Biogram – Serotonin: Fertilizer For Your Patience & “Herbicide” For Your Liver

21 November 2012 by Nsikan Akpan, posted in Biogram, TBS Journal Club


Serotonin: Fertilizer For Your Patience & "Herbicide" For Your Liver

(mirrored from here)

Seeing the beauty in biology is easy. The earth’s canvass is painted with life…from the microscopic and abstract to the grand and inspiring. We are inundated with amazing images of life, some obvious, many obscure.

To this end, That’s Basic Science is joining forces with Tessa Beligue Photography to bring you…


Biogram: A Biology Photolog.
In brief, Tess will provide the pretty pictures, and I’ll attach some scientific mumbo jumbo.


      For instance, these wonderful images1 (above and right) provide a glimpse into a mouse’s dorsal raphe, which is a small pocket of neurons located in the brainstem. These neurons produce the neurotransmitter serotonin (stained pink on the right), which they use to communicate with other neurons in the brain. Although relatively small, the dorsal raphe sends axons (stained blue to the right and grey above) to the regions of the mind that regulate fear and decision-making. As such, it plays a pivotal role in myriad behaviors, such as appetite, anxiety, depression, and sleep
      Growing evidence now supports a link between patience and serotonin levels in the dorsal raphe. But the awesome power of serotonin isn’t limited to the dorsal raphe; in fact it’s not even limited to the brain. The second half of this Biogram will outline how tweaking serotonin in the liver can promote regrowth after injury.


Can’t Wait
With the oncoming holiday season, and the mega-consumerism that goes with it, shopping lines are sure to be lengthy at malls and Walmarts across the country. Some people will handle the long waits with grace befitting Princess Di. Others will cut in line, frantically dart back and forth in search of the best cashier, and sneer at the elderly lady who can’t remember whether her card is “debit” or “credit” at the checkout counter.
Patience is a virtue often ignored during this season, but a lifetime without it can have some serious consequences. Probably one of the best illustrations of this fact is the famous Stanford Marshmallow experiment. First conducted by Walter Mischel in the early 1970s, the experiment involves placing an irresistible treat (a cookie or marshmallow) in front of a young child sitting at a table. The child is told if s/he can wait 10 minutes without devouring the snack, then they will be rewarded with a second.
Turns out in the long run that kids who waited the entire time—the patient brood—were less likely to be overweight or addicted to drugs as adults, fared better on their SATs, and had more stable marriages/relationships.
Broadly speaking, impulsivity can be broken down into impulsive choices and impulsive actions. When the kid eats the cookie before the time is up, s/he is making an impulsive choice by sacrificing a greater future reward for a short-term gain.
For a good example of an impulsive action, look no further than your purse or pockets. Do you ever check your cellphone for a message, even when it hasn’t vibrated...precious seconds of your life gone forever? If so, you’ve committed an impulsive action by lacking the restraint to avoid an undesired behavior.
For decades, the neurotransmitter serotonin has been thought to factor into impulsivity—both choices and actions—but debate remains over exactly how. Which parts of the brain are critical for this behavior? Is there a way to change an individual’s brain chemistry so they will be more stoic?
Recently, a group of Japanese scientists learned they could test the patience of lab rats by mirroring the methods of the Stanford experiment. Their furry subjects were taught to expect food/water after they had poked their nose through a hole, but only after keeping their noses in in the hole for at least 7-11 seconds.
Pull out too early, and no treat for you...that’s what she said.
When the researchers turned off the serotonin neurons2 in the dorsal raphe, the rats became restive and could no longer wait the desired time for the treat. But why?
Fig. 1 - Dorsal Raphe and Prefrontal Cortex

Like I mentioned before, the dorsal raphe is connected to several regions in the brain, one of which happens to be our decision-making center: the prefrontal cortex (Fig. 1). After shutting down the dorsal raphe, serotonergic signaling to the prefrontal cortex was reduced, and the rats were less patient.

Many groups have examined the relationship between the dorsal raphe, prefrontal cortex, and impulsivity, but these studies from Japan are amongst the first to target the dorsal raphe in isolation. Previous attempts have typically manipulated serotonin levels throughout the brain, which has produced contradicting results: impulsivity was elevated in some cases, while during others, it was reduced. These new results help to resolve some of the debate in the field.
New research from the University of Newcastle has exposed how serotonin controls our ability to recover from liver damage. Although serotonin is popularly thought of as neurotransmitter, the bulk of it—approximately 90%—is found outside of the nervous system, where other cell types use it as a chemical messenger.
Serotonin factors into wound healing because to recover from an injury, our bodies must successfully balance two processes:

The body’s first priority is to seal the wound as quickly as possible, via a process called “fibrogenesis”. The body’s repairmen (platelets and special cells called fibroblasts) are recruited to the scene of the crime and start producing tiny fibers of collagen. These fibers fill the wound, like plaster in a wall, and create a scar across the damaged area. 

Turns out that platelets use serotonin as a messenger to coordinate their efforts with fibroblasts.

While scarring is taking place, the body is also trying to regenerate the cells that were lost. Optimal healing will have a minimal amount of scarring and plenty of regeneration. 
Unfortunately, as humans age, we lose the ability to regenerate, while scarring becomes more prominent.
Even in the liver, 2nd only to the skin in regenerative capacity, falls victim to this shift in power. Such is the case with cirrhosis of the liver, most commonly seen in adults suffering from alcoholism or hepatitis C viral infection.
Prof. David Mann and his partners in Newcastle found that they could sway this balance in favor of regeneration by targeting the liver’s resident fibroblasts: hepatic stellate cells3. His group learned in 2006 that stellate cells regulate the scarring process in the liver by responding to serotonin produced by platelets4.
Elsewhere, it had been proposed that stellate cells prevent other liver cells—namely hepatocytes—from regenerating after an injury. Hepatocytes are the liver’s workhorses; lose too many without replacing them, and the organ fails.
In their latest publication from Nature Medicine, Dr. Mann discovered that stellate cells can keep hepatocytes from regenerating during an injury, but if you block serotonin, the hepatocytes proliferate successfully.
In this study, mice with liver damage5 were treated with a drug that stops serotonin from interacting with stellate cells. This treatment reduced scarring after liver injury, while triggering hepatocyte regeneration, which improved overall liver function and survival.
Hepatic stellate cells in mice and humans respond in a similar fashion to serotonin, so this strategy could be applied to human disease in the future6.


Geek Notes (for the scientists):

Can’t Wait
1the wonderful images…Serotonin (5-HT) neurons expressing Green Fluorescent Protein (GFP) under the transcriptional control of the Pet1 gene promoter in the dorsal raphe. Pet1 is found exclusively in serotonergic neurons. Left panel: green/blue is staining of GFP, pink is staining for serotonin. Lower panel: GFP staining alone. Immmunohistochemistry. 10x magnification. [© Tessa Hirschfeld-Stoler and Columbia University. All Rights Reserved. Do not use or reproduce.]

2When the researchers turned off the serotonin neurons…Accomplished by infusing a 5-HT1A receptor agonist into the dorsal raphe with reverse dialysis. Activating the 5-HT1A receptor, one of 14 mammalian receptors, inhibits of adenylyl cyclase activity and opens K+ channels, which results in neuronal hyperpolarization and decreased neurotransmission.

3hepatic stellate cells…Technically, they are pericytes that exhibit a myofibroblast phenotype upon activation (i.e., to repair an injury).
4by responding to serotonin produced by platelets…Rat and human hepatic stellate cells express five different serotonin receptors (5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, and 5-HT7), but during an injury they elevate the expression of 5-HT1B, 5-HT2A, and 5-HT2B. Of these three, 5-HT2B is responsible for why hepatic stellate cells control hepatocyte proliferation. The authors show that activating 5-HT2B receptors on hepatic stellate cells leads to the expression of transforming growth factor β1, which blocks hepatocyte proliferation. Therefore, if you reverse this process—turn off 5-HT2B—then hepatocyte proliferation should increase, which is what they report.
5mice with liver damage…Blocking 5-HT2B receptors or eliminating hepatic stellate cells was beneficial in 4 different models of liver injury: partial hepatectomy, Bile duct ligation, and carbon tetrachloride treatment (acute and progressive).
6this strategy might be applied to human disease in the future…some 5-HT2B antagonists, like the one used in this study, have been clinically approved to treat pulmonary ailments; thus, they could be repurposed for clinical trials with liver disease.

The Papers
Can’t Wait

Miyazaki KW, Miyazaki K, & Doya K (2012). Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (31), 10451-7 PMID: 22855794

Miyazaki K, Miyazaki KW, & Doya K (2012). The role of serotonin in the regulation of patience and impulsivity. Molecular neurobiology, 45 (2), 213-24 PMID: 22262065

Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, Ellis E, Lakey AF, Burt AD, Douglass A, Wright MC, White SA, Jaffré F, Maroteaux L, & Mann DA (2011). Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease. Nature medicine, 17 (12), 1668-73 PMID: 22120177
Mann DA, & Oakley F (2012). Serotonin paracrine signaling in tissue fibrosis. Biochimica et biophysica acta PMID: 23032152

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