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Scicurious Guest Writer: Thoughts about depression from under the sheets

The views expressed are those of the author and are not necessarily those of Scientific American.


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Please welcome the first of the Scicurious Guest Writers, Nicole Baganz!

Sunday.
6:00 AM. The clock glared at me, so I pulled the sheets over my head. It’s freezing out there.

10:03 AM. I never sleep this late. Just… can’t… get… out… of… bed.

1:12 PM. I haven’t eaten anything all day. Just the thought of food is absolutely disgusting.

3:22 PM. Phone rang. Caller ID showed that it’s Mom. Sorry Mom, I really don’t feel like talking right now.

4:02 PM. It took every ounce of energy I had to drag myself to the bathroom. Arriving in the room that is located 2 feet from my bed felt like a victory. I rifled through the medicine cabinet, stuck the thermometer in my mouth and collapsed on the bathroom floor. 103.2° F. Yep, I’m sick.

Sleepiness. Fatigue. Loss of appetite and motivation. Lethargy. Leave me alone. We all know what it feels like to be sick. Clinicians collectively describe this group of symptoms as “sickness behavior”. Evolutionarily speaking, the idea that the immune system would produce these symptoms makes sense. An organism infected with a pathogenic bug should retreat from its social group to protect others from the spread of infection. The organism essentially shuts down in order to send every ounce of energy to the immune system to battle the bug that has invaded the body’s cells. This sickness state would facilitate recovery of the organism and also protect the community from the spread of the infection by limiting the interaction of the infected party from its entire social group.

All of the symptoms of sickness behavior are displayed not only by people who have an infection, but also by those who have been diagnosed with Major Depressive Disorder (MDD). Could sickness behavior and MDD be linked? What happens in the brain to produce sickness behaviors, and how might these relate to depression? Mice are good models for scientists to use to study the effect of immune system activation on brain function and behavior (research studies that subject people to infectious agents before probing their brains in the name of science draw few willing volunteers). Laboratory mice also display sickness behavior when their immune systems are turned on. Sick rodents sleep more, eat less, and lose interest in drinking sugary water (usually a scrumptious treat for mice). They also stop interacting socially – mice are, by nature, very social creatures that like to sniff, groom, lick and cuddle up to their roommates.

Indeed, a recent study using mice illuminates one facet of how the immune system can control specific features of behavior. Cohn et al. (2012) investigated the behavior of healthy and sick mice that lived together. The researchers showed that when two healthy male mice are housed together, a social hierarchy forms, with one mouse taking on the role of the “alpha-male”. One of the mice taunts and attacks the other in order to demonstrate his dominance, a show of a sort of rodent machismo.


(Source)

Researchers identified the dominant mouse in the pair and injected him with lipopolysaccharide (LPS), a component of a bacterial membrane that activates the immune response and produces sickness behavior. Then they observed what happened to the social behavior of the pair of mice. After treatment with LPS, the dominant mouse was less easily distinguished from the healthy mouse, suggesting that the social hierarchy had been disrupted. In other words, the dominant mouse not only appeared to be uninterested in declaring superiority over his roommate, he didn’t seem to want anything to do with him whatsoever. What happened in the previously dominant mouse to cause him to withdraw from social interaction when he became sick?

Social withdrawal is both a symptom of sickness behavior in rodents and a cardinal sign of depression in humans. Because depression has long been linked to serotonin (5-HT), a neurotransmitter or signaling molecule that communicates between cells in the brain, 5-HT was the first suspect to interrogate. 5-HT levels in the brain are tightly controlled by the serotonin transporter (SERT), a protein that lives in the membrane of 5-HT neurons.

SERT recycles 5-HT that is released from the neuron and basically acts as a 5-HT vacuum cleaner. Therefore, SERT mainly controls how long the 5-HT signal lasts. Drugs like Prozac, a selective serotonin reuptake inhibitor (SSRI), block SERT and therefore the 5-HT signal lasts longer, allowing it to “talk” more to other cells. Because SSRIs have been shown to relieve the symptoms of depression in some patients, 5-HT and SERT are the stars of a plethora of research on depression. Recent research suggests that chemicals released during an immune response also can affect SERT and 5-HT. Activating the immune system with LPS increases SERT activity, turning it into a super-vacuum for 5-HT. SERT becomes extremely efficient, rapidly whisking any 5-HT signal out of the synapse before it can communicate with other cells. Therefore, the effect of immune activation on SERT is “opposite” that of Prozac – we could even say it’s “pro-depressant”, producing behaviors that look like depression in animals, and decreasing 5-HT signals. If the sickness behavior produced by immune system activation is linked to a super-powered SERT, can turning “off” SERT, by blocking it with an SSRI prevent social withdrawal? In the same study on social hierarchy in male mice, Cohn et al. showed that the ability of LPS to disrupt the social hierarchy was lost when the dominant mice were first treated with an SSRI. In other words, blocking SERT stopped the immune system from making mice antisocial.

5-HT is only one of many players in the development of depression, and the link between the immune system and other brain chemicals is indisputably more complex. 5-HT is just the tip of the iceberg. These lines of research investigating the relationship between the immune system and the brain 5-HT system may help millions of depressed people who may be struggling with potentially immune system-hijacked brains. Depression is the primary cause of loss of productivity and missed work days in the U.S. In both depression and illness, people lose motivation to go to work or do much of anything at all (including answering the phone when Mom calls). In the case of infection, sickness behavior is a normal response to halt the spread of the bug and help the organism get better. In the absence of an infection, however, depressive symptoms could arise from inappropriate immune system activation. Ultimately, these studies could shed light on what happens in the depressed brain and begin to erase the stigma that remains attached to mental illness.

Cohn DW, Kinoshita D, & Palermo-Neto J (2012). Antidepressants prevent hierarchy destabilization induced by lipopolysaccharide administration in mice: a neurobiological approach to depression. Annals of the New York Academy of Sciences, 1262, 67-73 PMID: 22823437

Nicole Baganz is a neuroscientist in the lab of Randy Blakely at Vanderbilt. She got her Ph.D. from the University of Texas Health Science Center at San Antonio and now studies how stress and immune system activation affect brain serotonin and mood. She also loves yoga and is trying to find a way to perform her experiments while simultaneously assuming a new smiley-facing mouse pose.

Would you like to be a Scicurious Guest Writer? Scicurious is mentoring one guest writer per month here at the Scicurious Brain. For more information and to apply, please see here.

Scicurious About the Author: Scicurious is a PhD in Physiology, and is currently a postdoc in biomedical research. She loves the brain. And so should you. Follow on Twitter @Scicurious.

The views expressed are those of the author and are not necessarily those of Scientific American.



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  1. 1. Petra 6:00 pm 11/28/2012

    Thanks Nicole; your research is interesting, yet it’s important to appreciate the term “dis-ease”

    When one is ill and has a dis-ease it forces one by physical conditions to move away from others. Yet it has a purpose as well to force one to take time to appraise life and in that new insights are possible.

    Though in MDD the dis-ease arises when people feel out of their comfort zone in being faced with problems, (often long term) to which there are no immediate answers and thus frustration commences which leads to depression. Yet, in removing oneself from others it offers an opportunity think about what one values, reassess goals and ambitions, decide if one’s social construct is beneficial, therefore asking all of the big questions.

    However, your research has focused on a very short term problem over most likely a very long term problem, though the source material is actually unrelated.

    But if we ask what the nature of cancer may be, we might simply address it by asking, “what’s eating on you?” And that’s cancer in it’s most simplistic terms. And oddly, most who suffer from cancer have possessed a very long term problem which as been bothering them, much as though a hidden depression but it erodes the body at it’s weakest point and emerges as cancer.

    All in all dis-ease whether it’s caused by a socially initiated illness or something of the mind that manifests itself into dis-ease in the body, it has a purpose and it’s self appraisal. IE: leave me alone because I need time to think and regroup even if it arrives without a known recognition that’s the purpose of the exercise; eventual enlightenment.

    Link to this
  2. 2. tulin20m 1:29 am 11/29/2012

    Very interesting, so with theories about immune activation to things like candida or industrial chemicals, could this actually make sense of a lot of depression in the U.S.?

    Link to this
  3. 3. Neosteo 4:21 am 11/29/2012

    “All disease begins in the gut.” Hippocrates

    80% of our immune system resides in the gut hence the use of gram-negative bacteria in the test subjects to elicit a response.

    90% of serotonin is produced in the gut along with other neurotransmitters such as opioids. If the balance of gut flora is out of sorts the bad bacteria take over causing a chain reaction that leads to a neurochemical imbalance which can manifest as addiction, depression or other symptoms of disease.

    Link to this
  4. 4. bucketofsquid 3:12 pm 11/29/2012

    With out my lovely Zoloft, every day is like the beginning of this article.

    @Petra – Science is still exploring the mind/body interface. Most cancers and a variety of other diseases are known to be caused by microbes, particularly viruses in the case of a wide variety of cancers. Be careful not to assume the mind controls the immune response and not vice-versa.

    Link to this

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