act through the hypothlamus in the brain that eventually stimulates hormone production in the adrenal gland (BOOM...Mind = BLOWN #1)

1. The 'Fight or flight response' - I'm sure you've all heard of this one (so I'm not going to spend too much time talking about it). But essentially, norepinphrine released from sympathetic neurons stimulates the release of epineprhine (also known as adrenaline) which then goes on to act on multiple different tissues.

Sympathetic neurons converge on the adrenal medulla. Secretion of NE causes release of Epineprhine from the Adrenal Medulla.

But the main pathway I would like to focus this topic on is the Hypothalamic pituitary Adrenal  (HPA axis):

Stress stimuli cause hypothalamic neurons to release corticotropin releasing factor in the anterior pituitary gland (APG). The APG will then release adrenocorticotropin hormone (ACTH) into the bloodstream which acts on the adrenal cortex to release cortisol into the blood

    2. HPA axis = CORTISOL. I wrote out the pathway (which is totally sweet to know by the way..) just to give you an idea of the stimulation and release of the hormone. 

If it was confusing, then please walk away from this section with this:

• Stress is a environmental stimulus that acts on neurons in the hypothalamus that release hormones into the blood that act on the adrenal gland...

And BOOM goes the dynamite!


 II) Cortisol is a Stress hormone, so what does it effect-

Cortisol why is it important?

• Corisol's main effect is to prevent hypoglycemia (meaning prevent decreases blood sugar). Cortisol acts on target cells by binding to glucocorticoid receptors.

Note: All nucleated cells have glucocorticoid receptors. If this doesn't trip you out, then consider that basically the only non-nucleated cells are red blood cells (BOOM...Mind = BLOWN #2)

Question? Why would this be important

• Any environmental stimuli that activates this stress response. Let's say its a second big ass predator (on top of the first big ass predator mentioned earlier) comes at you, your body can synergistically coordinate a single response to get the hell out of dodge (BOOM...Mind = BLOWN #3)

So, what tissues are effected:

1. Liver - Cortisol acts on the hepatocytes (liver cells) to promote the release of glucose into the blood (through the production of new glucose or gluconeogenesis).    
2. Skeletal Muscles- Breaks down skeletal muscles to provide substrates . Cortisol causes breakdown of proteins in muscles to amino acids which can then be used by the liver to increase glucose output (BOOM...Mind = BLOWN #4).
3. Enhanced Lipolysis- Cortisol increases fat breakdown to promote uptake of fats in the liver to increase glucose output.
4. Suppresses the immune system**- Cortisol acts as an inhibitory signal to promote immunosuppression.

Key point: to reiterate, the main purpose of cortisol production is to prevent hypoglycemia, which makes sense in an environmental context as in the case for animals.

III) Chronic stress- The suburban paradox-

Earlier I noted that stress is associated with environmental stimuli. For animals, the cortisol stimulated stress response makes sense: get the hell out of dodge when I see a big ass predator.

Notice, that in the human context, we don't necessarily have that dilemma. Therefore, stimuli that trigger the stress response in our instance can be triggered psychological manifestations or better yet our emotions.

Remember: cortisol is essential for life! 

However, just like many things in life, too much cortisol (or chronically elevated levels = chronic stress) can be especially dangerous, take these examples:

i) Cortisol suppress the immune response:

Cortisol exerts its effects on the immune system by: a) inhibiting the inflammatory signals (e.g., cytokines such as NF-kB) and up-regulates the expression of anti-inflammatory proteins (e.g., I-Kappa 8).

• This is actually why cortisol is used as a therapeautic drug to deter inflammations in many sports-related injuries. 

Downside: Excess production of cortisol can inhibit your adaptive immune response 

• Chronic stress can inhibit and reduce the amount of CD8+ and CD4 lymphocytes (i.e., Cytotoxic and Helper T cells). CD8+ cells will kill viral infected cells to prevent the spread of disease, while CD4+ cells will stimulate alternative immune cells like plasma cells which produce antibodies. Patients with depleted lymphocytes in this instance, also were diagnosed with psychological disorders (e.g., attachement disorder in this case).

Why is this important? Chronic stress can lead to disease progression.

Example: ALS: Amytrophic lateral sclerosis: is a fatal neurodegenerative disease that results in neural and muscle breakdown.

Chronically stressed mice (in this case increased cortisol production over time) exhibited decreased survival rates compared to non-stressed mice. Figure from Fidler et al. 2011.

Chronic stress can also lead to detrimental long-term effects such as reproductive failure, heart disease and alternative neurodegenerative disorders.

Cortisol will continue to be associated with the negative connotation of the stress hormone, however, let us not forget that this conserved hormone has an evolutionary advantage of conferring an adaptive response to evade danger and avoid predation. As we have seen, excess cortisol production can have harmful long term health effect that are directly associated with stress. Denoting both of these aspects, however, we notice that in proper balance the effect of cortisol is negligible. We can essentially think of our bodies then as "perfect  machines." Just like machines, they will respond to external input and respond accordingly. The response in our case (aside from disease associated patterns) can be stimulated from our mindset. This is especially the case if you've ever heard of "The Secret" by Rhonda Byrne outlying the Law of Attraction or the theory of metacognition: how you think is perpetuated into the universe and is reciprocated accordingly. Essentially if you think positively you will get a positive response and vice versa.

Of course, this is easier said then done. Stress is a normal part of life (and an essential one at that). There will always be environmental triggers that elicit the stress response. However, being aware of your emotional status and now having a better understanding of the underlying physiological mechanisms can help elucidate more positive outcomes. Besides, if we were happy all the time, life would be a little dull (imagine a world full of Tony Robbins').

With that in mind, maybe Bob Marley's ideology can be useful. Next time your in a stressful situation, just think about his message to you hoo hoo... Now excuse me while I go stress over studying for another midterm, while I conclude with the ending quatrain from Writle's famous poem:

Life's battles don't always go,

To the stronger or faster man,

For sooner or late the man who wins,

Is simply the man who thinks he can.

References:

Ciriaco, M, P. Ventrice, G. Russo, M. Scicchitano, G. Mazzitello, F. Scicchitano and E. Russo. 2013. Corticosteroid-related central nervous system side effects. Journal of Pharmacology and Pharmacotherapeutics 4: 594-598.

Fidler, J. A., C. M. Treleaven, A. Frakes, T. J. Tamsett, M. McCrate, S. H. Cheng, L. S. Shihabuddin, B. K. Kaspar and J. C. Dodge. 2011. Disease Progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.

Journal of Federation of American Societies for Experimental Biology 25: 4369-4377

Hill, R. W., G. A. Wyse and M. Anderson. 2004. Animal physiology. In Endorcine and Neuroendocrine Physiology, pp. 400-409. Sunderland, MA: Sinauer Associates, Inc.

Jaremka, L. M., R, Glaser, T. J. Loving, W. B. Malarkey, J. R. Stowell and J. K. Klecolt-Glaser. 2013. Attachment anxiety is linked to alterations in cortisol production and cellular immunity. Psychological Science. 24(3): 272-279.

Kultz, D. 2005. Molecular and evolutionary basis of the cellular stress response. Annual Review of Physiology. 67: 225-257.

Ross, A. P., A. Ben-Zacharia, C. Harris and J. Smrtka. 2013. Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropin hormone. Frontiers in Neurology 4(21): 1-12

Petes, L. E., B. A. Menge and A. L. Harris. 2008. Intertidal mussels exhibit energetic trade-offs between reproduction and stress resistance. Ecological Monographs 78(3): 387-402.


Images and Videos (Taken in order of appearance):

1) Bob Marley Video "Three Little Birds:" http://www.youtube.com/watch?v=zaGUr6wzyT8

2) Bobsled jpeg: http://www.etsy.com/listing/170340599/cool-runnings-poster-multiple-sizes?ref=market

3) Dr. Kristin Hardy Lecture slides. Fall 2011. Slide 6, 14_Endocrine.pdf

4) Dr. Kristin Hardy Lecture slides. Fall 2011. Slide 27, 15_Endocrine.pdf

5) Ross et al. 2013.

6) Fidler et al. 2011