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More Complexity: Thyroid Hormones in the Brain

Wishful

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I was checking something about thyroid hormones in the brain, and found this paper interesting: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978256/

Thyroid hormones are definitely important for proper adult brain function, but it's certainly not as simple as "a normal level of T4 in serum = everything is okay". There are several feedback loops in the brain to keep the levels of T4 and T3 at appropriate levels. "Additionally, untreated hypothyroidism in the adult is associated with severe intellectual defects, abnormal balance and defects in fine motor skills, spasticity, and deafness"

Astrocytes are important for converting T4 from serum to T3 in the brain. Since astrocyte function might be affected by immune system activation, it's possible that this will affect T3 levels in the brain.

"Thyroid hormones mediate CNS effects primarily through thyroid hormone receptors (TRs), members of the nuclear hormone receptor family (4, 7, 8). TRs bind to the DNA regulatory regions of target genes to activate or repress transcription through interactions with accessory proteins known as coregulators." I think this is at least a possibility for having genes play a role in predisposition to ME. The paper (falsely) considered T2 to be inactive, but my experiences with supplemental T2 convince me that it too is important in transcription. A boost to T2 seemed to produce something that lasted a consistent 21 days before abruptly failing.

The paper introduced me to another new (to me) brain cell: tanycytes. "Deiodinase 2 <converts T4 to t3> is only expressed in selected cell types within the CNS: astrocytes and tanycytes." Tanycytes are specific to the hypothalamus. Here's a paper on them:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605593/

"Abstract
Tanycytes, glial-like cells that line the third ventricle, are emerging as components of the hypothalamic networks that control body weight and energy balance. They contact the cerebrospinal fluid (CSF) and send processes that come into close contact with neurons in the arcuate and ventromedial hypothalamic nuclei. Tanycytes are glucosensitive and are able to respond to transmitters associated with arousal and the drive to feed. At least some tanycytes are stem cells and, in the median eminence, may be stimulated by diet to generate new neurons. The quest is on to understand how tanycytes detect and respond to changes in energy balance and how they communicate with the rest of the nervous system to effect their functions."

I thought that those of you thinking about theories for ME involving thyroid hormones, the hypothalamus, or the brain in general might be interested. Brain chemistry sure is complex.

For those interested in theories involving the gut: https://www.frontiersin.org/articles/10.3389/fnbeh.2016.00210/full

That paper shows that astrocytes can induce gastric mucosal damage due to stress (in rats). I'll let others think about how likely it is that this might be involved in ME.
 

Pyrrhus

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The paper introduced me to another new (to me) brain cell: tanycytes. "Deiodinase 2 <converts T4 to t3> is only expressed in selected cell types within the CNS: astrocytes and tanycytes." Tanycytes are specific to the hypothalamus.
Definitely interesting. The paper lends more credence to the hypothesis that the rise in obesity is due to hypothalamic dysfunction, not due to changes in diet or activity over the last couple of decades.
 

Wishful

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the hypothesis that the rise in obesity is due to hypothalamic dysfunction, not due to changes in diet or activity over the last couple of decades.
Possible, but also possible that crappy diets or stressful, chaotic lifestyles affects the hypothalamus, which then causes obesity.

When I was first trying to figure my disease out, even before I knew about ME, it seemed simple: my immune system was releasing IFN-g causing my microglial cells to produce neurotoxic kynurenines. I could rule out astrocytes because they didn't produce IDO. Now I know that astrocytes certainly could be involved, and so could NG2-glia and now tanycytes. It just keeps getting more complex.

Brains work on connections between data, so I post these 'papers that might possibly be connected' so that our minds can have more data to make connections between. You can't connect tanycytes with a response to T2 if you've never heard of tanycytes before.
 
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To me one of the clues in all this is what does not work as a treatment.
Yes, although it's possible for some treatments to not work because of the specifics of that disorder. Minocycline is supposed to calm activated microglia, but it had no effect on me. Does that mean that my microglia are not activated, or that something in ME is blocking minocycline's normal action? Maybe it's one of the other glial cells being overactive? There are drugs that could be used to test some of these theories, but they are effectively unavailable. We can buy guns and ammo, but not 1-methyltryptophan. :grumpy:
 
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Possible, but also possible that crappy diets or stressful, chaotic lifestyles affects the hypothalamus, which then causes obesity.
Very good point. Cause and effect are always difficult to disentangle. Our modern diet includes more highly processed foods and more trace amounts of non-food chemicals that may have somehow leaked into our diet from plastic packaging or from elsewhere. And no one would deny that 2020 is a very stressful, chaotic year.

But let's not forget what life was really like a hundred years ago. Diets were crappy then, too. Most people could not afford to eat meat or high quality vegetables and malnutrition was widespread. And as stressful and chaotic as our lives may be today, they're nothing compared to the stress and chaos from famines, unchecked pollution from the industrial revolution, world wars, deadly diseases without vaccines, wildly fluctuating economies, depressions, and ethnic/religious persecution.

By the way, some people use the term "NG2-glia" to refer to the cells in mice. In humans, they would refer to the cells as "oligodendrocyte progenitor cells (OPCs)". Some people use both terms for humans, though.
 
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There are new findings for NG2-glia, beyond just OPCs.

"Neuron-glia antigen 2-expressing glial cells (NG2 glia) serve as oligodendrocyte progenitors during development and adulthood. However, recent studies have shown that these cells represent not only a transitional stage along the oligodendroglial lineage, but also constitute a specific cell type endowed with typical properties and functions. Namely, NG2 glia (or subsets of NG2 glia) establish physical and functional interactions with neurons and other central nervous system (CNS) cell types, that allow them to constantly monitor the surrounding neuropil. In addition to operating as sensors, NG2 glia have features that are expected for active modulators of neuronal activity, including the expression and release of a battery of neuromodulatory and neuroprotective factors."

Also: "These cells are distinct from mature oligodendrocytes, astrocytes or resting ramified microglia and represent a fourth major glial population"

That's what I mean when I say that it keeps getting more complex. Here's a type of cell that they thought was well understood, and it turns out to play a much larger and more complex role in brain function. Since these cells are monitoring the brain environement and signalling other cells, a malfunction there could potentially cause the chronic neuroinflammation we see in ME. Is minocycline not having an effect on my ME because microglia are not activated, or is it because minocycline actually deactivates microglia through the activity of NG2-glia, and that function is malfunctioning in ME? It's much harder to rule things out from negative results when you don't clearly understand all the factors and subsystems that are involved.

I read a paper recently about thyroid hormone activity in the brain. It certainly sounded professional, but they said that T3 gets deiodinated to T2, which is inactive. IIRC, this paper was published in 2016, and T2 was proven to be an active thyroid hormone somewhere in the 1960's. So, how valid is the rest of their paper? How many neurology papers are based on the assumption that NG2-glia are completely understood as OPCs?

Maybe some committee is now trying to come up with a new name for NG2-glia to avoid confusion with all the assumptions made for the old model.
 
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NG2-glia also supply nutrition to neurons.
Maybe they do, (and that's yet another possibility for brainfog) but that paper is about oligodendrocytes, which may be created from NG2s; there may be other cells that produce oligodendrocytes. NG2-glia also produce astrocytes and astrocyte-like cells, depending on where they are in the brain, but aren't the sole source of astrocytes. Maybe some of the variations we see in PWME are a result of certain types of brain cells expressed in different regions of the brain.