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

[JaimeS]

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

• 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.

 

[JaimeS]

More amusing mouse quotations:

Marble burying shows stereotypical mouse digging behaviour and is often used to demonstrate anxiety, with an increase in marbles buried indicating an anxious state [20]. However, Thomas and colleagues [21] have suggested this is not the case, but rather that it reflects perseverative and repetitive behaviours.

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

-J

 

[JaimeS]

Here, we have introduced the circulating cytokines with a systemic immune challenge and therefore any changes in behaviour are likely to be due to the increased levels of inflammation, rather than the other way around.

....these people think changes in behavior cause inflammation in normal circumstances? (Not unless I stub my toe!)



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

-J

 

[JaimeS]

Most important bit:

Recent research studying behavioural changes in response to inflammatory challenges often focus on the role of specific cytokines in the CNS. Two major pro-inflammatory cytokines are TNF and IL-1. It has been suggested that the only role for TNF in sickness behaviour is to compensate for dwindling IL-1 [9, 42]. In apparent contradiction to this, our data has shown that a systemic challenge with LPS results in significant up-regulation of CNS TNF, with no significant elevations of IL-1. This selective up-regulation of particular cytokine and chemokine subsets has also been observed in human studies using vaccines [43]. The role of TNF, specifically, as a mediator of sickness behaviour, is evident in studies using anti-TNF drugs, which appear to reverse sickness behaviours when they are given systemically [10]. It has also been shown that TNF receptor knockout animals show a distinctly different behavioural phenotype, specifically an anti-depressant phenotype in the forced swim, compared to littermate controls [44], where no such behavioural change has thus far been noted in any of the IL-1 knockout animals (personal communication). Clinically, TNF presents an interesting prospect. Anti-TNF therapy has been shown to be anti-depressant in the absence of a clinical improvement in symptoms [45], whereas, much like the knockout mouse example, no such data exists for anakinra, the IL-1 receptor antagonist mimic. With studies in depressed patients beginning to investigate the potential of inhibiting cytokines in treatment-resistant depression, there is a clear positive role for cytokines such as TNF in the regulation of mood [46]. However, the mechanisms by which TNF mediates changes in behaviour, and its potential role in both sickness and depression, are yet to be explored.

Perhaps the most commanding results here are the changes we have observed in the 5-HT system. In this study, treatment with LPS caused a significant increase in 5-HT2A receptor expression in a number of discrete brain regions. We have also demonstrated that this results in a functional outcome, i.e. there is a significant alteration in 5-HT2A-mediated behaviours. This is in accord with our previous studies on acute sickness, where increases in 5-HT2A receptor expression were also associated with functional changes [24]. Our data also indicate that these changes are receptor specific, rather than a general change in 5-HT receptor expressing cells, as we do not see similar changes in other 5-HT receptors, such as 5-HT1A (S5 Fig). The involvement of the 5-HT2A receptor in mood is currently controversial. Studies from the late 80s indicate that receptor expression increases in patients with suicidal depression [47–49], with further data suggesting that this increase may be non-neuronal [50]. In terms of inflammation, and as a consequence sickness behaviour, increases in 5-HT2A receptor expression have been seen in models of inflammatory pain [51], as well as in other studies using LPS [5] indicating that systemic inflammation is capable of regulating this response in vivo. The mechanisms by which changes in receptor expression occur were beyond the scope of this study; however, hypotheses can be generated based on existing research. Studies linking the 5-HT2A receptor with inflammation have suggested that its activation may result in the down-regulation of inflammatory cytokines [52], specifically TNF expression [53]. Furthermore, studies in cultured glioma cells have demonstrated an inhibition of inducible nitric oxide synthase (iNOS) by 5-HT2A agonists [54]. Work by Zhang and colleagues [51] demonstrated that the up-regulation of 5-HT2A after inflammation was not co-localized with 5-HT, indicating that it was not in serotonergic neurons. Furthermore, 5-HT2A receptors have been shown to be present on astrocytes and microglia [55]. Therefore, increased 5-HT2A receptor expression after a peripheral inflammatory stimulus could potentially occur in non-neuronal cells for the purposes of potentiating an anti-inflammatory response in the CNS.

Done for now! Night, everybody!

-J

 

[alex3619]

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.

 

[heapsreal]

I just think the mice have been brought up in a bad environment and abused as children, surely that would affect their marbles ????

 

[sarah darwins]

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.

 

[duncan]

To me, the concept of "sickness behavior" has the feel of springing from the fancies of a veterinarian longing to be a psych.

Wait...

 

[Sidereal]

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.

 

[lansbergen]

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.

How many sick animals have they seen? .

 

[MeSci]

I just think the mice have been brought up in a bad environment and abused as children, surely that would affect their marbles ????

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.

 

[MeSci]

I just think the mice have been brought up in a bad environment and abused as children, surely that would affect their marbles ????

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.

 

[biophile]

A little bit of related humour:

Neuroskeptic ‏@Neuro_Skeptic

According to a shocking new study, you are at risk of being killed and eaten by a cat! (research was in mice).

https://twitter.com/Neuro_Skeptic/status/619898007295787008

 

[Snowdrop]

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.

 

[Snowdrop]

Then there's this:

http://www.theguardian.com/science/2015/mar/20/mice-clinical-trials-human-disease

 

[JaimeS]

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,

Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology.

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,

Sickness behavior is a behavioral complex that is typically induced by acute infections and tissue injury.... The characteristic behavioral pattern consists of malaise, hyperalgesia, pyrexia, listlessness and disinterest in social interactions with the environment, lethargy, behavioral inhibition, reduction of locomotor activity....

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:

Acute and chronic inflammation are distinguished in terms of immune response patterns and time course. The time point of transition of acute inflammation to chronic inflammation is also related to the time when the energy stores become empty and this is estimated to be around 19 to 43 days depending on the nature of the energy store 152]. This transition is related to a number of inflammatory sequelae, including cachexia, insulin resistance, anemia, osteopenia and hypertension 152]. Sickness behavior thus plays a critical role in preventing the transition from acute to chronic inflammation following an acute trigger by compensating for the negative energy balance, redirecting energy to the activated immune cells, and so on 152]. Clinical depression, on the other hand, is accompanied by chronic inflammatory processes and is associated with less well defined trigger factors

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

 

[JaimeS]

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

 

[skipskip30]

I just think the mice have been brought up in a bad environment and abused as children, surely that would affect their marbles ????

Yes of course, childhood trauma must be the reason for it all! Thank goodness for marble burying mice curing us!

 

[Snowdrop]

@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.

 

[JaimeS]

@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.

Toned down a bit, but yeah. Good plan.

-J