Fawkinchit

Scientists at A*STAR's Genome Institute of Singapore (GIS) have discovered an unusual gene that controls the generation of neurons. This important finding, which is crucial in understanding serious diseases of the brain such as Alzheimer's disease, was reported in the 8th August 2013 issue of the prestigious scientific journal, Molecular Cell.

The central nervous system is composed of numerous cell types that develop into a complex, higher-ordered structure. The birth of neurons (known as neurogenesis) is a process that requires exquisite temporal and spatial control of hundreds of genes. The expression of these genes is controlled by regulatory networks, usually involving proteins, which play critical roles in establishing and maintaining the nervous system. Problems with neurogenesis are the basis of many neurological disorders, and the understanding of the molecular details of neurogenesis is therefore crucial for developing treatments of serious diseases.

Researchers at the GIS, led by Principal Investigator Prof Lawrence Stanton, discovered a key component within a gene regulatory network which controls the birth of new neurons, called RMST. Surprisingly, this new discovery is not a protein. Rather, RMST is an atypical, long non-coding RNA (lncRNA for short; pronounced as "link RNA"). The new findings demonstrate that the RNA does not produce a protein to handle the regulatory process. Instead, it acts directly as a regulatory mechanism. LncRNAs are a newly discovered class of RNA whose functions remain mostly unknown.

The new discovery of how RMST works within a gene regulatory network not only sheds light on the process of neurogenesis, but also generates new insight into how lncRNA works together with protein components to regulate the important biological processes of gene expression.

Prof Lawrence Stanton said, "There is now great excitement about the revelation that RNA is more than just a messenger carrying genetic information that encodes for proteins. New classes of RNA, called long non-coding RNAs (lncRNA), have been discovered, which are capable of unanticipated functional diversity. However, systematic functional investigations of exactly what, and how, lncRNAs do in our cells remain scant. Our study paves the way for understanding a crucial role played by a lncRNA in human neurons."

Associate Prof Leonard Lipovich, from the Center for Molecular Medicine and Genetics at the Wayne State University and a member of GENCODE, said, "In their paper in Molecular Cell, Stanton and colleagues show how RMST, a human lncRNA, directly regulates SOX2, a key transcription factor protein that is instrumental for directing the birth of new neurons. Even more intriguingly, they highlight that RMST controls SOX2 by directly interacting with the protein. The paper is therefore an important advance in the still nascent and controversial field of riboregulators, or RNAs that regulate proteins in our cells. DNA-binding proteins that turn genes on and off were traditionally thought to be distinct from RNA-binding proteins. Stanton et al, however, illuminate the cryptic, yet crucial, RNA-binding roles for DNA-binding transcription factors: lncRNAs just might be the definitive regulatory switch that controls these factors' activity."

GIS Executive Director Prof Huck Hui Ng added, "One cannot overemphasize the importance of neurogenesis, which is responsible for the normal functioning of one of the most important biological systems in the body. Larry Stanton and his team have made an exciting finding, one that could lead to new approaches in the treatment of neural diseases. This latest work has built upon their unique, interdisciplinary expertise, developed over the past 10 years at the GIS, in applying cutting-edge genomics technologies to the study of the human body."

The paper is titled "The Long Noncoding RNA RMST Interacts with SOX2 to Regulate Neurogenesis."

More information: The research findings described in the press release was published in the 8th August 2013 issue of Molecular Cell under the title "The Long Noncoding RNA RMST Interacts with SOX2 to Regulate Neurogenesis".

Provided by Agency for Science, Technology and Research (A*STAR), Singapore

Now this is significant

Seeing as this thread is twenty-something pages long, and is derailing a bit.. Qaiphyx would you mind summarizing your theory, so we can further the discussion on what may help? Kind of hard to figure out this discussion, moreover there's a lot of misinformation in it (e.g. "neurons cant regrow you have the same number since you are born " which is of course complete bullocks), but also some more sensible ideas (e.g. "HPPD attributed to certain drugs may carry certain consistencies to only their respective causal-drug", and possible neuroendocrinological dysfunction and the involvement of stress).

I've not much better to do at the moment, so I'll try to summarize some ideas that have been proposed in this thread:

• 5HT2a inverse agonism/antagonism/downregulation/dysfunction/involvement (possibly a little bit of a hyperfocus on 5HT, IMO)
• Involvement of (metabotropic) glutamate receptors?
• Calcium channels
• Prodopaminergics
• Neuro/excitotoxicity, both acute and prolonged
• (epi)genetics
• Mitochondrial respiration
• Cannabiniods, Glutamate, and Dopamine in psychosis
• Demyelination
• A bunch of stuff about psychosis and anti-psychotics
• Signal/Noise ratio
• And a whole lot of unrelated topics

Anyway, if you could summarize and post your hypothesis of your neurogenesis theory, then we can start contributing (instead of fussing about who comprehends Einstein's theories the best, which is totally irrelevant to the discussion). If I understand correctly, you seem to think that HPPD was caused by acute excitotoxicity in the visual cortex, which now needs neurogenesis to be repaired? So what do you propose? Intracranial NGF injections into the visual cortices?

So again: Could we please get back to discussing our ideas about HPPD causes and cures?

Yah I will as soon as I get some free time. I thought everything was pretty clear 

All people start without degrees 

That being said, Einstein went to a Swiss polytechnic university and obtained exceptional grades in mathematics and physics on his entrance exam. He was no amateur and received education in his field.

Which "theory on time" are you referring to? His special and general theories of relativity both deal with time, and how time is measured in different frames of reference. Both have been confirmed to a very high level of accuracy, and underpin much modern technology.

Hur hur hur. Regardless, just because were amateurs doesn't mean we cant accomplish great things. Its all about gravity, and in the end, though highly accurate, its incorrect and has been shown to be wrong by Marko Rodin.

And I was wrong Einstein did go to college.  

In for beach resort job

I think you guys are oversimplifying the brain, and the way it's chemicals interact with each other. The deeper you dig the less simple it becomes. Even companies that produce drugs for the brain (read: SSRIs) are unsure of how these work. Hell, they can't even measure the levels of seretonin in the brain; only the gut. 

 

I don't mean to discourage amateur research, but I think the premise of this thread "push/pull, north south," is taking a complex problem and pairing it with a simple solution. I doubt there is a way to reverse what we have done, but there is possibly a crutch that exists to help us. The brain wants to return to homeostasis, as does everything else in nature. I truly believe that brain reconditioning and "la la la, if I don't acknowledge the symptoms they will go away" will heal us. You're body was intelligent enough to create you from a fetus, and it knows that something is wrong now. If you give it the time, vitamins, and environment it needs, it will heal.

 

Thinks about the idea of brain plasticity. Anything from, exercise to diet will change your brain. Now, compare your lifestyle (thought pattern, activity level, nutrition, stress) of yourself now to how you were before hppd. A lot different, hey? Your reactions to your symptoms now could be perpetuating them, leading to some horrible hppd cycle.

 

My point being, I doubt a chemical will "push" your brain back to where it was. However, it will find it's way back if you let it.

 

Just my 2 cents

False, the brain though vast is a complex yet simple vibromimetic resonator

Also false, the brain will not heal itself, if you haven't noticed yet that the scars on your arms don't heal to normal skin tissue. And quadriplegics never walk again then you have ALOT of learning to do and seem like a dreamer.

I also question whether you read the entire thread, this is no long "amateur" research it's become obvious fact.

BTW einstein started without any degrees and never went to college, he's was given a degree. That should show you what "amateur" research does. BTW his theory on time is not correct.

Time to hit the books.

Why aren't stem cells discussed on this thread?

Seems to be a few reports coming out that they can repair brain damage as this is what it is, right?

They absolutely would I believe. But how would you begin to obtain them, and how would you get them in to the various parts of the brain.

^

This is purely my speculation but i think HPPD has more to do with changes in our brain rather than to say it is damaged. 

Like how the brain creates memory. Stem cell therapy isnt going to delete that memory...... or will it? i dont know anything about science but just my 2cents.

Its generally best not to make assumptions based off of no research. People do it alot for some reason though. Read this entire thread, its pretty much already been shown to be a case of neuroexcitotoxicity.

Lots of talk around the hppd campfire of this condition being a case of neuronal excitotoxicity.

Good! Not sure what the hppd campfire is though?

Does for me, if you take a really small dose, like REALLY small its not to bad. But I cant continuously take it.

http://en.wikipedia.org/wiki/Choline_acetyltransferase

 

AcetylCholine biosynthesis.

To my knowledge this would only increase acetylcholine, with no other real benefits. There are supplements out there that already accomplish this, inositol being one, I cant remember the others.

asdf

You want to change transcription factors via talk therapy? Sure, environment has an impact on our genetic activation, but would you know what to say, how loud at what pitch etc. to turn on that gene that we need? Or am I totally getting the implication of this wrong?

asdf

http://www.luisprada.com/protected/russian_dna_discoveries.htm

Someone find the english version of that book.

I'm just one guy.

Contact several thousand researchers by email and only received 2-3 responses. It's so shockingly upsetting that I have no words.

asdf

asdf 

Just curious Qaiphyx but at one point in time in early onset more than 15 years ago, I was taking 5htp supplements and I kid you not when I say my DP/DR and anxiety levels went through the fucking roof. Considering your knowledge base, would you know the reason why this happened?

I could only assume that its cause its a precursor to serotonin, were you on any other meds? Were there any other supplements? BTW 15 years? Wow man im really sorry!

Do re-uptake inhibitors make you feel at all wired or anything. Because i don't wanna get ahold of these things and spazz out like when i was sent to the insane asylom when i was on STP and a chineese man began stuffing large amounts of Zeprexa down my throat "Because i needed it" Yeah right that shit made my syptoms way worse, like pouring salt on an open wound.

 

I agree with the low dose- Benzo treatment but honestly man it only works so long.. and i don't like gulping down pills everytime my engine starts thumping and i start to hear my brain sizzle but do i have a choice? Id rather feel normal for an hour in my day than feel dissociated for 24....

It can be presumed that the stimulatory effect of reuptake inhibitors could make symptoms worse.

qaiphyx: How do you know the excitotoxicity is no longer present? I don't have anything to support this (yet), but it could be that through genetic alterations or other mechanisms, that some kind of excitotoxic "cycle" is taking place. Hyperexcitability/pre-seizural activity, can be/is, accompanied by excitotoxicity. What use is neurogenesis when apoptosis is still taking place then? Besides, neurogenesis mainly takes place in the hippocampus, and AFAIK never in adult visual cortex. By saying that neurogenesis is the true and only fix, you're simultaneously saying that there is no fix.

If as you say the inhibitory cells are dysfunctional/damaged, then that would only trigger a cascading event of excitotoxicity I'd suppose.

Also there's enough evidence suggesting the cerebellum (where most of these cells are located) is intrinsically involved with vision, so it wouldn't only affect anxiety and balance.

Just some thoughts straight out of bed here.. back to the tea

If you go over everythimg that I have posted recently you can see that the excitotoxicity is from 5ht2a receptor activation,  its all in the notes, it goes 5ht2a agonist > 5ht2a receptor > glutamate release > excitotoxicity > neuronal apoptosis. Im sure its hard to take on and alot of people are going to just be in denial about cause brain damage seems like a dead end, but its not, neurogenesis is possible, and can be proven easily to be so, its just figuring out how.

Also damage to specific sites in the cerebellum is all Ive shown, im sure that there is damage to inhibitory cells also in the visual cortex, and there should be some in the lobes, 

Also didnt know that the cerebellum was involved with vision can you provide the information on that.

Damn.. nice find qaiphyx!

So then one could try and go about modulating metabotropic glutamate receptors or gene expression (which would probably prove to be extremely difficult).

One thing that keeps coming back is the excitotoxicity though. Seeing as this would be easier to treat, I'd expect that taking the right combination of supplements/medications would be enough to reduce symptoms. Maybe this is partly the reason why Keppra works so well for some:

http://www.ncbi.nlm.nih.gov/pubmed/17408599

And it of course inhibits pre-synaptic calcium channels.

On mitochondrial damage and excitotoxicity from wikipedia:

It would seem to be that supporting mitochondrial function, by example, would be beneficial in mitigating excitotoxicity.. Or anything that could limit or reverse the excitotoxic damage really:

http://www.ncbi.nlm.nih.gov/pubmed/9541286

I'll look into this later, but it's definitely interesting, thank you!

The excitotoxicity cascade is no longer present in the brain, it is present during the influence of the hallucinogenic compounds. Once the hallucinogens are out of the blood stream the excitotoxic event ends. HPPD is a result of neuronal apoptosis(death) during the excitotoxic event. The only way to fix HPPD is through neurogenesis, the only other method of having a significant effect would be to somehow mimic the inhibitory cells such as the perkinje cells, or the golgi, which I assume would be impossible, and that would only effect anxiety and balance I believe, so visuals would still be there etc.

Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitterglutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by Glutamatergic Storm.

In post #414 you can see that 5ht2a receptors effect glutamate release, and AMPA receptors, this means that the everstimulation of the receptor will cause an over abundance of the release of glutamate, causing overexcitotoxicity and the death of selective inhibitory neurons. That basically seems to be it guys. All the connections seem to be made.

Wow this is awesome

Golgi cells areinhibitory interneurons found within the granular layer of the cerebellum. They were first identified as inhibitory by Eccles et al. in 1964.^[1] It was also the first example of an inhibitory feed back network, where the inhibitory interneuron was identified anatomically.

This ties in with the inhibitory feedback that I was talking about in the beginning of this thread, that there may have been damage to these inhibitory cells, and the brain now lacks the ability to modulate anxiety!

The question now just remains, do hallucinogens cause damage and burn out of these cells through excitotoxicity or are they turned off through receptor triggers.

Personally im leaning towards excitotoxic burnout.

This is probably a piece of gold right here.

Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT_2A–mGlu2 and not by monomeric 5-HT_2A receptors.

The mGluRs perform a variety of functions in the central and peripheral nervous systems: For example, they are involved in learning, memory, anxiety, and the perception of pain.^[3] They are found in pre- and postsynaptic neurons in synapsesof the hippocampus, cerebellum,^[4] and the cerebral cortex, as well as other parts of the brain and in peripheral tissues.^[5]

Like other metabotropic receptors, mGluRs have seven transmembrane domainsthat span the cell membrane.^[6] Unlike ionotropic receptors, metabotropic glutamate receptors are not ion channels. Instead, they activate biochemical cascades, leading to the modification of other proteins, as for example ion channels.^[7] This can lead to changes in the synapse's excitability, for example by presynaptic inhibition ofneurotransmission,^[8] or modulation and even induction of postsynaptic responses.

This is a whole list of connections that might possibly link to symptoms of HPPD in other disorders. Feel free to do research on all these to see what you can find.

5-HT_2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotoninergic terminal rich areas, including neocortex(mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes,^[8][9][10] by enhancingglutamate release followed by a complex range of interactions with the 5-HT_1A,^[11]GABA_A,^[12] adenosine A₁,^[13] AMPA,^[14] mGluR_2/3,^[15] mGlu5,^[16] and OX₂receptors.^[17][18] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,^[19] and in the Purkinje cells.^[20][21]

In the periphery, it is highly expressed in platelets and many cell types of thecardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT_2A mRNA expression has been observed in humanmonocytes.^[22]

In the rat cerebellum, the protein(5ht2a receptors) has also been found in the Golgi cells of the granular layer,^[19] and in the Purkinje cells. --->

Purkinje cells, or Purkinje neurons(/pərˈkɪndʒiː/ pər-kin-jee), are a class of GABAergic neurons located in thecerebellar cortex. They are named after their discoverer ---->

People with cerebellar ataxia may initially present with poor balance, which could be demonstrated as an inability to stand on one leg or perform tandem gait. As the condition progresses, walking is characterized by a widened base and high stepping, as well as staggering and lurching from side to side.

Interesting line of connections there, symptoms of hppd sometimes have been known to exhibit balance disorders, seems to be linked to cerebellum purkinje neurons.

asdf

I think perhaps he might be referring to some LSD-LTP induced excitotoxicity:

 

 

Seems that glutamatergic excitotoxicity is what happens with LSD ingestion, be it direct or indirect. 

 

His reasoning is actually not strange: http://www.nature.com/npp/journal/v26/n5/pdf/1395848a.pdf

Basically the idea was, that changes (neural or genetic, maybe in the form of LTP, doesn't really matter for now) had occured which caused chronic glutamatergic (and thus ionic calcium) excitotoxicity. Hyperexcitability (convulsant activity of substantial degree, as seen in HPPD) tends to involve this as well: http://en.wikipedia.org/wiki/Epilepsy#Pathophysiology.

 

Despite the extremely low dosing, it can't simply be said that Keppra isn't doing anything for him. As he said himself though; he hasn't tried Flunarizine without Keppra, so perhaps you are right. But it could be that because they both interact with calcium transmission, they're working synergistically. Also from his report, it seems that such a low dose was effective for him. Yes, might be placebo. But honestly I think that if he didn't have a profound sustainable revitalizing epiphany of some sorts, he would've been smart enough to know that it was an isolated incidence of placebo, subsequently he would probably haven't gone through the trouble of posting his results. He's obviously tried various things, and would know how to discern between placebo and actual effect.

Hate to be talking in the third person though, so maybe @Survey could join the discussion?

Yah that would great if he would, he has some substantial research and evidence. Obviously intelligent.

Sibelium (flunarizine) is indicated in:

 

-Prophylaxis of classic (with aura) or common (without aura) migraine

 You missed the whole point of the response. Good job bro!

asdf