raw_transcripts/lecture_4.txt

A quick.

Poll.

I have three clocks here.

It has very different times.

My my phone says 10 a.m..

The U.S. system says 10 to 10.

The other one says ten.

What time do you have a ten?

Okay, if I.

A bit.

I really need those of you at the back to

tell me if I lapse into a little bit of.

An.

Indecipherable must I load.

Myself up with a bunch of.

Anti cough medicine stuff?

Since I last saw you on Monday?

I've had a bit of a cold, and when I

get congested I tend to speak a bit more quietly.

So please do tell me if you can't hear me

right.

And that was all a bit of a lead in

to this lecture's title.

It says Neurotransmitters, but which I like to think of

as why do drugs work in other parts and discipline.

This might be called psychopharmacology, which is the idea that

specific neurochemicals.

Specific chemicals have.

Specific effects on.

Brain systems.

And we want to try and understand some of that

today.

As I said, if I.

If I'm not audible at the back.

Please let me know.

I'll just try and speak louder.

I just can't get much feedback myself.

At the moment.

So I want to frame this lecture around cocaine.

Cocaine was first arrived, at least in Western societies about

150 years ago, being used for many years in the

South Andes, for example, as a stimulant for workers in

the high out alpine regions.

When brought to Europe, the.

Drug was first used as a.

Local anaesthetic.

We won't be going into its local anaesthetic properties at

all and was initially in the hopefully as a hopeful

treatment for morphine addiction soon, however attracted widespread recreational use.

But if you look.

At the old advertisements, you say lovely, you know, it's

a sociological lesson lesson in the in the the value

of different substances.

This is an advertisement for.

The.

Cocaine basically as a local anaesthetic for your teeth.

Again, toothache drops really.

You know there's a lot of tooth problems back in

the day then, you know, things got a bit darker

study in scarlet you know, cocaine addiction, cocaine, the thrill

that kills this is now mid century.

And we're really heavily into the period of time where

drugs were really frowned upon.

And then more recently, of course, if you follow Netflix,

ET cetera.

There's a whole profusion of things about drug trade.

But the question I want.

To address here is why does cocaine have its psychoactive?

Not It's like my anaesthetic for the psychoactive effects.

Oh, that's a a device.

I didn't.

Know what that.

Was.

I wonder if it works.

For me.

Now.

There's evidence.

I'm here.

Okay.

I was wondering what that sound was.

It was very disturbing.

Okay, so the question is, why does cocaine change behaviour?

And I'm going to give you a very simple neurochemical

answer in a second.

And then the aim of this lecture is effectively to

break down the sentence.

And the sentence is that cocaine has its effects because

it blocks the re uptake of the neurotransmitter dopamine after

its release.

And it's finance, not just any old sign ups, but

a sign ups.

And by the end of this lecture, I what.

I hope to help you understand is what we think

is what neurotransmitters are.

And anyway.

Why does it have a specific effect?

I still find it striking that so many of these

drugs, these psychoactive drugs, LSD and etc..

Have such specific cognitive effects.

When you just smoke them, inhale them, eat them, whatever.

They get into your bloodstream, they somehow get to your

brain.

How is it these chemicals can have such a specific

cognitive effect when the brain is so exquisitely wired to

help us do things?

This dissonance between.

The global kind.

Of potential effect of cocaine and its specific actual effects

is what I hope to try and get through to

you today as.

Well.

It's really it's an annoyance.

And so, as you all know, you can ingest some

drug in many different ways.

This graph just simply serves to illustrate that the concentration

in the blood.

Depends on the route of administration, as does the time

course.

I don't want to take too much away from this.

The point being that there is.

Quite a.

Significant change in the blood concentration that lasts for a

while.

Then at some point in time that concentration falls below

this threshold level.

For.

Effect.

So before and after ingestion to have an effect when

when the concentration exceeds a particular level.

The other.

It's going to be a few definitional slides in this

lecture because really setting you up for the rest of

the lectures, we need to.

Make sure that you are all on.

Board with the kinds of phrases that we might.

Use.

Many drugs, too much drugs, something what we call a

dose response curve.

That is what we call sigmoid function typically looks like

this.

On the x axis is the drug dose of.

The drug going from low to high.

On the Y axis is the effect of that drug,

whether it be on behaviour or on a specific neurochemical

systems.

And you can see that again, as you increase the

dose of a drug, you might expect to see an

increase in the effect of that drug, which then saturates

afterwards.

Increasing the amount of drug in the system doesn't have

any further effect.

And the reason for that, that saturation is.

Because at some.

Point in time this drug is basically.

Occupying all the.

Potential sites it might have in.

The brain.

Again, this is the idea of a threshold that below

this particular concentration you won't be able to experience or

at least be able to detect the effect of those

substances.

The other thing you should.

Be aware.

Of is that drugs can have multiple effects on different

systems in the body and in the brain.

So, for example, many of you may be aware.

That the drug.

Morphine, which is an agonist of opioid receptors in the

brain.

It's both important for pain relief.

It's why it was developed or it was used.

But at higher doses, it can lead to arrest of

breathing and death.

And the reason for this is that if you look

at the dose response curves for the drug in the

two different behavioural effects, that is the pain relief on

the left and the yellow.

Any effect on breathing on the right?

In the blue you see the different regimes, different concentrations

of the drug are appropriate.

In the two cases.

So there is a margin of safety where you might

be able to have an energy equal pain relief effect,

but you won't have any impact on breathing.

Now, the actual reason.

The major reason for this in this particular case is

illustrative of all drugs.

Is that the type of receptor for morphine that's present

in the brain?

Again, we'll get there in a second.

But the type of the receptor that the present in

the pain system is a slightly.

Different type of receptors and that is present in the

breathing.

System.

And the.

Two receptors have slightly different sensitivities.

To morphine.

And so therefore.

As you increase the dose of morphine, you get more

effect on one of the systems before we get an

effect on the other system.

So the idea that you can have these different effects

at different concentrations relates.

To the fact that different.

Receptors for this.

Agonist have to be found in the brain systems.

Okay.

So the major as I said, the major question I

want to ask in this lecture is why do these

drugs work at all?

I want to put to you a thesis that the

drugs that we are interested in usually act.

At the sign ups between neurones.

I want to suggest that they usually have their.

Effect by changing the strength or duration.

Of activity.

Of particular neurotransmitter systems.

In those same lapses.

And I want to suggest that it's possible for.

Drugs to.

Ingest, to have a systemic.

Administration ingested.

Injected.

Digested, etc..

Have a specific effect because they activate specific pathways of

neurones.

Through the brain.

And we'll go.

Through a few of those pathways at the end of

this lecture.

That is, each of these pathways has a particular neurochemical

signature.

And to try and illustrate that, I want to.

Help you understand how neuroscience has changed since I started

as an undergraduate student.

And now this is a photo, I think.

It was about ten years old, this.

Photo now.

But at the time it was revolutionary.

For me.

This photo is a black.

And white version.

It is a is an image of a slice taken

through the hippocampus of a mouse in the hippocampus.

It's a beautiful structure.

And it has this really dense layer of cells.

Called the principal cell layer.

And you can see at high magnification these cell lines

here.

So each of these little pyramidal shape things is one

of the nerve cells in the perimeter, in the principal

cell.

And all these little processes up here that dendrites do

coming off.

Now, when you first when.

When histology synonymous with first looking at the hippocampus.

First, these cells looked.

Identical to them.

However, recent.

Technologies, for example, by being able to genetically manipulate a.

Mouse.

Have allowed researchers to insert little proteins into cells, the

expression of which.

Depends on the particular types of neurochemicals that those cells

produce and those.

Proteins in turn for when you stimulate them with light.

And so what.

You can what seem to be a relatively homogenous mass

of cells in the hippocampus, for.

Example.

Is now much, much more clearly.

Now a really diversity of cells.

Each of which has a different neurochemical signature.

And I want to outline this to you, particularly because

even in my lifetime there's been a massive change in

what we understand about the specificity of pathways in the

brain because of these kinds of techniques.

So a lot of what I am going to tell.

You is probably going to be out of date in

ten or 15 years as we.

Learn more and more about.

The specificity of those systems.

Okay.

So in the next section, we're going to talk about

how we define neurotransmitters and your modulators.

We've discussed two major neurotransmitters.

In the last.

Lecture, those GABA.

And glutamate.

And I alluded to the fact that there are many

other neurotransmitters, just to remind you of assign naps and

what neurotransmitters do.

This is a sign ups the presynaptic space here in

green, the post and haptic membrane here.

Someone pointed out in the last lecture this line is

point in the wrong place.

It should actually be pointing to the presynaptic membrane here.

These are little bags of vesicles of neurotransmitters that have

docked at the presynaptic membrane and release the.

Contents into space.

For these neurotransmitters.

Can cross that little space to sign acting cleft and

have an action on receptors at the person action membrane.

So that's the sign ups activated when an action potentially

invades that sign.

So there's been a lot of discussion for many years

now.

About what neurotransmitters are and which substance we might like

to call neurotransmitters.

It seems like a pretty easy question to ask, but

actually.

It's tremendously difficult.

And the reason for this is that there are many

chemicals that are released in the brain.

And whose release depends on the activity of neurones.

But not all of those chemicals.

Actually act as something that transmits.

Information from one neurone to another.

They're not really.

Neurotransmitters.

Neurotransmitters.

The idea.

In the name is helping.

Transmit signals.

From one to another.

A lot of his.

Chemicals might be released as.

By-products of just simply.

Stopping active or clean up.

Processes and stuff like that.

So we have to define what a neurotransmitter is.

And there's a fairly generally agreed definition now that I

think 40 years old, which is it's stated here, neurotransmitters

are those molecules that are made and stored.

By the presynaptic.

That's the.

Neurone who sign up to these.

Is a putting this cosmetic membrane, the prisoner.

So that neurone has to make and store that substance

that's kind of important to that neurone.

So it's making and.

Storing.

That substance is released.

At the presynaptic terminal.

When that terminal is activated, that doesn't make any sense.

If you have a substance that's being just released.

All the time because it's not going to be able

to transmit any information, its release level won't depend.

On the activity.

Of the neurones.

This neurotransmitter has.

To be its release has to be dependent on the

activity of the presynaptic.

And finally, it seems a bit of a.

Of course, but that substance has to have an effect.

On the postsynaptic.

Near as I said before, there are many chemicals in

the brain that are.

Released at the when neurone is active.

But not all have effects on person.

I think neurones and therefore not all transmit information.

To those neurones.

Similarly, we can define a neurotransmitter receptor as molecules that

are activated by them.

So there's many proteins.

In the cell membrane.

All of those are activated by a neurotransmitter.

So they need to be activated by a.

Neurotransmitter.

And they need to be able to change.

The flow of ions, either directly or indirectly.

Into.

The person active.

So as we discussed in the last lecture, sodium chloride

ions are the primary mechanisms that.

Finds use in this.

Process.

I want to note here that each neurotransmitter may have

several receptors.

As we discussed before, the morphine.

Morphine has multiple opioid receptors.

And each.

Neurotransmitter may.

Have several receptors which express some different neurones.

Sometimes even in the same neurone, unfortunately.

And may be different.

Be sensitive to the neurotransmitter again by analogy to the

morphine thing.

Breathing is affected at one concentration of the neurotransmitter, whereas

pain is effectively another concentration.

Because the receptors for morphine are different in those two

cases.

I've said before, but I'm just going to reiterate because

we do tend to focus on the other neurotransmitters, but

the major neurotransmitters in the brain are glutamate.

And it's some people who think that every.

Neurone in the brain is sensitive to the expression of.

Glutamate, and that is it has.

Sinuses, closing spaces that express receptors for glutamate and GABA.

It's not the case that all neurones in the brain

express or make glutamate.

Think about.

It.

If you look at the cerebral cortex, for example, we

find that about 80% of the neurones in the cerebral

cortex express or make the neurotransmitter glutamate, and they send

back neurotransmitters to the neural.

Whereas 15 to 20%.

Of those Neurones Express and gather and send that one

the person.

If you have a think about that, that seems a

little bit strange.

It's such an imbalance between the amount of neurones.

That produce excitatory neurotransmitters, any amount of neurones that produce

inhibitory neurotransmitters.

Because wouldn't that mean that the brain.

Is hyperactive time?

It's not actually the case.

Indeed, the average.

Number of spikes to.

The neurone, the cerebral.

Cortex.

Every step of.

Action, potential neurone, several cortex produces every second is about

one.

That means, you know.

Several billions.

I think, that were being produced in your brain every

second, but only about one of those per year.

And the.

Reason for that is that the.

Actual.

Inhibitory surface to surface in cerebral cortex acts as the

principal surface.

In addition to these two major classes of neurotransmitters, there

are many other.

Putative and identified neurotransmitters.

And indeed.

This list would change next year because again.

Every year it seems that we identify.

Another chemical as a putative single neurotransmitter in the brain.

The major ones that we would talk about today acetylcholine.

Dopamine, serotonin and noradrenaline.

But you should also know that there.

Are a bunch of other ones.

Including what are called neuropeptides loop proteins, effectively the active

neurotransmitters.

Also nitrous oxide purines endocannabinoid.

Which is the target of THC.

So there's a lot of other ones is thought.

There for a reason.

There's at least 20 or 30.

Substances or neurotransmitter at the stage and as I say,

more being.

Discovered each year.

And then I would define for you what neurotransmitter uptake

means.

So one thing we talked about in the last lecture

is that these neurotransmitters.

Get released into the.

Sinuses.

And the synaptic cleft.

And if you think about it, if they just hang

around there, they just continually.

Activate the person at the exit.

They're bound to the person that's receptors.

Causing ions.

To flow into the postsynaptic neurone, and that pretty well

renders those sinuses useless.

So they can't change the.

Information that the signalling becomes stopping.

Stop and stop and stop.

It is always active.

So we have to get around that some way.

We have to clear that out.

Of the fine, finance those neurotransmitters.

Resetting the.

Science so that can continue to signal more than new

information.

And that's what these re uptake, so-called re uptake mechanisms

are.

There's many of them I don't even know these in

complete detail.

But you won't be able to see much of the

things on this slide.

But if you look at the presynaptic neurones releases the

neurotransmitters into synaptic, they cross the postsynaptic neurone.

And you remember that around these sign ups is.

As we discussed in the last.

Slide, also these glial cells and.

Other forms of non neuronal cells.

It turns out.

These re uptake mechanisms.

Can be found at.

Of those three signs.

The glia actually have very important vacuums.

For this to suck up a lot of the neurotransmitters

and listening to the assignments resetting that so that.

Some of the neurotransmitter gets for some reason.

Unknown to us absorbed into the postsynaptic and some of.

The neurotransmitters get reabsorbed.

And that makes more sense.

But then you can repackage that neurotransmitter.

If you want.

Into another.

Basically, we use that neurotransmitter.

So these people, transporters which take neurotransmitter across the cell

membrane into one of these three cells and out of

this line ups is basically the re uptake mechanism.

This these kind of rehab mechanisms exist for most, if

not all, of the neurotransmitters.

And we'll be.

Discussing the specific one for me, which is important for

the effects of cocaine towards the end of the lecture.

There's a few other terms I need to help you

understand.

It's one that you see a lot in the literature

is these two words agonist and antagonist.

And unfortunately.

These words get.

Used in.

Very different ways by different.

Literatures.

So just trying to accommodate them into some sort of.

Synthesis here for.

You to help you understand.

And agonists can be thought of as a drug that

increases the effect of a neurotransmitter.

Whereas the antagonist is a drug that decreases The New

York Times.

Generally speaking, an agonist that increases the.

Effect of the neurotransmitter.

Does so by increasing production.

Or storage of the your.

If you're making more of it, that's a pretty significant.

You've got more.

To give.

You sign ups.

Or it could increase the release of neurotransmitter.

You've already got enough there, and now you're sending more

fans of this food to the.

Membrane to release.

Into the finals.

Or you could stop.

The New York Times would have been clear so you

could alter those reuptake.

Transporter mechanisms.

Or you could actually.

Bind.

Directly to the.

Postsynaptic.

Receptors as if you.

Were a neurotransmitter and activate those postsynaptic receptors.

So there's multiple ways.

Of increasing the effect of neurotransmitter in the brain's.

And you can do basically the.

Opposite for an antagonistic.

Effect.

The next slide, I think.

Yes.

Do not write these things down.

You can look at them at your leisure.

What this does is try to show you is an

example.

Different drugs and how they might have an effect on

different parts of the neurotransmission process.

I will go through a few just to illustrate it.

For example, L-dopa, which you may know has been targeted

for.

Parkinson's and so forth.

Acts as a precursor but does not mean and we

get the drug.

Meaning the second.

There are other drugs, for example.

Botulinum toxin or Botox.

Inhibits the release of neurotransmitters, in.

This case, acetylcholine.

Into the spine.

Therefore paralysed.

Can anyone tell me why Botox paralyses muscles?

So yeah, so we're not going to talk about it

at all.

But one of the most important snacks is in the.

In the it was.

One of the most important sinuses in the in the

whole body.

Is the.

Neuromuscular junction, the junction between neurones and the muscles that

they have an effect on.

The neurotransmitter at that neuromuscular junction is acetylcholine.

So if you block.

The release of acetylcholine into that sign.

That.

You effectively.

Paralyse those muscles because they're no longer getting stimulated, you

want to paralyse muscles.

And a difference is that with changes.

Other drugs, for example.

Can block the.

Synthesis of enzymes as an.

Antagonist or block.

Presynaptic receptors as an antagonist.

For example, cure are a very potent paralytic blocks.

Again, acetylcholine release affects your muscle production and because of

that paralyses.

Unlike Botox, it has.

A much more of contract.

It's much more powerful and therefore the rest of breathing

death.

You can also have have.

Much weaker effects by adding atropine because anyone been to

an eye doctor has something to stop the eyes.

Pupils dilate.

Yes.

First of all, across the story, I mean, I realise

this practice is dying out.

So the reason for that.

Is that acetylcholine.

Is the major neurotransmitter.

Of the parasympathetic nervous system.

And if you remember the difference between sympathetic.

And sympathetic, nervous and sympathetic nervous system of flight arousal,

increased.

Pupil dilation, when.

You get more sympathetic activity and vice versa than.

Parasympathetic.

If you block the parasympathetic system, you effectively increase the

weight of the sympathetic system.

So you get people dilation.

So these different chemicals are acting in different ways.

As I say, I don't want you to write down

all these things that just there's a way for you

to understand how different drugs have different effects on the

whole process of neurotransmission.

And I thought that might be a little bit vague

and complicated.

You get worse.

Unfortunately, neuro modulator, as anyone heard this term before.

Maybe I shouldn't say, You know, it's important.

And your modulator is a is a messenger release when

you're on, that often affects groups of neurones.

So unlike a classic neurotransmitter, these substances.

Have effects often on a large.

Number of.

Neurones.

They often have slow affects.

They seem to modulate the activity of neurones.

Without really providing this fine grained information of the New

York Times.

Confusingly, unfortunately, some.

Neuro modulators also act as neurotransmitters.

So you're going to have to.

Deal with that in your head as you go through.

This course.

One way to think of.

One way I like to think of neuro modulator is

that basically, has anyone ever done sound mixing frequency with

anyone.

Even on your.

Computer, to do the.

Ones.

Who have.

But mixing gets to got like.

Three channels of dials that can push up and down.

Right?

Like in Mozart sneakers.

So you've got like 32 channels or something like that,

65 to 60.

You can change the game, the loudness of each of

those channels.

We're not changing.

The content of the music that's being played that's taking

place.

So you can modulate.

What the sound sounds like without actually driving the content.

I think of newer models, that kind of thing.

Yeah.

Amplifying and.

Amplifying some sounds with some neural.

Activity.

We're not actually changing.

The structure of that directivity.

So think of these new.

Modulators as.

Like a big mixing desk for the brain.

And clearly, you know, if you do.

Something like shutdown.

31 out of 32 channels, I mean.

Leaving one.

Active, you're going to really.

Have a major spectrum and also have very subtle effects.

You can tweak attention.

You can help with learning just by changing the game

on some of these things.

I was going to go through the slight backseat.

I might leave.

But the only thing I wanted to point out from

the slide is that your modulators can increase the activity

of slowing and decrease the.

Activity of sinuses.

But I think I'll.

Leave this one for the moment.

If we want to, we can discuss it afterwards.

I will spend most of this lecture.

In talking about.

Specific.

Neurotransmitter systems.

I've told.

You already that glutamate.

And GABA are the two.

Major.

Neurotransmitters in the brain.

We're going to ignore them for the rest of this

lecture.

Because these other.

Systems are thought to have particular key role in cognition.

And I sometimes wonder why it.

Is that these transmitters are given such ubiquitous.

Such importance in neuroscience.

When actually the.

Bulk of work in the brain is done by glutamate

and these things are we will execute.

I think it's because it's so ubiquitous.

Kaplan glutamate that they don't have specific effects that are

being pointed really to.

If you have something that has a system wide effect

like glutamate.

Fiddling with the effects.

Of those particular neurotransmitters isn't.

Going to have a huge specific sort of very specific

effect on cognition.

To have a specific effect on cognition.

You need the substance to be expressed by a limited.

Number of neurones with a particular set of connections.

And that's the case for the following.

Systems that we're going to go through some detail.

So I'm going to go through all.

Four of these.

Don't try to copy this down.

We're going to be bigger in slightly next lines.

All four of these systems are going to be described

within the context of the road brain for the simpler.

And that's why we have lost the knowledge.

Each of these schematics here shows a slice as if

down the centre of the brain like this way.

And what this shows you is kind of like the

overall structure of the rat brain.

In each case, at the back of the brain is

the cerebellum.

If you ever see the cerebellum slide, you go back

to the brain at the front of the brain in

the rat.

Anyway, So effectively the top of the brain is up

here, sometimes called the dorsal surface, dorsal fins.

And the bottom.

Here, ventral surface.

It's important that this is given to you here, by

the way.

Back towards the spinal cord or whatever.

The opposite of courteney's.

Ventral and.

Dorsal.

So back to the brain front of the brain of

the brain.

Part of the brain.

Each of these little purple things I'm going to show

you in each of these.

Slides.

Is the location of the.

Sort of the cell bodies of the neurones we're going

to be talking about.

There's not just one you on there in these cases.

Eyes, but this is the.

Location.

Of those bodies.

These are the black lines.

Indicates in a very schematic way.

The projections of the.

Axons, the bodies from that area for the rest of

the time.

So let's have a look at the first one.

The first system that we concentrate on is noradrenaline or

the north entrance system.

And if you're reading American textbooks.

It's the north atmosphere, not norepinephrine, something like that.

So noradrenaline is the same thing as norepinephrine.

So this is a very special system.

All the cell.

Bodies for the neurones that.

Produce this neurotransmitter are found in a little area called

the locus, really found their brain junctions with migraine in

the brainstem.

In Iraq, there are about 300.

Nerve cells in that.

So what is in that region?

Sorry, 3000 in that region.

In a human, there are about.

10,000.

If you compare that, for example, in the human 86

billion.

Neurones in the brain.

This is only 10,000.

A drop in the ocean.

If you had an impact, a stroke in your cortex

and lost only 10,000.

However, if you lost.

These neurones, you would notice.

And the reason for that is that these neurones project

almost everywhere in the brain.

They send.

Axons to almost every pore in the brain.

And therefore they release.

The neurotransmitter noradrenaline to almost every location in the brain.

The excellence of these individual neurones are very large.

They cover many millions of cells.

Over several decades.

We now understand that they have multiple roles, but they

can be kind of class in the following term.

That is the idea that they promote.

Vigilance for arousal.

So, for example.

If you say I also want to know, by the

way, that noradrenaline is the major.

Neurotransmitter of the sympathetic nervous system, which is why it's

involved in blood pressure and stuff like that.

And you should also know distances involved in sexual behaviour

and appetite, as you see in later lectures, as well

as decisions which were.

Also seem like lectures.

And one of the more interesting things that features of.

The small group of neurones in this little area of

the brain.

Is its activity.

It seems like.

We can attract this.

Activity with.

These little set of neurones by measuring your pupil diameter.

Not directly.

It's not that.

These.

Neurones directly protect the people, but their effects on the

brain surface and.

Manifest.

In the signs of the people.

So, for example, in this work.

From Darius Jones and his colleagues in Monkey, what's shown

here is the average number of action potentials produced by

a new.

White animal reporting from the three of us.

That's in the bottom curve.

And on the top.

Is the.

Pupil diameter, with.

Dilation being.

Larger and.

District of being smaller.

This is a very long time.

This is about an hour of recording or even an

hour and.

A half of.

Recording.

You can see that over time, the number of spikes.

Produced by the cell and other cells.

Near it varies.

So sometimes it's about two, sometimes it's about one spike

perspective.

It's a factor of two.

From the variance in the activity of these.

Cells.

When you can see that the number of executions being

produced by the cells varies with the pupil diameter, such

that when you have large pupils, that's indicative of these.

Those haven't quite high rates.

And that correlation of causation and correlations is now used

quite.

Frequently to try and assess.

The state of the system in humans, because we can

measure pupil diameter fairly.

Straightforwardly with the.

Top electrode and really it's in humans.

So we can track the activities population of neurones simply

by looking at your pupil diameter.

Many things affect the people.

Don't have very controlled experiments.

Be able to.

Rule them.

Out.

But in the right conditions you can.

Try to affect.

This vigilance.

Or arousal system.

Indeed, perhaps particularly for this lecture.

You may know that you're exposed in relationship, which is

the idea that performance is based on the intermediate.

Level of arousal.

When you have low arousal, good.

We have very high.

Arousal, very distractible.

Good.

When you somewhere in between those two extremes.

That's when you perform it best.

And actually, strikingly, the activity, the neurones.

In this little area seem.

To vary in a.

Way that might be expected by some underlying this relationship.

So, for example, when you're measuring from the stimulus and

you're measuring the activity of neurones in each of these

bars, the approximate activities of.

Neurones that fires fire, the more active.

The heat and the arrow in this case is, by

the way, the onset of a particular.

Task.

You can see that when the animal is inattentive.

Or not, alert monkeys when they're doing experiments, Wolf, has

been.

Several minutes.

If not longer.

You sign and they don't really want to participate in

this experiment and just kind of go to sleep.

Or when they go to sleep, they become inattentive.

And you can see the activity in the local cities

is reduced in these conditions, whereas when the animal is

highly distractible.

Seems to be wanting to do the task wasn't able

to accomplish it might be to terminate the trial too

early, etc..

You can see also that the activity.

In local surrealists has increased during these conditions in a

chronic way.

And then some.

Nice intermediate position.

The arm was engaged, is actually able to do the

task is performing well.

In this case you have low activity in the really

in general, the little little epochs of high activity seemingly

signalling the.

Fact that the animal is actually attending to particular aspects

of the path has been undertaken.

So these neurones really seem to track quite well the

vigilance that an animal is producing, be a.

Task, engage aspects of.

Their activities.

Behaviour.

Get to the point where it's over the cuts, defence

cuts.

Why do you think they should be much more distinct.

Kind of reforms?

Is that what you mean?

And why Is it because you have a record that

you have to use against other?

What do.

You mean?

Why, for example, is this black over here and this

black is here?

Is that is this what you mean by overlap?

Sorry, I'm not quite sure what you mean.

By the overlap.

In on the x axis.

The thing that.

Is pointing that out, I didn't actually describe what this

chart which is.

Important.

These are what we would call histograms.

Or.

Event time.

Histograms of periosteum stimulus time variances.

If you will see this word eighth grade line.

Who go through more in a couple of weeks time.

Each little box.

Now indicates the average.

Number of spikes produced by neurone or the total number

of spikes because you find you're in a particular time

period.

In this case, what was showing before is on that

axis of these black things.

It's time.

But the access component here is just some schematic idea

of what activity is.

So there are actually very different axes and they're not

meant to be taken seriously as a kind of relative

to each other.

So each of the stages.

Is the same time scale.

And they have.

No relationship to the other actually on the ground.

I think.

We.

Will go through stages ad.

Nauseum in about two.

Weeks because the next system is the cholinergic.

System and the set of colony.

Is the major.

Neurotransmitter of the parasympathetic nervous system, which also neurotransmitters.

The neuromuscular junction.

And it's also produced in several places in the central

brain in particular.

But until now that no one knows how to say

that.

But also here, the medial septum in the coordinate nucleus

and importantly, the nucleus.

Now, these different groups of neurones, which have different projections

to the rest of the brain, also seem to have

different.

Functions in combination.

So example.

Those cholinergic neurones that are down, in.

Fact.

They seem to connect to separate.

Seem to have an influence.

The influences animals waking.

Up from sleep and going back to sleep and other

forms of arousal.

By contrast, the neurones that are in the medial.

Septum known to be very.

Important prospects for navigation.

And a large prediction of a campus influence activity.

The present projection primarily and in those in numerous besides

seem to project to the cerebral cortex.

You can therefore influence learning intention.

The cerebral cortex is a strong hypothesis that calling is

one of the major neurotransmitters of helping us tend to

different parts of our brain and therefore the outside world.

The next one is serotonin, which many of you were

familiar with, at least in name.

And this neurochemical is produced by neurones whose bodies.

Line these beautiful little nuclei in the brainstem called the

regulating events.

And there's three or four that actually separate the 3.3

of them at least, which produce the substance serotonin.

And again, these axons, these neurones project in many different.

Parts of the brain.

I'll show you in a second, was stunned to.

Learn that they're not all the same description.

But for a long time it's been assumed that they

were doing pretty well.

The same.

Function.

What that function is, is not really.

There is some models out there, but I don't think

anyone would agree on them yet.

I would note that LSD is an agonist of serotonin

receptors.

And if those of you who.

Are interested in.

The idea of using.

Small amounts of energy in therapy, for example, might be

important to.

Know that at UCL.

As well as Imperial, there are ongoing programs looking at

the use of small.

Amounts of those to help people.

Overcome depression of the major illnesses.

MDMA is also very active in the serotonin system, has

an effect on sinuses by multiple mechanisms.

It was originally used as an appetite inhibitor.

But it also targets the hypothalamus.

And is a tool in marriage therapy.

As you well know.

I suspect selective serotonin.

Reuptake inhibitors.

Or SSRI, is a.

Major.

And potent human.

So as we've discussed before, we now should not have

to decide for that selective serotonin reuptake inhibitor, selective serotonin.

System, serotonin, that's neurotransmitter.

It changes the way that neurotransmitters in.

Particular.

Inhibit so that you're going to therefore increase the level

of suppression in the sense that it's believed in.

So SSRI is basically work to increase the amount of

serotonin in some finances.

Which synopses are.

Important.

For the antidepressant effect?

It's not known.

If there.

Is a substantial debate about how and why these substances

are having their effect in those people who are receptive

to it as an antidepressant.

There's an interesting study which is going to suggest that

serotonin may have very.

Similar cognitive effects across multiple species.

This is a.

Lovely study in octopus.

I like it because it's very clear.

You'll see here there's an octopus, a lovely pitcher in

a tank, and there's two doors, the hand octopus hands

from his central tank, one to an inanimate object, the

other one to him, playmate.

So the question is, does the.

Octopus choose to spend more time with an object or

playmate?

And then does that change when you add in the

eye to the tank and you can almost almost the

focus on this one here we see that the social

activity of the.

Octopus.

Goes up substantially after introducing MDMA to the tank.

All the other relationships seem to be non-significant.

So, for example, it does seem to spend a little

less time with the object.

It doesn't seem to spend any more time in the

centre.

It does seem to spend.

More time that might.

Be increasing.

The social.

Activity of these.

Octopuses in a similar kind of way to how it

does in humans.

Yes.

Oh, sorry.

It's very hard to say what you should just say.

Just say something if I got.

Into the.

Spotlight.

Yeah.

Well, so good to have this episode of Facebook or

something like that.

Yes, actually, if you just come.

Back to it in the next slide.

I think that a lot.

Of that uncertainty around the.

Specificity of these drugs.

So why does it seem to have precisely the same

kind of effect, have different kinds of things?

Apart from the fact that the different individuals are very

different.

Anyway, getting set aside for a moment, I think a

lot.

Of that comes down to the fact that these systems.

Are much less homogenous than we thought they were.

Very kind of of that.

You know, we used to think these were all basically

the same thing, but now it's very clear or becoming

very clear.

They do quite different things.

So, for.

Example, this study from a couple of years ago shows

that some of those neurones project the frontal cortex and

others projects the amygdala.

Now, those of you who don't.

Know about the amygdala will find out ad nauseam again

this course.

Later that there is very important fear generating behaviours.

Frontal cortex, on.

The other hand, reporting in.

Hallucinations and executive.

Control.

And three different groups of neurones and it.

Is in at least in rodents.

Seem to project to these two.

Different regions because I think a lot of the reason

that these substances can have to protect is because there'll

be different sensitivities.

And maybe.

Of those climaxes of circuits that are involved in particular

substances.

So depending on which.

Form the kind of tapping into more about, you have

a different kind of stuff.

But it.

Could well be I can't.

Remember, I come in with this study whether they explore

the difference, sometimes.

I think they did those of you.

Know this, but they called 5ht receptors and there's multiple

subclasses.

Not common there, but it's highly likely that it's different

expression patterns.

But it's a good question.

Yes, but it's just stories here that certain lunatics of

projects to the frontal cortex is activated by rewarding exhibited

by punishment, whereas that which is projects, the amygdala is

activated by space.

Just to point out really something to think about too

much, but just to point out that what we thought

of as kind of model systems are now being pulled

apart and.

Described as pretty separate systems.

Or maybe the same neurotransmitters.

So I want to spend the last 5 minutes just

talking about don't mean because that's how we started off

trying.

To understand why cocaine has its.

Specific effect and dopamine has two major sources, one in

the substantia nigra and one in the mental area.

Sitting.

These two areas sit next to each other just here

in the midbrain.

Now, substantia nigra has a large projection to the.

Pelvis and striatum.

It's very important to work on control.

For that reason.

Degeneration to the substantia nigra.

Neurones is.

The basis of.

Parkinson's and Parkinson's.

If you.

Haven't come across.

It is a debilitating disease whose early stages.

Are indicated by substantial tremors and tremors.

Basically.

The absence of control of your muscle.

Movements.

This happens because of the type of nurturing signal that

normally comes to suggest migrants, not in the present.

I want to show you one video.

It's going to be video, but uses deep brain stimulation,

which is the idea that we can put an electrode

into the brain to.

Simulate.

The now absent.

Signals to try and recover those neurones and signals.

And it's an amazing video.

Here it is placed in the brain and then comes

level with the top of the nose and the ear.

And it is connected to a battery in my chest

and in my head, the skin of my chest here.

And this is controlled.

I can control the amount of the voltage coming in.

I can control the length of time that the pulses

and I can identify the number of times per second

as it goes in my chair myself now.

So I'm not having to issue.

Personal hygiene.

It took my concentration.

It's up to.

90% of my term.

I'm trying to control it.

I'm thinking about Parkinson's all the time.

I'm not terribly I'm not concentrating on my conversation with

him at all.

Okay.

It's seen as quite.

I've seen that many times.

I support it deeply affecting.

So what's happening there.

Is that the deep brain stimulation implant is effectively replicating

what the.

Nerves would.

Normally be.

Providing.

And that controls the.

Tremor or helps some control the tremor.

I've got a slide in there about deep brain stimulation.

We want to think we go through this again next

lecture.

The other major system that users don't meet is the.

So-called reward system that stems from the vengeful, sentimental area.

Of several places.

But the main circuit that's been studied is that from

the bedroom has been married to the.

Nucleus accumbens.

And thought that this circuit is one of the ones

primarily responsible for experience.

Of reward.

And potentially pleasure.

So why do we continue to do something?

Well, why do we do something again, just because we've

got something.

Positive out of this time?

It was a rewarding experience.

The teaching.

Signal that would tell us how we would.

Like to repeat that.

Behaviour.

That's the reward.

Signal.

It turns out that these neurones in the middle area,

the projects, the nucleus accumbens, so every indication of being

part of a circuit that helps us learn from positive,

rewarding events.

So if I've told you that cocaine changes behaviour because

it blocks the uptake of neurotransmitter opening, and that has

a specific effect potentially because.

It's a very specific.

Circle in the brain that.

This expresses this certain perception.

I haven't yet told you what.

Cocaine does it blocks the uptake of don't mean in

back into the presynaptic areas from the sign ups that

re uptake that transporter that normally active.

During out of the sign.

Out into the presynaptic space is blocked by cocaine cocaine.

Increasing the level certainly in the sign ups.

And in particular.

We think the finance.

Between the beta and the nucleus.

Accumbens.

And that.

By having an action on that side, it.

Increases the reward or pleasure.

Signals.

In the brain.

That's the reason.

That cocaine.

Could have an impact.

On.

Parkinson's disease.

I'm pretty sure I may be wrong is that the

two receptors, the.

Receptors slightly different.

I'd have to look.

I don't know the answer to that.

Again, a bit like the serotonin question.

I think the.

Question is whether or not.

There's different circuit sets of different receptors and different chemicals.

Being both the trigger for.

This is the topic from the video, the nucleus accumbens.

I put it here to indicate that actually many of

the substances.

That we think are psychoactive drugs, opioids.

Caffeine, nicotine, cocaine seem to have an action on this.

So this could be a common sentence for the mode

of action for a lot of these addictive substances.

They activate or activate.

Circuit that normally leads to the sensation of.

Reward, sensation of pleasure.

And that's one of the reasons they're likely to be

addictive.

It's not the only reason.

Clearly, one of the reasons they're likely to be so

hope.

Of being able to break down that sentence and that

you've understood a little bit more about why some drugs

work.

That includes a kind of like foundational series of lectures.

I suppose next week we'll be talking a little bit

about research methods that we can use to study brain

activity.

And then we'll be looking at this brain.

So thank you and have a good day.

All right, let's just keep talking.

Six months after the holidays.

Yeah, that's good.

But I don't think we know enough about the differences

between different organisms in the same place that.

We don't know the.

Answer to that.

Question.

Because that would be my question.

Which is really some people don't think it's a good

question.

I have no contact with someone else.

That's why it seems like complexity.

What what kind of thing?

Yeah, exactly.

So why.

I'm.

Calling.

Because.

It's.

Not can.

Look.

At.

Requirements.

That makes sense.

How do you go about doing stuff like this?

Because I mean.

Otherwise, except.

As required by applicable because we want to participate.

The central focus on the subject in the weeks before

Google, which might be possible this.

Week, is something.

That we support.

But I think it's difficult for people to try to

keep up to date with all the of.

Okay.