Thursday, January 30, 2014

Mental Time Travel

Travis Suttle

Have you ever wondered how athletes pull things off like this?
That's a triple cork 1440, or three backflips and four spins simultaneously! To perform a trick like that, it takes a insane amount of athletic ability (and some big cojones), but most importantly, it involves training the brain using motor imagery.  Through motor imagery, humans can imagine actions and develop neural circuits for those actions without even performing the movement at all.  In some situations, motor imagery is used to imagine performing actions in the future, which is a form of mental time travel.

Through mental time travel, one can imagine a possible future event and prepare for it by determining an appropriate reaction to the situation.  So before that snowboarder even left the jump, he had likely practiced that trick over and over again in his head picturing the world spinning and turning upside down.

MENTAL TIME TRAVEL

Mental time travel is a term coined by Dr. Thomas Suddendorf referring to a human's ability to mentally project themselves into the future or back into time. The definition of mental time travel is voluntary behavior that solves a problem that an organism may encounter in the future.  Mental time travel is usually based on the recollection of previous events (episodic memories) and increases the flexibility of the reaction next time the event or a similar event occurs.  Humans have an extraordinary ability to foresee events and plan accordingly, whereas other animals are simply reacting to stimuli, rather than predicting stimuli then planning actions.

Action sports athletes are not the only people who benefit in training this way.  Sports psychologists have been teaching visualization methods to improve athlete performances for years.  For example, Tiger Woods is known to be a master of visualization (seen herewhich has led him to go down as one of the most successful golfers of all time.  The video discusses the pre-shot routine that Tiger goes through where he "visualizes the golf shot using his hands, fingers, and body awareness" to come up with the correct technique to make the best shot. So Tiger isn't "just doing it" after all, and he certainly is keeping more secrets that the one his wife found out about (double pun).


Another exemplification of the mental time travel involves Air Force Colonel George Hall, a pilot who was shot down over Vietnam and captured as a POW.  He spent seven years in a North Vietnamese prison where he played golf in his mind everyday to pass time. He used motor imagery over and over to establish motor circuits and develop his swing.  After he was rescued and returned home, he decided to play his first game of golf in over seven years at the 1973 New Orleans PGA Open where he shot a 76 (a really good score)!




So how can we do this?  Researchers found that the neural network activated while performing a movement is also activated while imagining oneself performing that movement.  Surprisingly, imagery training in athletes, stroke patents, and musicians significantly increases the electromyography (EMG) activity of target muscles in comparison to resting EMG activity.  This means that imagining oneself performing an action is actually sending electrical signals to the desired muscles but the signals are not strong enough for the muscle to completely contract. In another study, imagined weight lifting with the forearm showed a linear increase of EMG amplitudes with increasing magnitudes in weight.  In other words, your brain is sending stronger signals when you imagine lifting heavier weights.  


The prefrontal cortex is thought to play a crucial role in motor imagery, as patients with left lateral prefrontal lesions were unable to imagine a motor task.  In general, the prefrontal cortex is believed to be involved in attention, cognition, and performing actions.  The corticopontino-cerebellar tract (which has connections to the prefrontal cortex) is important in coordination of movements and has been shown to establish and consolidate fine motor skills through reorganization in the sensory-motor system.  So now that we know the neural network proposed to be responsible for the learned responses through motor imagery during mental time travel, lets take a look at how the scientific community believed these neural networks were first established.


Evolution of Mental Time Travel
So how did we gain this capacity to time travel using our imagination?  For mental time travel to have evolved, it must have had an effect on survival or reproduction for natural selection to work on.  Dr. Thomas Suddendorf and his colleagues believe that mental time travel changes behavior in the present, which therefore may increase survival chances in the future.  For example, when preparing for a job interview, one might think of questions that an interviewer may ask, then formulate responses to them and simulate the situation in his or her imagination; this in turn, may increase one's chances of getting that job.  Now if getting the job is a life or death situation (or a situation that results in reproduction), this interview becomes an event that natural selection can act on.

Here's another example of a situation that our ancestors could've experienced.
Lets say you're an early hominid that was banned from your tribe and you're scavenging the forest alone.  All of a sudden, a sabertooth jumps out and chases you, but you manage to escape.  In the process of escaping, you accidentally cut yourself on a small rock. As you sit and ponder about the situation (mental time traveling) in your cave, you recall the sabertooth chasing you as well as cutting yourself on that darned rock (recalling episodic memories).  Thankfully, you have an extra large prefrontal cortex in comparison to other early hominids and therefore, you can picture yourself in the same situation with the sabertooth (mental time traveling), but this time you are wielding the sharp rock you cut yourself on and you attack the sabertooth (motor imagery).  After imagining the situation, you run out of your cave, grab the sharp rock, make a spear, and kill the sabertooth.  You then drag the sabertooth back to the village you were previously shunned from and all the ladies adore you for your bravery (increasing your evolutionary fitness)!

Potential Evidence
Okay enough story telling, let's get back to it!  Around 2 million years ago, the genus Homo emerged with an increased brain size, which possibly represents the time that language and mental time travel were born.  Tools and weapons made of stone are the earliest evidence of foresight - they were used repeatedly and transported in anticipation of future use. Great apes do throw objects, but they are not known to carry them around.  Carrying weapons for defensive use must have been strongly selected for as early humans were believed to be the prey of much larger animals.  This foresight may have allowed us to outcompete our ancestors and predators leading to their demise and our prosperity.  In further support, area 10 of the human prefrontal cortex is much larger than the prefrontal cortex of all of the other apes relative to the total brain volume (see the figure below).  Area 10 of the prefrontal cortex is the cortical area believed to be involved in higher cognitive functions such as planning of future actions.  This suggests that the increase in size of area 10 may have played a large role in hominid evolution as it allowed early hominids to plan for future situations.
BIGGER IS BETTER!

Let's get a little philosophical to conclude this blog entry. If we are the only animals on earth which have such unique foresight, we alone may be driven to consciously guide the planet into the future.  Furthermore, we carry the responsibility of making decisions about the future and getting them right.  For example, what if we are in a situation where an asteroid is in course to collide with earth?  We are the only animals on earth with the capability to foresee the consequences and chose to act.  Hopefully this isn't the choice we make...

Lastly, in the words of Albert Einstein himself: "Imagination is more important than knowledge."  This quote especially applies when your imagination allows you to predict a situation and develop complex motor functions to respond to the situation.


Works Cited:


Goldman-Rakic, P. 1988. Topography of cognition: parallel distributed networks in primate association cortex. Annual Review of Neuroscience 11:137–56.


Johnson, S.H. 2000. Imagining the impossible: intact motor representations in hemiplegics. Neuroreport 11:729–732. 

Lotze, M., and U. Halsband. 2006. Motor imagery. Journal of Physiology Paris, 99:4-6.

Semendeferi, K., E. Armstrong, A. Schleicher, K. Zilles, and G.W. Van Hoesen. 2001. Prefrontal cortex in humans and apes: a comparative study of area 10. American Journal of Physical Anthropology 114:224-241.

Suddendorf, T., and M. Corballis. 2007. The evolution of foresight: what is mental time travel, and is it unique to humans?. Behavioral and Brain Sciences 30:299-313.


Zhang, H., L. Xu, S. Wang, B. Xie, J. Guo, et al. 2011. Behavioral improvements and brain functional alterations by motor imagery training. Brain Research 1407:38-46.

Zhang, H., Z. Long, R. Ge, L. Xu, Z. Jin, et al. 2014. Motor imagery learning modulates functional connectivity of multiple brain systems in resting state. PLOS One 9:e85489.

Images and Videos
http://blogs.discovermagazine.com/neuroskeptic/files/2010/12/time2btravel2bbrain.jpg
http://www.2oceansvibe.com/wp-content/uploads/2010/01/tiger-woods-secret-500x702.jpg
http://mshistorynow.mdah.state.ms.us/images/734.jpg
http://www.tremorjournal.org/article/downloadSuppFile/175/figure-175-2-web
http://www.troll.me/images/keanu-reeves/what-does-that-even-mean.jpg
https://www.youtube.com/watch?v=0Aog4xWIbrI

Monday, January 27, 2014

Ruffling Feathers: How Carotenoids Affect Sexual Selection in Birds

By: Emily Smith
Recently, my friend Griffin saw this refrigerator magnet and said "That red bird has more carotenoid pigments. That's an indicator of better immune function and fitness, so he will attract more females."
I don't know what he is so cranky about…he should have better luck finding a mate than that smug Bluebird!
That got my gears turning about if and why this is the case. How do we tell which birds allocate carotenoid pigments to mate selection? What else can carotenoids be used for and where can we find them? Most importantly, what the heck are carotenoid pigments??
Beta-carotene, one of the more well-known carotenoids
http://www.sas.upenn.edu/~patricam/Beta-carotene.png
Carrots are packed with beta-carrotene (Ha!)
http://www.redorbit.com/media/uploads/2013/01/BetaCaroteneDiabetes_012313-617x416.jpg
Carotenoid pigments, such as beta-carotene (shown above), are organic compounds only produced by plants, algae, and certain bacteria and fungi [1, 2, 4, 5]. The carotenoids are responsible for the observed distinctive pigmentation, for example, the bright orange color of carrots. Because vertebrates cannot produce carotenoids, many animal species get their unique colors from their diet; the processes involved in the breakdown, modification, and transport of pigments are responsible for the bright plumage of some birds [2]. It is similar to the mechanism for the orange skin you might get from eating too many carrots! Many factors can affect what carotenoid pigments can be ingested and what colors can be produced such as environmental availability and animal physiology [5].

Carotenoids are known to have significant physiological functions, especially in aiding the immune system [1-5]; specifically, carotenoids seem to stimulate T-lymphocyte response efficiency [4] and act as potent antioxidants, cleaning up cellular waste from the immune system kicking pathogen butt. It has also been suggested that carotenoid compounds support the production of steroid hormones that regulate reproduction such as testosterone and estrogen [5]. In other words, carotenoids play a huge role in keeping birds (and other animals) healthy and happy!
http://www.ngrla.com/images/2013/07/bird-birds-beautiful-colorful-838862.jpg
Aside from the various physiological benefits, carotenoids can be allocated to plumage or other secondary sex characteristics of birds such as the bill or the leg scales. These pigments are obtained from the diet, then the bird's gut takes over to modify, transport, and assimilate the resulting pigments to determined locations [2, 4, 5]. The ability to use ingested carotenoids depends on an animal's genotype and physiology. For instance, birds must have the right intestinal receptors to absorb dietary pigments,  have the correct enzymes to modify them or break them down into useable pigments, and they must have the efficiency to use the pigments once absorbed and transformed [5]. The effects of local nutrient availability and incorporation complicate things slightly…different species--or even the same species in different locations--have different enzymes and receptors that recognize and convert these pigments to reflect plumage color. To illustrate this, Dr. Alan Brush studied the house finch, Carpodacus mexicanus, in captivity and in the wild and found 3 color variants: red, orange/yellow, and pale [2]. He postulated that the observed color differences in the finch populations were due to lack of certain pigments. He found that red birds produced three pigments: beta-carotene, isocryptoxanthin and echinenone (both modified forms of beta-carotene). Orange/yellow birds produced beta-carotene and isocryptoxanthin only, whereas pale birds produced beta-carotene and echinenone only [2]. Even though these birds had the same diets, regional effects led to differences in pigment metabolism such that yellow and pale birds could never reach the same red pigment observed in native birds, even with beta-carotene supplementation [2].

In any case, male birds with the right machinery can put on an irresistible display for the females. Birds of Paradise (shown in the video below), not unlike hip-thrusting rockstars, can use a combination of flamboyant colors and dramatic movements to woo their mates:




So, how many of you think: "WOW! Carotenoids function in immunity AND colorful plumage for mate selection?? Sounds like a win-win situation to me!" Show of hands…NOW!

Well you're all wrong! There are trade-offs at play here, which bodes well for female birds looking for a mate with the best genetic and phenotypic background. Males that do incorporate carotenoid pigments into their plumage must do so at the cost of not having available carotenoids circulating in the blood to aid the immune system. Birds that are battling an infection or just have a weaker immune system than others will allocate more carotenoids to the body's defenses, resulting in a duller color in the feathers or bill [1-5]. This acts as an "honest" display of fitness and immune function in males; the brighter the male, the fewer carotenoids being shunted for immune function and the more carotenoids making him the bold and beautiful macho-bird he is. Females prefer bright, sexy males, so this sexual selection leads to brighter and sexier males (and females hard-wired to be attracted to them) in subsequent generations. The video below explains the phenomenon of sexual selection well:



So how exactly do we know there is a trade-off between secondary sex characteristics like bright plumage and immune response? By using…drumroll please... SCIENCE!!! Several research groups studied avians such as blackbirds [3] and finches [1, 2, 4] by observing key characteristics before and after an immune challenge. These parameters included: bill/plumage color (determined by sight and by high-performance liquid chromatography), serum carotenoid levels (determined by HPLC), and antibody production. The challenge was administered in the form of sheep red blood cells (SRBC) or control injected into the birds, injection with lipopolysaccharide from E. coli, and/or a phytohemagglutinin (PHA) skin test. They predicted that if there is a significant evolutionary trade-off, then visual and chemical decreases in carotenoid-based pigments will occur in the treated groups.
Figure 1 from Faivre et al. (2003). Blackbirds challenged with sheep red blood cells (SRBC) had a significant decrease in bill color relative to birds injected with PBS alone. [3]

Birds that were in the experimental groups exhibited marked differences in bill/plumage color, lower serum carotenoid levels, and high antibody production due to the movement of pigments out of the bloodstream and into affected tissues as part of the immune response [1-4]. Males that had a significant drop in bill/plumage color had an inversely correlated immune response, meaning these colorful sex characteristics are dynamic traits that reflect the current health status of the male [3]. Additionally, an excess of dietary carotenoids supplemented in the feed or water of birds did not significantly change the allocation of pigments. Regardless of what is available, most carotenoids will be shunted to the immune system when challenged. However, supplementation of extra carotenoids does boost the immune response significantly compared to birds fed a regular diet [4].
Figure 3 from McGraw et al. (2003).   (a) Male finches that had higher levels of plasma carotenoids had a stronger cell-mediated immune response. (b) Male finches that had more red beaks were able to mount a better response to SRBC injection. [4]
Whereas some signals and behaviors can be "cheated" without much cost to the bearer, only the healthiest males can afford to put on lavish displays of color. This is known as the "handicap principle" because if all males could use all available carotenoids for pigmentation, these signals would be meaningless and would make the advantage of producing them moot [5]. Allocating the pigments to be stored in "nonrecoverable forms" such as plumage puts the bird at risk if an attack on the immune system occurs [5]. This metabolic costliness ensures that these signals are meaningful.

In summary, healthy males use their intake of dietary carotenoids to brighten their plumage and attract a female mate. These heritable traits are passed down to their offspring and the trend continues. If the males fall ill, their colors become dull as they fight disease and they become less attractive to prospective females. Just like when we get the flu, we become pale and sickly looking…not exactly a handsome appearance. It looks like the colorful birds must find a balance between looking good and feeling good, and effectively apportioning carotenoids can pay off big time!
Winner!


Stay sexy, my feathered friends!




References:
1. Alonso-Alvarez, C., S. Bertrand, G. Devevey, M. Gaillard, J. Prost, B. Faivre, and G. Sorci. 2004. An experimental test of the dose-dependent effect of carotenoids and immune activation on sexual signals and antioxidant activity. The American Naturalist 164:651-659.

2. Brush, A. 1990. Metabolism of carotenoid pigments in birds. The FASEB Journal 4:2969-2977.

3. Faivre, B., A. Gregoire, M. Preault, F. Cezilly, and G. Sorci. 2003. Immune activation rapidly mirrored in a secondary sexual trait. Science 300:103.

4. McGraw, K. and D. R. Ardia. 2003. Carotenoids, immunocompetence, and the information content of sexual colors: An experimental test. The American Naturalist 162:704-712.

5. Olson, V. and I.P.F. Owens. 1998. Costly sexual signals: Are carotenoids rare, risky, or required? Tree 13:510-514.

Whatever, Whatever, I Do What I Want: Hedonism and Why The Things We Do Can Be So Addicting.



By: Michael Spelman


Hedonism is the idea that we as people have every right to maximize the pleasure we attain from life (Hedonism bot here knows what I'm talking about); and why shouldn't we? Our brains are literally wired in a way that promotes rewarding behaviors. It is because of this wiring that when  a commercial comes on TV for a big, juicy, one and a half pound, double Philly-cheesesteak chipotle burger (or maybe a succulent kale salad for the vegetarians out there?) being held/eaten by Kate Upton or Ryan Gosling in minimal clothing, our primal instincts run wild and we find ourselves throwing money in every direction to obtain this pleasure explosion of a sandwich (at least that  is how advertising is supposed to work). Or maybe you aren't as "turned on" by food as I am. Perhaps your "go to" pleasure is alcohol, or cigarettes, or shopping. Maybe you are one of those adrenaline junkies that needs to jump out of a perfectly good airplane or mountain in a wing suit and zoom past cliff-sides going 200mph just so that you get through the day with a smile on your face. Personally, that type of thing gives me the heeby-jeebies and my heart drops every time I watch a video like that.

But all differences in pleasure preferences aside (for now), the reason we do these things that may be fattening, life-threatening, malicious, maniacal or anything in between, is due to the fact that we have very specific neural circuitry involved in reward and behavior. Specifically, a complex interconnected network of dopaminergic neurons (neurons that release/respond to dopamine) serve to integrate our senses (thalamus) with our conscious decision-making ability (prefrontal cortex, PFC), our memory (hippocampus), our emotions (amygdala), and even our motor outputs (ventral tegmental area, VTA, and substantial nigra, SN). While this image may seem a bit confusing with all the arrows and brain regions, it is actually quite simplistic in summarizing the intricacies of the circuit. What I mean by saying it is simplistic is that the circuit does not necessarily go only in one direction (from sensory input to motor output) as it seems to show: the sensation of reward can actually arise from an action that generates a pleasurable sensory output. Picture this: as a little kid, you were at a pool (your own, a friend's, doesn't matter really); as you are walking by the edge of the pool, someone picks you up and throws you in; during the pre-splash flight you notice you actually enjoy this feeling of elevation; now whenever you go to a pool, you try and find a way to jump from the highest possible object because you have developed this intrinsic propensity to succumb to gravitational forces. As most of us probably know, this "intrinsic propensity" is due to the release of adrenaline from the sympathetic division of our autonomic nervous system (remember fight or, in this case, flight?). This adrenaline release has now become intricately associated with feelings of pleasure and joy and in order to replicate it, you need to replicate the initial stimulus (heightened elevation and the feeling of falling). So now you spend all of your time jumping out of airplanes.


Those of you who have taken any introductory psychology course can recognize this pattern of paired stimulus with a sensation, or expectation of reward as Pavlovian conditioning 101; the feelings of reward have been conditioned by memory to be associated with the neutral stimulus of high elevation, even in the absence of the rewarding stimulus. This is precisely how individual differences in pleasure preferences can arise. For instance, as a child I learned to associate the sensation of being full to an overall sense of well-being. Obviously different foods have different smells and tastes and appearances so I began pairing certain smells and certain styles of foods to good feelings (that burger description above is still in my mind). Nowadays I don't even need to see or smell food that is within my grasp; I am a sucker for good advertising (I would buy these edible cookie cups in a heartbeat if I knew where to get them).

Obviously not everyone has the same preferences, but the general idea here is that any activity or process or thing can become entrained in our minds as a rewarding behavior through conditioning and learning. This all comes back to the reward circuitry in our brains. We begin to associate memories and emotions with these good feelings and this results in the activation of the circuit even when we just think about the activity or thing or process. You may find yourself asking, "yeah, so what?". The issue arises when people begin to crave these pleasurable feelings beyond a point of self-control and become addicted to chasing them. This can occur when the pleasurable behavior begins to be used to ameliorate some negative event or emotion.

Because the initial conditioning and pairing of stimuli are physiologically engrained in the reward circuit, there should be a physiological explanation for the transition from benevolent hedonism to full-fledged, compulsive addiction, right? Many researchers have focused on elucidating this mechanism, and their results are quite interesting.


According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) addiction can be defined as "a maladaptive pattern of substance use resulting in significant negative physical, social, interpersonal or legal consequences". Here I am modifying the term "substance" to include any behavior that promotes hedonic pleasure. As I mentioned above, when one such hedonic pleasure becomes an outlet for escaping negative life events, things can get bad. For example, after a bad break-up from a long relationship, you go to the store and buy a gallon tub of ice cream and then proceed to eat the whole thing at home while watching some sappy love movie based on a cheesy novel. Now, that isn't so bad (other than the potential health consequences of eating a gallon of ice cream in one sitting). But what about when other negative life events occur and you begin doing this every time something goes wrong? Without even consciously doing it, you begin to ignore your health/weight, shunt your responsibilities, and severely limit your social interactions for fear of more bad things happening. So now this hedonic pleasure (enjoying ice cream) no longer is a source of happiness, but has become a way of escaping the negative events in your life. Not only that, but that 1 gallon of ice cream is no longer enough because you've started building a tolerance to its soothing effects. This tolerance leads to compulsive ice-cream buying and consumption and now you can't get through the day without it anymore! (I am probably dramatizing this for effect, but this really does happen)
Volkow and colleagues have shown that exactly this type of behavior is what ensues in drug addicts, and it is due to a physiological change in the pattern of activation of this reward circuit. A progression from making conscious decisions (PFC) to ameliorate some negative emotion, to an unconscious reward-seeking pattern of behaviors results in compulsive behaviors that serve to promote relief from withdrawals and negative emotions. As shown in the image below, there is a change from activation of the more anterior brain structures in the non-addict, to the more posterior brain structures in the addict.





Initially, the anterior brain structures serve as a physiological mechanism of self-control and inhibit poor decision making. However after repeated learning or substance use, these inhibitory controls become overridden and the posterior brain structures act similarly to a reflex pathway: without even consciously thinking about it or choosing to, an addict will respond to stress or aversion by carrying out reward-seeking behaviors.

Now you may again be thinking to yourself, "So what? I eat ice cream/jump out of planes all the time and I am not physiologically addicted". And my first response would be to tell you to attempt to put down the carton/parachute and see how long you can go without it. All jokes aside though, it is likely because you have a well-established sense of self-control and can resist the urge to give in to your hedonic pleasures. For other people however, it may not be as simple as that (many adrenaline junkies die every year by trying to achieve the ultimate rush).

Researchers have hypothesized that there are many potential risk factors that predispose certain individuals to developing addictions. These include such things as stress, violence, aggression, developmental environment, social environments, and even genetics (we talked about the nAChR subunit alleles in the lateral habenular nucleus in our physiology lecture; for information on this and other neurotransmitter receptor influences, check this out). Many of these risk factors have been shown to be very influential in the development of addiction using mouse models and various conditioning paradigms. 


All-in-all, we inherently strive to make ourselves feel good by doing those things that we have learned to promote our own happiness. It would seem to insult the intensive and complex process of evolution that led to the development of this physiological reward circuit in our brains were we to not use it for hedonic pleasure. The key to maintaining this pleasure however, seems to lie in the maintenance of an appropriate level of self-control. When this self-control is diminished, our brain circuitry can cause us to do some unbelievably malevolent things without even really being conscious of it. That is unless someone develops a way in which to abolish such reward-seeking/addictive behavior and cures them with lasers

References:

1. Classical Conditioning- Ivan Pavlov. 2008. video. youtube.com. Web. 20 Jan 2014. <http://www.youtube.com/watch?v=hhqumfpxuzI>.

2.  Sommer, W. H., and R. Spanagel. 2013. Behavioral neurobiology of alcohol addiction. Springer 13. Retrieved from http://www.springer.com/biomed/neuroscience/book/978-3-642-28719-0

3. Dubuc, B. (2014). [Web log message]. Retrieved from http://thebrain.mcgill.ca/flash/a/a_03/a_03_cr/a_03_cr_que/a_03_cr_que.html

4. DSM. 2012. Clinical Practice Guidelines. American Psychiatric Association. Arlington, VA: Retrieved from http://www.psych.org/practice/dsm

5. Miller, M. C., and J. Segal. Understanding addiction: How addiction hijacks the brain. HelpGuide.org. Retrieved from http://www.helpguide.org/harvard/addiction_hijacks_brain.htm

6. Lynch, W. J., K. L Nicholson., M. E. Dance, R. W. Morgan, and P. L. Foley. 2010. Animal models of substance abuse and addiction: Implications for science, animal welfare, and society. Comp Med 60: 177-188. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890392/

7. Dick, D. M., and A. Agrawal. 2008. The genetics of alcohol and other drug dependence. Alcohol Research & Health 31: 111-118. Retrieved from http://pubs.niaaa.nih.gov/publications/arh312/111-118.pdf

8. Volkow, N. D., G. Wang, J.S. Fowler, D. Tomasi, and F. Telang. 2011. Addiction: Beyond dopamine reward circuitry. Proceedings of the National Academy of Sciences 108: 15037-15042. Retrieved from http://www.pnas.org/content/108/37/15037.full.pdf html

9. Chen, B. T., H. Yao, C. Hatch, I. Kusumoto-Yoshida, S.L Cho, F.W. Hopf, and A. Bonci. 2013. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature  496: 359-362. doi: 10.1038/nature12024

10. Cottone, P.. Laboratory of addictive disorders. Retrieved from http://www.bumc.bu.edu/busm-pm/research/laboratories/lad/
2. 

Friday, January 24, 2014

Alcohol Consumption: the Good, the Bad and the Atrofreaking kidding me?

By: Joshua Mier


Have you ever listened to the song "Have a Drink on Me" by ACDC? I'm just joshing, of course you have! If not, then maybe I'm talking to the wrong generation... However, there is something nostalgic about classic rock songs that bring me back to the fond memories of good times with good people: lake trips, beach bonfires, backyard barbeques and even the occasional wedding reception (although in my opinion, "Mony Mony" by Billy Idol is the all time classic wedding hit). Still, no matter the situation, alcohol seems to be the recurrent factor involved in many of these celebrations. This is for good reason too, as one could argue that it is the quintessential social stimulant that helps bring people together at gatherings. From the elegantly decanted vino, to the aromatically balanced brew or the even the simple yet smooth old-fashioned whiskey; everyone has a unique preference on their choice of drink. So what category do you belong to?

Part of the 53%! I'd like to think of myself a beer connoisseur. (C) World Health Organization 2011.


Any way you shake it (James Bond pun definitely intended), alcohol is infused into the human dynamic and has been since the dawn of civilization. It should be of no surprise then, as to the curiosity that accompanies attempting to unravel the underlying physiological mechanisms that proliferate our feelings of euphoria upon drinking this magical elixir. Therefore, my aim here is to i) briefly attempt to define what alcohol consumption is and the economic relevance behind our obsession with it, in order to ii) provide a context for the absorption, metabolism and the effector targets as alcohol is consumed and is transported throughout the body (by this I simply mean the organs involved in the "booze cruise," of alcohol through the body). Aboard this luxury booze cruise, we'll be making some pit stops at several tissues along the ethanol route, to see how alcohol affects the system(s) involved: a) the blood, and the b) liver. To make it interesting, I've decided to break up these two sections into three parts:
  1. The Good- interesting factoid about the physiology of drinking that you could tell your friends about next time your putting a few back.
  2. The Bad- Obvious as it sounds, I'll include some information that coincides with the consequences of drinking.
  3. The Atrofreaking kidding me? This final section I'll introduce some recent research developments that may or may not shock you about the consumption of alcohol.
Fun Fact (0): I say "Atrofreaking kidding me," since its a play on words of "atrophy" which refers to a reduction in size (for example when skeletal muscle shrinks).

Obviously, the field of alcohol research is very complex and if you're bummed about me skipping the brain, then feel free to check out this simple tutorial about how alcohol effects the brain (narrated by a dude with an Aussie accent to make it sound sweet):
Alcohol effects on the brain

I) What is alcohol consumption and why should I care?

It may cost you if you don't: according to the U.S. Public Health Service Guidelines, the economic cost of drinking in the USA in 2006:
  • $223.5 billion
    • This statistic includes the cost of healthcare, legal and government fees in addition to the actual consumption of alcohol.
The National Institute of Alcohol Abuse and Alcoholism (NIAAA; a sub-institution of the National Institute of Health) constitutes one standard drink as:
  • 0.6 fl oz (18 mL) or 14 g  of pure alcohol

Another way to look at it. Image taken from NIAAA: www.niaaa.nih.gov
The amount of alcohol in one standard drink is then used to define the effect of moderate drinking. This category is defined as the amount of ethanol (EtOH) consumed per day. Typically in the USA, the amount of drinking is categorized by the following (I'm a beer guy so I'm going to use beer as a reference):
  1. Light drinking = 0-33 (g) EtOH/day
    •  ~2.5 beers
  2. Moderate drinking = 34-49 (g) EtOH/day
    • ~ 3.5 beers
  3. Heavy drinking = > 50 (g) EtOH/day
    • > 4 beers
Fun Fact (1): these numbers vary widely across reports and countries. This same review reported that, in both Finland and the U.K., heavy drinking is > 80 g EtOH/day.

Question: How does this relate to the Blood Alcohol Concentration (BAC)?

The BAC is a relationship based on the concentration of alcohol within the blood. Since alcohol is readily absorbed in the bloodstream it is determined by the percentage of alcohol (g) / volume of blood (mL). Everyone has an image of drunk driving tests when they think of BAC:

He's thinking: "Man, if only I remembered the Widmark equation..." (Image taken from www.fieldsobrietytests.org)
This concept is calculated using the Widmark method (developed by Swedish researcher Erik M.P. Widmark). There are many factors that contribute to the amount of alcohol within the blood (hydration, age, sex, weight, time, etc.), however, the general formula is as follows (beer with me, because its cool to know!):

BAC = ((0.806 x SD)/(BW x Wt)) -(MR x DP)
  • 0.806 = Mean water weight in the body
  • SD = Number of standard drinks (g)
  • BW = Body water constant (Male = 0.58; Female = 0.49)
  • Wt = Weight in kg
  • MR = Depends on drinking habits (example: average moderate male = 0.017)
  • DP = Time of drinking (in hours)
The corresponding value is then expressed as: g/100 mL. (So you would divide your answer by 100).

For example: I'm a 135 lb male (61 kg). Let's say I put down three beers over 2 hours. My theoretical BAC then should be:
  •  0.009% (or 0.009 g/mL)

Pretty Cool Huh!

II) Booze Cruise: The Good, the Bad, and the Atrofreaking kidding me?

Taken from www.healthcentral.com.
I) The Bloodstream: when you drink an alcoholic beverage, the amount of alcohol absorbed into the bloodstream depends primarily on:
  • the concentration of alcohol that enters the small intestine.
The amount of alcohol absorbed in the blood also depends on several additional factors:
  • Blood flow/heart rate
  • Food in the stomach*



*Everyone's heard of eating before you drink to not get too drunk and here's why:
  • There is absorption of alcohol within the entire gastrointestinal tract (meaning all the way from your mouth to the rectum), but primarily depends on the retention of alcohol in the stomach, which is effected by the amount of food present. This is because the small intestine represents the area of greatest absorption of alcohol!
Fun Fact (2): Alcohol consumption and dehydration: Ever wonder why your so dehydrated after a night of drinking?
  1. Effect on Antidiuretic hormone (ADH)- Alcohol consumption inhibits your bodies ability to produce a hormone that helps to promote reabsorption of water from the kidneys.
  2. Effect of increased osmolality- Drinking actually pulls water out of your cells! This is because water flows from a region of low osmolality to high osmolality (meaning that there are more dissolved stuff in your blood than in your cells causing water to move out). Alcohol increases the osmolality of your blood.
Together, this shows that you literally lose more water in your urine the more alcohol that you drink. This in turn could exacerbate your hangover!
 
a) The Good: Antioxidant can help deter lung-related diseases associated with alcohol consumption:
  • Cilia (which are the hairlike projections in your throat that push mucous and other bad stuff out!) show increased damage correlated with alcohol consumption. In a recent study, researchers found that by increasing dietary supplements of two available antioxidants (N-acetylcysteine and procysteine) rats were found to have increased ciliary function in response to alcohol as opposed to rats that just were given alcohol.
b) The Bad- Increased consumption of alcohol (chronic usage) can lead to hardening of the arteries (atherosclerosis)-
  •  Consumption of alcohol can lead to dilated blood vessels (vasodilation) increasing the rate of blood through the circulatory system. Chronic consumption, however, can have the opposite effect: nitric oxide (NO) is a potent vasodilator and increases in response to small concentrations of alcohol. Increased concentrations of alcohol consumed over time, however, can actually inhibit epithelial cells from producing NO whereby causing increased constriction. It also can activate immune cells to form plaques in the bloodstream leading to heart disease.
c) The Atrofreaking kidding me? Increased alcohol consumption in women has been shown to increase the risk of breast cancer!
  • Breast cancer is the leading cause of cancer within women in the United States. Epidemiological data (or the study patterns involved in human health problems) has shown that female heavy drinkers (note the pattern of heavy drinking talked about earlier, which in this case is > 3 standard drinks per day) are equated to a 40-50% increased risk of developing breast cancer. The authors were even quoted to say that around 50,000 cases of breast cancer around the globe has been attributed to increased alcohol consumption!
RR = relative risk. Taken from Seitz et. al. 2012

II) The Liver: The liver is the major site of alcohol metabolism. As the alcohol circulates throughout the bloodstream, it passes through the liver where it is broken down into acetylaldehyde and eventually acetate, which enters the mitochondria for further processing within liver cells

a) The Good: The liver is a powerful organ! Liver cells retain three different mechanisms that can breakdown alcohol, which depend on the amount of alcohol ingested!

Functional components of the liver are called hepatocytes (or liver cells), which facilitate these three different mechanisms:
  1. Alcohol dehydrogenase (ALDH)- these enzymes are present in the cytosol (the "fluid" inside the cell). At moderate to low concentrations of alcohol, these enzymes breakdown ethanol into acetylaldehyde. This chemical component can then be further broken down into acetate within the mitochondria for energy.
  2. Microsomal Ethanol-Oxidizing System (EOS)- as the amount of ethanol increases within the blood, ALDH can become "overworked" (or saturated). These microsome EOS systems then are activated (which are present in the smooth endoplasmic reticulum) which breakdown the excess alcohol.
  3. Peroxisomes- if the levels of alcohol are so high that they become toxic, then the peroxisomes use both ALDH (stored within these vesicles) in addition to hydrogen peroxide to breakdown the excess alcohol.
Fun Fact (3): Alcohol tolerance?
  • Some people develop a alcohol tolerance, after repeated drinking episodes over time. This may be attributed to an up-regulation (increase in synthesis) of ALDH. As more ALDH is present in the cytosol of liver cells, more alcohol can be broken down in the liver. Therefore, as more ALDH is present, the rate at which alcohol in the blood can exert its effects on the brain decreases. This is one reason why some people of the same age, weight or gender can have different tolerances to alcohol.
All of these pathways have components in common: NADH or NADPH (Nicontinamide adenine dinucleotide & Nicotinamide adenine dinucleotide phosphate respectively).


Image taken from: www.chemwiki.ucdavis.edu
This shows the relative reduction (electron has been gained: NADH) and oxidation (electron has been removed, NAD+) states of each molecule. The reduced form (of both NADH and NADPH) of both coenzymes are utilized in the catalytic breakdown of alcohol. One method to help ameliorate the effect of a hangover, is to have adequate levels of these compounds (hint: these precursors are also known as Vitamin B3).

Fun Fact (4)- Acetylaldehyde, which is formed during the breakdown of alcohol, can also enter the bloodstream. High concentrations of this substance are also associated with the "hangover effects" in addition to the dehydration and secondary metabolites formed during the breakdown of alcohol.

Fun Fact (5)- Ever wonder why your so hungry after hours of drinking?
  • Gluconeogenesis ("Generation of new glucose in the blood) involves multiple enzymatic catalyzed reactions to produce glucose within the liver. The glucose is then released into the blood where brain cells utilize the sugar for energy (your brain solely runs on glucose, with few exceptions). In order for the first set of reactions to take place, however, your liver cells require NADH or the reduced form of the molecule to perform these reactions. If you notice, however, the breakdown of alcohol depletes the NADH reserves in the liver cells and increases the amount of the oxidized form or NAD+. Thus, alcohol causes hypoglycemia (or decrease in glucose levels in the blood) as a direct result of the breakdown of alcohol. So next time you get the munchies after drinking, don't blame your liver cells for getting hungry, since they will be working double time as it is.

b) The Bad: The most common disease associated with alcoholism is the formation of a "fatty liver" (termed hepatic steatosis)-
  • During increased consumption of alcohol, the liver undergoes a transformation, in which fat accumulates in the liver (or increases in the amount of triglycerides or "fats"). This may be attributed to the inhibition of fatty acid breakdown (also known as fatty acid oxidation) that occurs within the liver. If an alcoholic continues to drink, they run the risk of fatty liver disease culminating in cirrhosis which is the leading cause of death among heavy drinkers.

The "white circles" in the fatty liver are fat droplets. Notice that in normal livers, the concentration of these droplets are negligible.

Fun Fact (6): Use it or gain it? Some people that drink in excess can gain weight. Why is this?
  • One reason (among many) that people gain weight during heavy gradual drinking is due to the breakdown of alcohol itself. Earlier, I mentioned that breakdown of alcohol leads to acetylaldehyde which is further processed into acetate in the mitochondria of liver cells. Acetate is a very important molecule as it is a precursor that fuels both TCA cycle (major energy producing pathway) as well as fatty acid anabolic pathway (fatty acid producing pathway). Your cells can "sense" the concentration differences and the energetic demands of the cell: if no energy is required (TCA cycle), then it will be stored as FAT in this case.
c) The Atrofreaking kidding me? The chronic consumption of alcohol may be the signal for your immune cells to attack your liver cells: Chronic alcohol ingestion may be the signal for your body to literally kill itself.
  • Earlier, I discussed the three mechanisms by which alcohol is broken down in the liver. Chronic consumption of alcohol, however, may lead to the production of reactive oxygen species (ROS). As alcohol is broken down in the liver in high concentrations, the overproduction of acetate (as a result of acetyaldehyde breakdown), in addition to the Microsomal EOS pathway, can lead to the production of ROS. These ROS may also activate inflammatory cascades leading to the activation of cells involved in the production of cytokines (white blood cell signals). These cytokines, in turn, then activate immune cells called Kupffer cells. These cells normally respond to gram negative bacteria and express a protein called Tumor necrosis factor alpha. Normally, this protein would be produced to help preclude the threat of infection by killing infected cells. However, overproduction of this component could lead to the breakdown of liver tissue (called hepatic necrosis) which is thought to contribute to alcoholic liver disease (ALD).

Taken from Miller et. al. 2011. Overexpression of Tumor Necrosis Factor as a result of alcohol can kill liver cells.

Alcoholism will continue to be a hotly debated topic, as long as our demand for the substance continues. However, this is not to say that drinking is all that bad. In fact, there are some benefits to drinking: I) earlier I mentioned that antioxidants can lead to decreased damage to cilia within the throat. Wine actually contains a high amount of antioxidants. II) In addition, wine contains a substance called resveratrol which has been shown to activate proteins involved in the breakdown of reactive oxygen species (the very thing activated in liver cells as a result of increased alcohol consumption...Go figure right?). It really all depends on moderation. Please note, however, this is not meant to completely deter you from enjoying your favorite alcoholic beverage (in fact, as soon as I'm finished writing this, I'll probably enjoy a cold one myself!). I mainly wanted to illustrate some of the issues that can be attributed to the consumption of alcohol, as well as to spur interest into the mechanisms that occur within our bodies as a result. So next time your about to "have yourself a brew," (-to quote the immortal Johny Cash), have a drink on me...But perhaps, just make it one ;).

Citations

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Gastineau, C. F, W. J. Darby and T. B. Turner. Fermented food beverages in nutrition. New York, NY. Academic Press. 1979.

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Lieber, C. S. Medical and nutritional complications of alcoholism: mechanisms and management. New York, NY.  Plenum Medical Book Company. 1992.

Miller, A.M, N. Horiguchi, W-I. Jeong, S. Radaeva and B. Gao. 2011. Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines. Alcoholism: Clinical and Experimental Research 35 (5): 787-793

Seitz, H. K, C. Pelucchi, V. Bagnardi and C. L. Vecchia. 2012. Epidemiology and pathophysiology of alcohol and breast cancer. Alcohol & Alcoholism 47 (3): 204-212.

Simet, S. M., J. A. Pavlik and J. H. Sisson. 2013. Dietary antioxidants prevent alcohol-induced ciliary dysfuntion. Alcohol 47: 629-635.