The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
Discuss the article on the Forums.

A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in

Discussion in 'Latest ME/CFS Research' started by JaimeS, Jul 11, 2015.

  1. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    Some really weird language that hints at ME being psychiatric but up to the point where I am, has not yet said so overtly. Still, it's an interesting one. My favorite silly bit is that mice have "reduced marble burying behaviors" which is clear proof that they are depressed. (Or tired, or bored, but whatever.)

    Full text from http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130643

    Research Article

    A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice
    • Yvonne Couch ,
    • Qin Xie,
    • Louise Lundberg,
    • Trevor Sharp,
    • Daniel C. Anthony
    [​IMG]
    • Published: July 6, 2015
    • DOI: 10.1371/journal.pone.0130643
    Funding: This work was supported by the Biology and Biotechnology Research Society (UK) in vivo additional studentship to YC/DA/TS.

    Competing interests: The authors have declared that no competing interests exist.

    Abstract
    It is well documented that serotonin (5-HT) plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS), which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5mg/kg i.p.), at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS.
     
    natasa778 and Violeta like this.
  2. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    More amusing mouse quotations:

    Yes... because whenever you attribute human characteristics to mouse behavior, you can very well be seeing what you wish to see!

    -J
     
    Hutan likes this.
  3. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    ....these people think changes in behavior cause inflammation in normal circumstances? (Not unless I stub my toe!)

    :bang-head:

    Tell me I'm missing something here and a paper didn't travel past so many gazes and keep a statement like that.

    -J
     
  4. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    Most important bit:

    Done for now! Night, everybody! :D

    -J
     
    sarah darwins, Valentijn and Marco like this.
  5. alex3619

    alex3619 Senior Member

    Messages:
    12,489
    Likes:
    35,091
    Logan, Queensland, Australia
    This is argument by "might-be". It might be this, it might be that, and so in conclusion we might be right. They do use warning words, caveats, Focusing on the biochemistry is probably better than attributing psychological states. So is keeping the behaviour observations as strict uninterpreted observations.

    Let me point out though that increased serotonin receptor function has been observed in an old study of CFS, not sure from when, but I think it was from Scandinavia.
     
    JaimeS and Valentijn like this.
  6. heapsreal

    heapsreal iherb 10% discount code OPA989,

    Messages:
    8,881
    Likes:
    8,182
    australia (brisbane)
    I just think the mice have been brought up in a bad environment and abused as children, surely that would affect their marbles ????
     
    Scarecrow, catly, bertiedog and 9 others like this.
  7. sarah darwins

    sarah darwins I told you I was ill

    Messages:
    2,467
    Likes:
    10,480
    Cornwall, UK
    Has anyone tried CBT/GET on the mice? Surely you could use the promise of cheese/the threat of a cat to get the little buggers past their fear of marble-burying beliefs. If that sorted out their immune systems, job done. QED.
     
    catly, bertiedog, JaimeS and 4 others like this.
  8. duncan

    duncan Senior Member

    Messages:
    2,038
    Likes:
    4,467
    To me, the concept of "sickness behavior" has the feel of springing from the fancies of a veterinarian longing to be a psych.

    Wait...
     
  9. Sidereal

    Sidereal Senior Member

    Messages:
    3,097
    Likes:
    17,173
    :lol:
     
    garcia likes this.
  10. lansbergen

    lansbergen Senior Member

    Messages:
    2,505
    Likes:
    2,710
    How many sick animals have they seen? .
     
    catly likes this.
  11. MeSci

    MeSci ME/CFS since 1995; activity level 6?

    Messages:
    7,968
    Likes:
    12,806
    Cornwall, UK
    They have certainly been abused. This is what a forced swim entails.

    It is a disgrace that time, money and lives continue to be wasted on this kind of cruel nonsense.
     
  12. biophile

    biophile Places I'd rather be.

    Messages:
    1,520
    Likes:
    16,577
  13. Snowdrop

    Snowdrop Rebel without a biscuit

    Messages:
    2,896
    Likes:
    10,089
    Funding: This work was supported by the Biology and Biotechnology Research Society (UK) in vivo additional studentship to YC/DA/TS.

    from the B & B R S UK website:
    About us
    We are one of seven Research Councils that work together as Research Councils UK (RCUK). We are funded by the Government's Department for Business, Innovation and Skills (BIS).

    Our budget for 2014-2015 is around £509M (£459M on research and capital grants and £50.5M for training and fellowships), and we support around 1600 scientists and 2000 research students in universities and institutes across the UK.

    Maybe there are some promising lines of inquiry for ME research that we could suggest they follow.
    One's that don't involve torturing mice or calling them lazy because they like their marbles above ground.
     
    MeSci, catly and sarah darwins like this.
  14. Snowdrop

    Snowdrop Rebel without a biscuit

    Messages:
    2,896
    Likes:
    10,089
  15. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    Both Maes [7] and Dantzer [8] suggest that sickness behaviour is an acute response, characterized by similar behavioural phenomenology as depression but with a pyretic component, and that behavioural responses persisting after 24 hours should be considered depression, rather than sickness.

    That honestly doesn't sound like something Maes would say. His thinking is usually far more nuanced than "if someone is still listless 24 hours after an illness, they are now depressed."

    Yeah, just read the abstract for the cited article, and Maes et al. make it clear that depression is one form of chronic inflammation, and he specifically separates it from other chronic inflammatory disorders. He even says,

    Emphasis mine.

    'Sickness behavior' may sound bad, but the term just means how people behave when they are ill rather than implying the illness is all in one's head.

    Maes states,
    Finally, I searched the article in question for where on earth Maes et al. could have possibly implied that sickness behaviors that perpetuate for more than 24 hours are depressive, and of course I could find no such implication. I did, however, find a statement that entirely contradicts that statement:

    Emphases mine.

    He constantly distinguishes between depression and "other" chronic inflammatory states throughout the article. He has never said "depression is ME" or even implied it. In fact, as I recall, he has an article titled something like "the differences between ME and sickness behavior". He also wrote the article that said that biologically, there was precious little difference between MS and ME. It was brilliant and exhaustive.

    Sorry, but it really burns my biscuits to see a less reputable group of researchers be all, "I'm right because More Reputable Researcher X agrees with me oh who cares no one will ever check trolololoz". It's gross. You have a PhD, and I presume you didn't pull it out of a crackerjack box. Act like it.

    -J
     
    Battery Muncher and Valentijn like this.
  16. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    LOL, guys, I'm sorry for posting two really crappy research studies in a row. But I think it's important that we be aware of the bad research as well as the good. :(

    -J
     
  17. skipskip30

    skipskip30 Senior Member

    Messages:
    237
    Likes:
    1,409
    Yes of course, childhood trauma must be the reason for it all! Thank goodness for marble burying mice curing us!
     
    JaimeS likes this.
  18. Snowdrop

    Snowdrop Rebel without a biscuit

    Messages:
    2,896
    Likes:
    10,089
    @JaimeS

    There is a comment section (as yet unused) for the this research article.
    I think some of your comments in post# 15 might be appropriate there.
     
  19. JaimeS

    JaimeS Senior Member

    Messages:
    3,193
    Likes:
    11,790
    Mid-Ohio Valley, United States
    Toned down a bit, but yeah. Good plan. :)

    -J
     
    sarah darwins and Snowdrop like this.
  20. sdmcvicar

    sdmcvicar

    Messages:
    58
    Likes:
    239
    So there's a ton of studies out there involving bacterial LPS, as this is the outer coat of bacteria that your immune system first recognizes as the sign of a bacterial infection. Inject it into mice and you get the symptoms of a bacterial infection (up to and including death at higher doses) without the actual infection. This tool helps researchers separate out the two factors. We now know, for example, when you have a sinus infection, the resulting pain, fatigue, bleariness, etc are primarily your body conning you into taking it easy so you don't use up the resources it needs to fight the infection. Very little of it has to do with the damage the bacteria are doing to your cells or any substances they secrete. However, subjectively, the result is very similar.

    That means that if you do anything different than your daily routine such as not going for your normal 5k run after work, or microwaving some Campbell's soup instead of preparing a balanced meal, or calling into work sick and staying in your pajama pants all day, you're engaging in "sickness behaviour". You could just ignore all those symptoms and go about your normal day. Not that it would be a good idea. Your doctor would tell you not to, as you'd be encouraging the infection to spread into your throat and lungs, actually making it harder to breathe and potentially reducing your O2 sats, increasing "sickness". Subjectively, it would also feel terrible.

    Now there is a useful underlying idea in this paper. It starts from several premises:
    1) A number of mental illnesses are now known to have altered cytokine profiles from healthy controls.
    2) Disease state does not necessarily correlate with concentration of cytokine "X".
    3) "Sickness behaviour" lasts longer than would be expected, suggesting some sort of memory of infection.

    So, these folks went and took normal, outbred mice and gave them LPS once systemically. The outbreeding is important because this means no specific phenotype present, and the population of mice tested should have some variability in response due to differences in genetics. These aren't ME or CFS mice. We don't know how to make those. Nor are they abnormally depressed mice. This, then, is the natural response to an immune challenge.

    As a result of the LPS injection, the amount of TNF mRNA and serotonin receptor mRNA goes up. This means cells are potentially producing more TNF, and more receptors for serotonin.

    Since no more LPS is injected (which is similar to eradication of a bacterial infection), the mice are expected to go back to normal after 24h.

    They don't.

    Therefore the body has modified itself, potentially by making cells more sensitive to serotonin and TNF.

    This is conceptually similar to the paradigm of stem and progenitor cells, which have increased expression of growth factor receptors, causing them to replicate and differentiate better than other cells due to small changes in their environment.

    My critiques:

    1) The behavioural stuff is all a "hand waving argument", as one of my physics profs used to say. Since you can't ask the mice why they're doing what they're doing, there's no way to eliminate observer bias. Were they less active because they were tired, or sleepy? Did LPS make them less anxious, or break a lifetime ambition of burying as many marbles as possible?

    2) The protein biochemist in me asks where the quantitative mass spec data proving there's more receptors being produced. Heck, I'd settle for a reasonable Western Blot.


    However this actually could very nicely fold into the discovery that PWCFS for less than 3 years have different cytokine profiles than longer term patients. Maybe our bodies have shifted to a new normal, more sensitive to the aftereffects of exercise, resulting in PEM. Now how can we characterize that, at a cellular level?
     
    JaimeS likes this.

See more popular forum discussions.

Share This Page