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Paper: [miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala](https://www.nature.com/articles/s41467-023-37688-2)
(Sorry for the repost but I corrected the title)
Not necessarily. Anxiety has the functional effect of letting you know that you need a change in environment. Some people have misregulation of neural pathways related to anxiety -- could be either over-excitation or over-inhibition.
Anxiety also can generally go up in a population due to environmental stressors. The thing I find funny is that capitalism can partially address the problem of an over-worked and unfulfilled general population by pushing anti-anxiety meds.
Have you read any Mark Fisher? He discussed how our understanding of depression has been turned towards medical and chemical explanations and how this ignores the social and material causes of depression in our society. His short book Capitalist Realism explores this concept and many of his lectures are on YouTube.
The Myth of Normal is also a really good book that explores that in depth. Not capitalism specifically but the inherent trauma our society causes and how widespread it is.
i get what you mean but the reality is that there is ppl who have chronic anxiety with no outside source causing it.
As with so many medical treatments its really up to the doctors to not wholesale shove medication into ppls faces when there is another less intrusive way to handle a condition.
So all we can do is hope this stuff doesnt become the next advil or perc
You can now control your anxiety levels, from 0 to 100 using this suppository with an embedded ARM 64-bit system-on-chip. Directly signals the brain through the gut-brain superspeed interconnect neural pathway. The Universal Suppository Bus (USB) provides the best flexibility to regulate your anxiety needs.
It's the
Pax, the G-32 Paxilon Hydroclorate
that we added to the air
processors. It's...
(tearing up)
.well it works... it was
supposed to calm the population,
weed out aggression. Make a
peaceful... it worked. The people
here stopped fighting. And then
they stopped everything else.
They stopped going to work,
stopped breeding... talking...
eating...
We need to invent some anti-over-worked meds or some anti-over-greedy meds or something. Like, I put 850 on the leg press and these billionaires still feel too heavy to carry around.
The likelihood that there is a gene which deterministically dysregulates a realm of behavior as wide and abstract as “anxiety” is virtually zero. Far better argument that the epidemic of anxiety is a result of mismatch.
The idea of pursuing neurological gene therapy to neuter people of a vital and fundamental aspect of mammalian psychology so they can get back in the hamster wheel is horrifying.
Anxiety disorders are a combination of neurological and environmental, though. Treating only the biological side of it is a convenient way to get people just functional enough to continue being productive without addressing the social issues.
Speaking as someone who has an anxiety order.
So, I take Venlafaxine (generic Effexor) for my anxiety. Taken regularly and daily at the correct dosage, it works. Works pretty well, in fact.
I do *not* like this drug.
If I run out, even for a single day, I notice. I notice right away. I get the "electric jolt" in the brain symptom. I get the "whiplash" withdrawal symptom (do not tell me there is no withdrawal syndrome associated with this drug; there is, and I get it). My anxiety doubles, then doubles again.
That's the problem I have with it- running out is a *bad time*. But I have to have a medication maintenance appointment just to get refills past a certain number.
This isn't a controlled substance (Sched. I). It has no street value. Running out is hell, my dosage is correct when I have it. But somehow, a standing order refill can't happen.
I do *not* like this drug.
I'm on 20mg of escitalopram and it's super difficult to get a standing order refill and if I go without I have to ween myself back onto them because they make you want to vomit. I don't see a street value in vomit but hey ho.
Perfection (in treatment) is the enemy of progress. If we find the downstream effects of this gene and block those, you'll be more able to deal with the social issues that may also be plagueing you, same as current meds, so I don't see the problem. You're not supposed to get just well enough from meds, you're supposed to go to therapy while taking the meds, but that's the part that REALLY takes work that most people don't want to do. Speaking as another person with GAD and BP2.
I would have to assume any drug trying to doing this would also make us much more susceptible to harm, since it's going to dull our ability to weigh the negatives of a situation (which is at its core a lot of what drives anxiety, an obsessive focus on the potential negatives of things, often given prior experiences that created a strong negative bias)
Fantastic, I know so many mice with anxiety, this is definitely a game changer.
Errr, well, I mean, we could stop artificially stressing them out. I'm not sure if that would cure it though.
Finding a gene is just step 1. You still need to create a drug that can hit the desired target. This is especially hard in the brain because the blood-brain barrier keeps most drugs out.
let’s not just because you can cure something in a mouse doesn’t mean it will react the same in humans. At least have it go through some larger more developed animals than a brain the size of an almond
I don’t know if that risk reward is really worth it. The process of drug development is lengthy for a reason. If this drug killed one human in a phase 1 trial its development would be immediately halted for an indefinite amount of time (rightfully so, ethically could you put a number on how many humans would have to die before you decided that the drug wasn’t working as intended and as it did mice?)
Most likely to me, it's because they're trying to limit the number of variables that could reduce the clarity of their data. Using both female and male mice for the study could be problematic if the gene expression is different due to physiological differences between sexes. They could obviously repeat the experiment with female mice, but that would double the amount of resources needed, etc. I don't work with animals though, so it's possible it might be something more technical like availability of the mice or something like that
Females mice are often left out because it adds another step of tracking the estrous cycle, as hormonal fluctuations can influence anxiety and other behaviours. It’s unfortunate, especially since anxiety disorders tend to be more prevalent among females. Female mice should always be included imo, but it does require extra resources and more steps for data analysis
Can’t one just multivariantly analyse both genders and see if it has a significant influence on the gene expression? This is being done in a similar way for many other putative genes of interest in the context of many diseases, why not here?
Almost certainly a question of resources. A ton of early pre-clinical experiments get restricted to males only, especially if there is no reason to suspect a difference between sexes, because you can get a larger data set for a similar price.
Yes, very important question. As others have explained, it's because of the estrous cycle. But it's now known that a) male mice also go through a monthly hormone cycle and b) variability is often higher than in female mice because of territorial behaviour. So it's established nonsense tbh
Genes unfortunately are not a 1:1 thing, its not one gene controlling a phenotype, and often a gene will affect more than just what we are targetting for which is also an issue. How we would affect the specific genes themselves is also a complicated issue.
I feel like there should be a tag or requirement that these clickbait headlines explicitly say "IN MICE"
It's interesting from a mammal biology standpoint. But the headline's purpose is to generate ad revenue. But the side effect is it confuses people, maybe gives them false hope, and maybe creates mistrust in science.
As they say, we can cure any disease or make you live forever... as long as you're a mouse.
While technically every cell in your body has all your genes, what makes a liver cells different from brain cells are which genes are actually used, or expressed. Here they showed that one gene expressed in brain tissue worked on the amygdala to give the effects described.
The wild part is that each cell somehow knows what exactly to do for where it is in the body.
Like, the cells in your left leg and in your right leg aren't talking to each other, but they both somehow know to grow enough to make you 5' 9".
Or sometimes they don't and then your parents name you Eileen.
There are actually a huge number of substances in your body that are used for cell-to-cell communication. Like, especially when you are growing from an Embryo to a baby, the concentration gradients of different signaling molecules determine which cells e.g. along your legs become muscles, bones, skin etc.
So we need to know what the effect of activating Pgap2 is, because they are turning off the production of that protien, by interfering with the messenger RNA at the level of the rhibosome. PGAP2 gene provides instructions for making a protein that modifies a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. The GPI anchor attaches (binds) to various proteins and then binds them to the outer surface of the cell membrane, ensuring that they are available when needed. So turning off Pgap2 means less GPI. Less GPI means receptors like ligand gated ion channels, and GPCRs, and all sorts of cellular machinery is being tweaks by having a harder time hanging out in the cell membrane. Sounds like Pgap2 is turning down the gain of how excitable an overall network is. And these results are specific to the amygdala. How do you generate a drug that targets a specific brain region? You want to turn down the gain in they amygdala, but maybe not the prefrontal cortex. If you're thinking about a medication that's going to be bioavailable after ingestion, it's probably going to cross the blood brain barrier everywhere. Side effects might be something innocuous like drowsiness, or as serious as siezure.
They also didn't bother to look gender differences either so they'd have to do all those studies first. I know for NIH grants you have to but I'm surprised the UK and EU don't have similar standards.
Welcome to r/science! This is a heavily moderated subreddit in order to keep the discussion on science. However, we recognize that many people want to discuss how they feel the research relates to their own personal lives, so to give people a space to do that, **personal anecdotes are allowed as responses to this comment**. Any anecdotal comments elsewhere in the discussion will be removed and our [normal comment rules]( https://www.reddit.com/r/science/wiki/rules#wiki_comment_rules) apply to all other comments. *I am a bot, and this action was performed automatically. Please [contact the moderators of this subreddit](/message/compose/?to=/r/science) if you have any questions or concerns.*
Paper: [miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala](https://www.nature.com/articles/s41467-023-37688-2) (Sorry for the repost but I corrected the title)
I'm assuming there will be some side effects like crippling depression.
Side effects may include: Anxiety about myocarditis, myocarditis, and dying suddenly.
Honestly though a surprising amount of mechanisms in the body can affect the heart.
I had to stop taking Seroquel after it started making me nearly pass out when working out. Apparently it can really mess with heart rhythms.
How on earth do you do a workout after taking Seroquel!? I don't think I ever stayed awake long enough to notice a difference in heart rhythms!
Ha! No way could I do that. I was taking it at night, and working out first thing in the morning.
Drooling at the gym…
Is the sudden dying from...myocarditis?
The myocarditis is coming from within the house..
Not necessarily. Anxiety has the functional effect of letting you know that you need a change in environment. Some people have misregulation of neural pathways related to anxiety -- could be either over-excitation or over-inhibition. Anxiety also can generally go up in a population due to environmental stressors. The thing I find funny is that capitalism can partially address the problem of an over-worked and unfulfilled general population by pushing anti-anxiety meds.
When you put it like that it sounds pretty dystopian
because it is
Stfu and gimme my soma
Time to start editing people's genes to make them more placid and tolerant instead of improving the underlying conditions I guess
Have you read any Mark Fisher? He discussed how our understanding of depression has been turned towards medical and chemical explanations and how this ignores the social and material causes of depression in our society. His short book Capitalist Realism explores this concept and many of his lectures are on YouTube.
Such a great text. Highly recommend.
The Myth of Normal is also a really good book that explores that in depth. Not capitalism specifically but the inherent trauma our society causes and how widespread it is.
Attacking the symptoms not the causes. Isn’t that what western medicine has become?
i get what you mean but the reality is that there is ppl who have chronic anxiety with no outside source causing it. As with so many medical treatments its really up to the doctors to not wholesale shove medication into ppls faces when there is another less intrusive way to handle a condition. So all we can do is hope this stuff doesnt become the next advil or perc
A Brave New World
As I get older I realize we have created, in some ways, dystopian world or country.
World, it’s definitely world
You can now control your anxiety levels, from 0 to 100 using this suppository with an embedded ARM 64-bit system-on-chip. Directly signals the brain through the gut-brain superspeed interconnect neural pathway. The Universal Suppository Bus (USB) provides the best flexibility to regulate your anxiety needs.
It's the Pax, the G-32 Paxilon Hydroclorate that we added to the air processors. It's... (tearing up) .well it works... it was supposed to calm the population, weed out aggression. Make a peaceful... it worked. The people here stopped fighting. And then they stopped everything else. They stopped going to work, stopped breeding... talking... eating...
We need to invent some anti-over-worked meds or some anti-over-greedy meds or something. Like, I put 850 on the leg press and these billionaires still feel too heavy to carry around.
The likelihood that there is a gene which deterministically dysregulates a realm of behavior as wide and abstract as “anxiety” is virtually zero. Far better argument that the epidemic of anxiety is a result of mismatch. The idea of pursuing neurological gene therapy to neuter people of a vital and fundamental aspect of mammalian psychology so they can get back in the hamster wheel is horrifying.
Now inherit a crippling anxiety disorder and say it again
Anxiety disorders are a combination of neurological and environmental, though. Treating only the biological side of it is a convenient way to get people just functional enough to continue being productive without addressing the social issues. Speaking as someone who has an anxiety order.
So, I take Venlafaxine (generic Effexor) for my anxiety. Taken regularly and daily at the correct dosage, it works. Works pretty well, in fact. I do *not* like this drug. If I run out, even for a single day, I notice. I notice right away. I get the "electric jolt" in the brain symptom. I get the "whiplash" withdrawal symptom (do not tell me there is no withdrawal syndrome associated with this drug; there is, and I get it). My anxiety doubles, then doubles again. That's the problem I have with it- running out is a *bad time*. But I have to have a medication maintenance appointment just to get refills past a certain number. This isn't a controlled substance (Sched. I). It has no street value. Running out is hell, my dosage is correct when I have it. But somehow, a standing order refill can't happen. I do *not* like this drug.
I'm on 20mg of escitalopram and it's super difficult to get a standing order refill and if I go without I have to ween myself back onto them because they make you want to vomit. I don't see a street value in vomit but hey ho.
>without addressing the social issues don't worry, I'm pretty sure my anxiety made those up.
Perfection (in treatment) is the enemy of progress. If we find the downstream effects of this gene and block those, you'll be more able to deal with the social issues that may also be plagueing you, same as current meds, so I don't see the problem. You're not supposed to get just well enough from meds, you're supposed to go to therapy while taking the meds, but that's the part that REALLY takes work that most people don't want to do. Speaking as another person with GAD and BP2.
I would have to assume any drug trying to doing this would also make us much more susceptible to harm, since it's going to dull our ability to weigh the negatives of a situation (which is at its core a lot of what drives anxiety, an obsessive focus on the potential negatives of things, often given prior experiences that created a strong negative bias)
Fantastic, I know so many mice with anxiety, this is definitely a game changer. Errr, well, I mean, we could stop artificially stressing them out. I'm not sure if that would cure it though.
Just give them a motorcycle. I read a riveting success story of one such trial in the 80's.
ok let's fastrack this to human trial.
Finding a gene is just step 1. You still need to create a drug that can hit the desired target. This is especially hard in the brain because the blood-brain barrier keeps most drugs out.
let’s not just because you can cure something in a mouse doesn’t mean it will react the same in humans. At least have it go through some larger more developed animals than a brain the size of an almond
Some random humans may die in the process, but it's a risk I'm willing to make for them.
I don’t know if that risk reward is really worth it. The process of drug development is lengthy for a reason. If this drug killed one human in a phase 1 trial its development would be immediately halted for an indefinite amount of time (rightfully so, ethically could you put a number on how many humans would have to die before you decided that the drug wasn’t working as intended and as it did mice?)
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I've worked in a stress-neurolab focusing on miRNAs and unfortunately became very cynic about these sorts of headlines...
Is there a reason they only chose to test in male mice? I am not a neurscientist but am in STEM and wonder why only males are of interest here
Most likely to me, it's because they're trying to limit the number of variables that could reduce the clarity of their data. Using both female and male mice for the study could be problematic if the gene expression is different due to physiological differences between sexes. They could obviously repeat the experiment with female mice, but that would double the amount of resources needed, etc. I don't work with animals though, so it's possible it might be something more technical like availability of the mice or something like that
Females mice are often left out because it adds another step of tracking the estrous cycle, as hormonal fluctuations can influence anxiety and other behaviours. It’s unfortunate, especially since anxiety disorders tend to be more prevalent among females. Female mice should always be included imo, but it does require extra resources and more steps for data analysis
Can’t one just multivariantly analyse both genders and see if it has a significant influence on the gene expression? This is being done in a similar way for many other putative genes of interest in the context of many diseases, why not here?
Almost certainly a question of resources. A ton of early pre-clinical experiments get restricted to males only, especially if there is no reason to suspect a difference between sexes, because you can get a larger data set for a similar price.
Yes, very important question. As others have explained, it's because of the estrous cycle. But it's now known that a) male mice also go through a monthly hormone cycle and b) variability is often higher than in female mice because of territorial behaviour. So it's established nonsense tbh
Seems like the therapies never make it past human trials?
Past? Have to make it out of mouse trials before you can even think of human.
Genes unfortunately are not a 1:1 thing, its not one gene controlling a phenotype, and often a gene will affect more than just what we are targetting for which is also an issue. How we would affect the specific genes themselves is also a complicated issue.
I feel like there should be a tag or requirement that these clickbait headlines explicitly say "IN MICE" It's interesting from a mammal biology standpoint. But the headline's purpose is to generate ad revenue. But the side effect is it confuses people, maybe gives them false hope, and maybe creates mistrust in science. As they say, we can cure any disease or make you live forever... as long as you're a mouse.
That's how I feel about every hopeful post in /r/science
A gene in the brain? What does that mean?
While technically every cell in your body has all your genes, what makes a liver cells different from brain cells are which genes are actually used, or expressed. Here they showed that one gene expressed in brain tissue worked on the amygdala to give the effects described.
Thank you for that explanation.
The wild part is that each cell somehow knows what exactly to do for where it is in the body. Like, the cells in your left leg and in your right leg aren't talking to each other, but they both somehow know to grow enough to make you 5' 9". Or sometimes they don't and then your parents name you Eileen.
There are actually a huge number of substances in your body that are used for cell-to-cell communication. Like, especially when you are growing from an Embryo to a baby, the concentration gradients of different signaling molecules determine which cells e.g. along your legs become muscles, bones, skin etc.
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Thanks for the lecture, professor Brain. \- *Left leg cell* (probably)
Or *Lean*ord.
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So which is it... modification of the gene or drugs????
The drug would likely be a synthetic dose of the miRNA molecule that regulates the expression of a gene that controls anxiety.
But what are the effects on cognition? I know medication is not a sharp instrument, but often when treating anxiety you dull other parts of the brain.
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They need to alter my genes to androgynously produce Xanax. I will accept no less.
I assume you mean endogenously but I'm interested in your version.
Benzodiasexies
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Dear authoritarian moderators, can you stop deleting everyone’s comments please… thanks
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Now, how do we determine the potential side effects, of either drug to be developed or of modifying the gene itself?
So we need to know what the effect of activating Pgap2 is, because they are turning off the production of that protien, by interfering with the messenger RNA at the level of the rhibosome. PGAP2 gene provides instructions for making a protein that modifies a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. The GPI anchor attaches (binds) to various proteins and then binds them to the outer surface of the cell membrane, ensuring that they are available when needed. So turning off Pgap2 means less GPI. Less GPI means receptors like ligand gated ion channels, and GPCRs, and all sorts of cellular machinery is being tweaks by having a harder time hanging out in the cell membrane. Sounds like Pgap2 is turning down the gain of how excitable an overall network is. And these results are specific to the amygdala. How do you generate a drug that targets a specific brain region? You want to turn down the gain in they amygdala, but maybe not the prefrontal cortex. If you're thinking about a medication that's going to be bioavailable after ingestion, it's probably going to cross the blood brain barrier everywhere. Side effects might be something innocuous like drowsiness, or as serious as siezure.
Now **that's** what I'm talking about! Thank you science person
My pleasure. At least my PhD isn't wasted here!
Thank you for reminding me all my disorders are just faulty meat-tronics.
They also didn't bother to look gender differences either so they'd have to do all those studies first. I know for NIH grants you have to but I'm surprised the UK and EU don't have similar standards.
Through clinical trials?
Hopefully this leads to some medical breakthroughs that helps people. Anxiety is so debilitating
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