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CRH-CRHR1 mutation

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The stress-response is classically divided into three categories: behavioral, autonomic, and hormonal responses.
CRH is believed to be involved in all three stress-responses, involving different brain regions [R].


CRH causes fear and anxiety [R, R] (via CRHR1[R]) and major depression [R]. CRH promotes anxiety in part by reducing cannabinoids in our amygdala.
This happens when CRH (CRHR1) increases FAAH in the amygdala, which causes a reduction in the endocannabinoid anandamide (AEA) [R].

CRH production takes place in the cerebral cortex, limbic system, cerebellum, locus coeruleus of the brain stem, and dorsal root neurons of the spinal cord.


Cortisol/Glucocorticoids inhibit CRH production in the hypothalamus. However, in the amygdala – a brain region involved in the behavioral stress response – cortisol increases CRH, leading to anxiety and fear [R].

Chronic stress increases CRH by decreasing negative feedback. CRH will not be inhibited by cortisol like it normally should [R].
Normally, after CRH is released, there’s also a spike in ACTH and cortisol, which feeds back to reduce CRH if you aren’t ‘resistant’ or ‘insensitive’ to the negative feedback from cortisol.
But if this negative feedback isn’t solid because of chronic stress and genetics then cortisol won’t reduce CRH by as much as it should.
This will occur when the cortisol (glucocorticoid) receptors aren’t functioning right. The result is too much CRH.
The other problem people have is when CRH doesn’t produce enough cortisol, so more CRH has to be produced for a given amount of cortisol [R].
In both cases, excess CRH is produced.

from selfhacked
 
I just wanna know how do you decrease CRH-CRHR1 activity and why does wikipedia state that CRH is made in the PVN only if thats not the case? It says CRH is secreted from the PVN to other places in which I assume it binds to CRHR1. But is it that CRH is made in the other locations but not activated the CRH has to first be released by the PVN so the CRH can bind to the CRH RNA in other locations to create CRH?



Does the CRH in the PVN once it is made send a signal to other locations (Amygdala) to create its own CRH production becuase they have their own CRH receptors? And if you decrease CRH mRNA in the PVN = less CRH = less signals towards making CRH to other locations = Less CRHR1 binding/activity everywhere?
 
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trainman04 said:
...your delusional and overeact like a woman...
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Nice.

CRH-1 antagonists exist, but there is a reason(actually many) why they aren't used to treat anxiety and depression, they generally aren't effective for one. It's often better to treat issues like those closer to the symptoms, mostly because there isn't one single underlying cause, if there was only one cause your brain would have already solved the problem for you, so its not only more effective to treat it closer to the symptom but generally much safer and more tolerable. If you continue to expirement on yourself by continuing this wild goose chase not only will you be dissapointed by the results you could end up causing yourself real harm, which is why no one here wants to help you.

Hell, let's say you adhere to the chronic stress theory of GAD and depression, and your gene mutation is causing overactivation of CRH to the point of developing these disorders not because you have suffered chronic stress but just because of the gene mutation(doubtful), guess what? It's too late, you've already been exposed to the stress reponse, you've already developed said disorders, reducing CRH at this point is too late, the neuroplastic and epigenetic changes have ALREADY occured, maybe if you prevented overactivation of CRH from birth it could have been avoided(doubtful, and you would have caused a host of other problems in the trying).

Here, I've got a quote for you, about a recent new blockbuster CRH antagonist which was going to cure depression, GAD, and a host of other illnesses!

A recent multicenter, randomized, double-blind, placebo-controlled trial found that pexacerfont (100 mg/day) did not separate from placebo on the primary outcome measure (the mean change from baseline to end point in the Hamilton Anxiety Scale score).[4] These results suggest that blockade of CRF1 receptor may not be a feasible treatment for anxiety disorders in certain human populations.
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(emphases added)

I am assuming you are very left brain dominant, so you think this is some math problem waiting to be solved, but it's not. You will have far greater results by seeing a therapist, using CBT, learning coping mechanisms, and making lifestyles changes such as good sleep hygiene, healthy diet, and an excercise regimen. Not to say drugs are useless, but you should probably stick to the ones with real empirical evidence behind them which have been deemed safe. We aren't here to help you turn yourself into a labrat, this isn't longecity.
 
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'Much smaller parvocellular neurosecretory cells, neurons of the paraventricular nucleus, release corticotropin-releasing hormone and other hormones into the hypophyseal portal system, where these hormones diffuse to the anterior pituitary. ''

I just wanna know, what decides how much CRH is made in other areas besides the PVN? Im trying to figure this out.
The PVN makes CRH constantly which binds to CRHR1 receptors and does other things but, What about the hippocampus or amygdala? Is it dependent on how much CRH the PVN makes and it has to recieve a signal from the PVN in order for the CRH receptors there to produce their own CRH? does the rest of the brain change how much CRH is made depending how much in the PVN is made? Becuase the hypothalamus supposedly controls everything.
 
If you decrease CRH mRNA production in the PVN, who knows what will happen, there are no selective agents that do specifically that, so it would require local injections of antisense RNA or the like directly into the specific areas of brain tissue... no ethics committee would ever approve that research to be done on humans, probably not even any of the higher primates.

Anyway if you mess with production of protein in one specific area of the brain, unless that protein is specifically produced in that one area of the brain (e.g. pituitary horomones) the remainder of the brain will usually be unaffected, as unless the protiens are secreted into e.g. the fluid around the brain or the blood, they will tend to stay where they are and not diffuse too far. Otherwise the brain would be much more homogenous and lose specialization.

So to sum your question up,
And if you decrease CRH mRNA in the PVN = less CRH = less signals towards making CRH to other locations = Less CRHR1 binding/activity everywhere?
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No.

I just wanna know, what decides how much CRH is made in other areas besides the PVN?
Click to expand...

Epigenetics, whether or not transcription factors have activated the production of CRH in the specific cell in question, etc. This is 2nd year cell biology stuff right here.
 
''Using genetic engineering, Zhang and her colleagues selectively removed the CRH gene from about 1,000 nerve cells in the hypothalamus of mice. (To do this, they used a genetic trick, knocking out the gene only in cells expressing another gene called SIM1.)The targeted cells were in the paraventricular nucleus, an area of the hypothalamus known to control the release of stress hormones (such as cortisol). But to Zhang’s surprise, the loss of CRH in those cells affected not only hormone secretion, but also dramatically reduced anxiety behaviors (vigilance, suspicion, fear) in the mice.
“We already knew that CRH controlled the hormonal response, but the big surprise was that the behavioral response was completely blunted,” says Majzoub. “It was a very robust finding: Every parameter we looked at indicated that this animal was much less inhibited.”''

https://www.psypost.org/2016/09/neu...utm_medium=cpc&utm_campaign=PsyPost_TrendMD_0

''Another surprise was that CRH secreted in the paraventricular nucleus goes to more places in the brain than originally thought — including areas that control the behavioral stress response. “It was a total surprise to us that the locus of control is in a tiny part of the hypothalamus,” says Majzoub''


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https://www.psypost.org/2011/09/study-decodes-how-brain-controls-generation-and-elimination-of-fear-6859?utm_source=TrendMD&utm_medium=cpc&utm_campaign=PsyPost_TrendMD_0

''With the help of genetic studies on mice, scientists from the Max Planck Institute of Psychiatry have discovered two opposing neuronal regulatory circuits for the generation and elimination of fear. Both are controlled by the stress-inducing messenger substance corticotropin-releasing hormone (CRH) and its type 1 receptor (CRHR1). The availability of these factors in neurons that release glutamate in brain areas of the limbic system activates a neuronal network which causes anxiety behaviour. .''

'' Interestingly, a specific activity pattern emerged in different neuron groups which release different neuronal messenger substances. In regions of the forebrain (cortex, hippocampus, thalamus, septum), CRHR1 is detectable in glutamatergic and GABAergic neurons. As the limbic system, these regions are linked and, as the current study shows, trigger fear-inducing behaviour in glutamatergic neurons.''


 
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Cool, now all you have to do is clone yourself and perform genetic engineering on the embryo...
 
or take a drug that reduces CRH mRNA in the PVN........... like clomipramine, makes more sense.
 
Social defeat
Likewise, the hypothalamus has a role in social defeat: Nuclei in medial zone are also mobilized during an encounter with an aggressive conspecific. The defeated animal has an increase in Fos levels in sexually dimorphic structures, such as the medial pre-optic nucleus, the ventrolateral part of ventromedial nucleus, and the ventral premammilary nucleus.[36] Such structures are important in other social behaviors, such as sexual and aggressive behaviors. Moreover, the premammillary nucleus also is mobilized, the dorsomedial part but not the ventrolateral part.[36] Lesions in this nucleus abolish passive defensive behavior, like freezing and the "on-the-back" posture.[36]


Fear processing

The medial zone of hypothalamus is part of a circuitry that controls motivated behaviors, like defensive behaviors.[29] Analyses of Fos-labeling showed that a series of nuclei in the "behavioral control column" is important in regulating the expression of innate and conditioned defensive behaviors.[30]
Antipredatory defensive behavior
Exposure to a predator (such as a cat) elicits defensive behaviors in laboratory rodents, even when the animal has never been exposed to a cat.[31] In the hypothalamus, this exposure causes an increase in Fos-labeled cells in the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial nucleus, and in the ventrolateral part of the premammillary nucleus (PMDvl).[32] The premammillary nucleus has an important role in expression of defensive behaviors towards a predator, since lesions in this nucleus abolish defensive behaviors, like freezing and flight.[32][33] The PMD does not modulate defensive behavior in other situations, as lesions of this nucleus had minimal effects on post-shock freezing scores.[33] The PMD has important connections to the dorsal periaqueductal gray, an important structure in fear expression.[34][35] In addition, animals display risk assessment behaviors to the environment previously associated with the cat. Fos-labeled cell analysis showed that the PMDvl is the most activated structure in the hypothalamus, and inactivation with muscimol prior to exposure to the context abolishes the defensive behavior.[32] Therefore, the hypothalamus, mainly the PMDvl, has an important role in expression of innate and conditioned defensive behaviors to a predator.
 
clomipramine acts as an anti-anxiety agent but not exclusively by messing with mrna.... to be frank it would be a good idea to try it as you are certainly displaying obsessive behavior here :)
 
No, it wouldn't, which is why CRH antagonists don't work. You should probably read a little bit about the chronic stress model of depression, chronic stress induces neurological and epigenetic changes which result in psychopathologies of anxiety disorders and depression which persist long after stressor resolution. Obviously one needs the stress response to end in order to heal, and the earlier the stressors are resolved(or the stress response stopped) the better, but those changes would persist. Not to say reducing the stress response couldn't help, but if you are already, and have been, suffering from said neuropsychopathologies then they will still persist.

Not to mention CRH is most definitely not the sole mediator of the stress response, and you can't extrapolate results from mice and rats onto humans.

How about you just take clomipramine for a while and see if it helps? Whether it is working by reducing CRH mRna or some other mechanism doesn't really matter does it? It's getting hard to talk to you when you don't have a basic understanding of the vocabulary you are using, one sentence you are talking about reducing CRH, the other you are talking about reducing CRH mRna which would be indicative of downregulation of CRHR1 expression levels, these aren't the same thing.

But if using a CRH antagonist, which would generally provide a much stronger response than some drug which happens to result in reduced CRH mRna(probably coincidentally because of the other mechisms which you have already written off as laughable), doesn't provide results then it is VERY doubtful that some coincidental reduction of CRH mRna is responsible for said results.
 
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CRH antagonist don't work if the person does not have excess CRH activity. It is like giving magnesium to someone who is not deficient then conclude it doesen't work cause it had no further/stronger effect.

CRH is the first step in the stress response so tackling that is easiest and most reasonable.

I will take clomipramine don't you worry about that but it is intresting to me becuase after all these years I have finaly found the reason for my 24/7 anxiety which I would describe as a constant fight or flight feeling.
In the past I thought I had excess serotonin which in my opinion is understandable , becuase nowhere on any forum /thread etc is there talk about reducing CRH and its role in anxiety so it took a little time for me to figure it out.
CRH by the way does increase serotonin release for your information, It activates multiple serotonin receptors 5ht3 for instance which I beleive is the reason for my nausea/dizzines and digestive issues.

I pretty much have all the information I need I think. What im still is confused about how the hypothalamus and other regions CRH are connected.
Here are some previous quotes from articles :
''CRH secreted in the paraventricular nucleus goes to more places in the brain than originally thought''


goes to more places? what does that mean? Not in the form of mRNA? becuase I was told and I quote '' single-strand RNA is far too unstable to survive a journey that long, so it's highly unlikely that crh mRNA produced in the PVN is migrating to other brain regions.'' ''What would be more likely is that secreted CRH from the PVN could induce a signaling cascade in other tissues (which express CRH receptor) which leads to CRH production there. ''
''a drug that blocks crh mRNA expression, either by blocking transcription or degrading the mRNA after transcription but before translation. This will lead to a decrease in CRH secretion and CRH activity on target cells, because there is no protein.'' ''changing CRH level will affect CRHR1 activation''
''Yes, with the side note that CRH protein is still being made in parts of the brain that are not PVN, including the amygdala and hippocampus. So while the main source of CRH (the PVN) is being blocked, there still may be some activation of CRHR1 in the pituitary by CRH made from these other tissues. ''


Not to say reducing the stress response couldn't help, but if you are already, and have been, suffering from said neuropsychopathologies then they will still persist.
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So whats your point with this?


Reducing CRH mRNA expression with clomipramine in the PVN leads to decreased activity of both CRH and in turn CRHR1 receptors in that area (hypothalamus).

But from what I can tell by reducing CRH in the PVN it has no direct effect on other regions which produce CRH (hippocampus,amygdala,PFC? etc).

Maybe it has an Indirect effect? Since decreased CRH and CRHR1 in the hypothalamus means you are more relaxed ? and thus less CRh is produced in other areas = less CRHR1 activation?

This leads the question, is the hypothalamus involved in emotions etc? The only quotes I have are from wikipedia talking about hypothalamus involvement in Social defeat and Fear processing. Maybe reducing CRH in the PVN leads to less of these 2 and thus reduces CRH activity in all other brain regions?

it mostly says the hypothalamus is involved with: ''hypothalamus controls body temperature, hunger, important aspects of parenting and attachment behaviours, thirst,[2] fatigue, sleep, and circadian rhythms.''

But nothing with anxiety/fear etc
 
CRH antagonist don't work if the person does not have excess CRH activity
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CRH antagonists have been tested in people with chronic anxiety/stress to no avail... how are you so confident in your theory, for a person who doesn't understand biology very well?
 
sekio said:
CRH antagonists have been tested in people with chronic anxiety/stress to no avail... how are you so confident in your theory, for a person who doesn't understand biology very well?
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becuase I don't think they most humans have excess CRH. It worked in rats with high CRH stress. And in my opinion the study done on animals are more credible then humans becuase most humans are just overplaying their feelings,I feel like people are faking all of the symptons like it's just a phase, They dont truly know what anxiety is like. I would like to see humans with excess CRH-CRHR1 and im sure you can test for that (blood test?) and they get to test these CRF antagonists.
 
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fncel-07-00173-g002.jpg
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Cortisol/Glucocorticoids inhibit CRH production in the hypothalamus. However, in the amygdala a brain region involved in the behavioral stress response cortisol increases CRH, leading to anxiety and fear - I guess from CRHR1 activation.

gr4.jpg
 
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So my theory is excess CRH mRNA in the PVN leads to high CRH and CRHR1 activation. The hypothalamus has a role in Social defeat/Fear processing etc. So these two compounds together (CRH-CRHR1) would increase activity in the areas in the hypothalamus that control Fear processing/social defeat. Cortisol inhibit CRH production in the hypothalamus. However, in the amygdala a brain region involved in the behavioral stress response cortisol increases CRH(which the cortisl signals these other regions amygdala etc to produce CRH and bind to CRHR1 so it depends on the hypothalamus how much CRH it makes and the cortisol signals other regions in the negative feedback). So could it be that excess CRH even tho ACTH and Cortisol should inhibit it in the negative feedback ,once CRH is released the cortisol will inhibit it but it will also increase CRH in the amygdala and thus CRHR1 activation in the amygdala(possibly in the PFC and hippocampus too?) leading to anxiety even tho there is a negative feedback, In this case the negative feedback only works if there is no excess CRH being made in the PVN. Becuase if there is too much CRH being made the cortisol will always increase CRH in the amygdala theres no getting away from that. I believe there is CRH mRNA made in the amygdala etc but they rely on how much the hypothalamus is making so if the hypothalamus PVN is in balance so would the CRH also be in other places .


so if I take clomipramine to reduce mRNA and it doesen't work then my problem is not excess CRH but might be either of these(Reducing CRH mRNA will also help in the case of gene duplication I assume?):

it is possible to have low mRNA but high protein expression becuase a single mRNA molecule can stick around and be translated many times and also longer half-life. = More CRH being made from less mRNA

or

constitutive protein activity - "Constitutive" activity means that the regulation of the enzyme's activity is gone, it's been mutated or something to allow it to always be active. = CRH protein is always active in the PVN etc (no enzymes regulating)

Solution to both would be carbamazepine or valproate which inhibit CRH release in the hypothalamus PVN rather than decrease the mRNA.


And I don't have a CRH-Tumor well atleast not in the brain and if it is not in the brain it cant affect me as I think it would.
 
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For one, CRH levels are raised as part of the stress response. It is pretty unlikely that anyone with anxiety/depression wouldn't have heightened CRH levels...but more importantly, you are now claiming that one can have anxiety completely independently of CRH, so how do you know lowering CRH or CRHR1 expression would help your anxiety?

But again, since you've already formed the hypothesis that clomipramine could help you, why don't you just try clomipramine?? You can even report back here in 6 weeks if it works and tell us all I told you so if it makes you feel better.

And unless you want to grow tits, I wouldn't pursue cimetidine any further...this is exactly the kind of thing I am worried about, that you will pursue some experimental treatment with dangers you don't understand.
 
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I will try clomipramine but it takes time to get an doctor appointment then to refer psychiatrist who can prescribe this stuff.

when did I say you can have anxiety without excess CRH? I believe people think they have anxiety/stress but they really don't, just weak minded, same goes with depression.


anyhow.

1. clomipramine (reduce CRH in PVN mRNA)
2. carbamazepine (inhibit CRH release in hypothalamus)
3. valproate ( decreases CRH in amygdala and PVN)
4. zyprexa (inhibits Stimulated crh release in hippocampus)
(any other brain region I missed?)
one of these gotta work. I guess im beating a dead horse at this point but it is nice talking to people who are knowledgeable in this area of subject,which im not , at all. I just got into this for the sake of anxiety and came across this crh-crhr1 stuff.
 
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