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What if you could get a shot in the arm and for the next few hours be able to
turn on parts of your brain that were inactive before?
What would you do with that power?
Well, such things are already possible, in mice.
All thanks to the relatively new technology called chemogenetics.
And it’s giving scientists a powerful way to study how the brain works,
from memory to movement.
Chemogenetics is a mixture of chemistry, engineering, and genetics.
It allows researchers to essentially install a lock on certain neurons,
and then administer the metaphorical key whenever they want.
To do that, they add an artificial receptor to an animal’s brain cells.
They can then use that receptor to activate or inactivate those cells
by giving the animal an injection of chemicals that bind to that receptor.
Now you do not need to worry about anyone controlling your brain with
chemogenetics because this tool is only being used in laboratory animals like mice.
But for now, the rodent experiments are giving scientists a lot of insight
into the inner workings of the brain.
So, how does this all work?
Well it starts with neurotransmitters, chemicals that carry signals
throughout your brain by traveling from neuron to neuron.
You can picture it like tossing a ball to your friend.
And different neurons are equipped to “catch” different neurotransmitters.
So rather than playing catch with your friend,
it is more like the two of you are standing on the street surrounded by other people
who are also sending other kinds of balls back and forth.
You might be throwing a baseball to your friend,
who’s wearing a catcher’s mitt and accepting the baseball when it comes to them.
But let’s say you accidentally throw the baseball closer to another person
standing in the street who’s holding a hockey stick because their friend
is sending them a hockey puck.
They wouldn’t be equipped to catch the baseball.
And your friend with a catcher’s mitt wouldn’t be ready
to stop a hockey puck from soaring past.
Ok, so you get it, right?
The balls are neurotransmitters, and the catcher’s mitt and hockey stick
are receptors, or molecular tools that receive specific chemicals.
Researchers can use this system to study
what a cell does by turning it on and off on demand.
To do that, they can introduce a receptor
that doesn’t have a neurotransmitter associated with it.
Like you put a soccer goal in the street, but nobody has a soccer ball.
Are we stretching this one too thin?
I don’t think so!
I think it works!
So then they would be able to install a lock and key system to turn cells
on or off whenever they wanted to.
If you control where the soccer goal goes and when the soccer balls show up,
you can make a remote control system for your brain.
And these custom receptors exist,
and they have a very intimidating name: DREADDs.
It stands for Designer Receptors Exclusively Activated by Designer Drugs.
They are a form of chemogenetics that places an artificial receptor, or soccer goal,
into the brain so that the researchers can introduce artificial neurotransmitters,
or soccer balls, to attach to them and change the way those brain cells behave.
The receptors won’t be found anywhere else in the body,
and nothing in the body binds to them.
They only take effect when a scientist also injects the specially designed drug.
This is important because these DREADDs were designed to add brain control.
If scientists injected something into the brain that ran amuck binding to
all sorts of unintended cells and activating unwanted behavioral pathways,
it would be out of control.
There would be way more side effects,
potentially making it less safe for the animal.
DREADDs can be introduced to mice either by surgery or genetic engineering.
The soccer ball for your new soccer goal
will often be a drug called clozapine-N-oxide, or CNO.
This technique debuted in a 2007 study.
First, researchers conditioned a mouse to be scared of a specific room.
They shocked the mouse’s foot when it entered the room,
and it would respond by freezing in place.
Foot shocks produce a freezing response in mice
that researchers can use to tell if they’re scared.
But when they turned off brain cells in the hippocampus, or memory center,
using inhibitory DREADDs, the mouse didn’t show signs of fear anymore.
Its freezing time was significantly decreased.
It was as if the mouse had forgotten that this room was scary.
Now, the point here is not to create, like, fearless mice.
Scientists use chemogenetics in rodents to learn which areas of the brain
are responsible for making memories by
switching them off and observing that they’ve kept memories from forming.
But they can also influence a mouse’s memories.
In 2012, the same team of researchers genetically engineered mice
to express DREADDs only on neurons that were active.
Now, these mice were trained in two different boxes:
a relaxing one, and a scary one where they got a mild foot shock.
The researchers basically set it up so that the cells expressing DREADDs
would be associated with memories from the peaceful first box.
So normally, mice would remember the foot shock and freeze in box number two.
But if they got a dose of CNO, they wouldn’t freeze…
like they were remembering box number one instead.
So the researchers were able to activate a different memory
than the one that would’ve otherwise been triggered in a mouse’s brain.
And these kinds of memory-manipulating experiments
produce real behavioral outcomes, like not freezing in fear.
But this is not something we’re going to be doing on humans any time soon.
There are definitely ethical limits to the manipulations we will undertake
with our own brains, and any clinical applications down the road
will have to be vetted very carefully.
But there are some potential ways chemogenetics could help us.
For instance, imagine if we could do something similar for patients with
post-traumatic stress disorder, helping them manage
the fear they experience in response to specific memories.
The patient could form a memory associated with something positive or calm.
Then, when they are in an environment likely to trigger negative memories,
they could theoretically activate the cells associated with the peaceful memories
to retrain their associations and replace the old memories.
And memory is just one of its potential applications.
Like the brain does a lot more than that.
DREADDs in the prefrontal cortex could control attention, for example.
The two most commonly used forms of chemogenetics
are excitatory and inhibitory.
Scientists either excite cells and make them more active
or inhibit cells and make them less active.
If they wanted to regulate attention, they might apply inhibitory chemogenetics to
the prefrontal cortex because that part of the brain
is involved in regulating attention behavior.
Some people have more activity in the prefrontal cortex than others,
which can make more focused attention difficult.
Using DREADDs, they could theoretically inhibit some of that prefrontal cortex
activity and decrease the competing signals in their prefrontal cortex
to have an easier time focusing.
Others might benefit from excitatory DREADDs
to achieve their optimal attention state.
Now we do have other methods of rewiring neural circuits, such as optogenetics,
which allows us to stimulate neurons with light.
But that’s invasive because it usually requires hardware
to be permanently affixed to the head.
After a one-time surgery, rodents recover fully from chemogenetic infusions
and heal as if they’ve never had brain surgery.
This technology would penetrate deeper into the brain than optogenetics,
and the effects would last longer after stimulation.
In other words, chemogenetics might lend itself to clinical application
better than its cousins, although there’s still a lot to learn before that could happen.
Figuring out how scientists would do that kind of thing
using rodents is the first step.
And in the meantime, we are learning a whole lot
about how the brain works that we could not learn before.
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Thank you for watching!
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