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Neurotransmitters, part 2

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Medical Neuroscience

Duke University

4.9 (1,310 ratings) | 120K Students Enrolled

Medical Neuroscience explores the functional organization and neurophysiology of the human central nervous system, while providing a neurobiological framework for understanding human behavior. In this course, you will discover the organization of the neural systems in the brain and spinal cord that mediate sensation, motivate bodily action, and integrate sensorimotor signals with memory, emotion and related faculties of cognition. The overall goal of this course is to provide the foundation for understanding the impairments of sensation, action and cognition that accompany injury, disease or dysfunction in the central nervous system. The course will build upon knowledge acquired through prior studies of cell and molecular biology, general physiology and human anatomy, as we focus primarily on the central nervous system. This online course is designed to include all of the core concepts in neurophysiology and clinical neuroanatomy that would be presented in most first-year neuroscience courses in schools of medicine. However, there are some topics (e.g., biological psychiatry) and several learning experiences (e.g., hands-on brain dissection) that we provide in the corresponding course offered in the Duke University School of Medicine on campus that we are not attempting to reproduce in Medical Neuroscience online. Nevertheless, our aim is to faithfully present in scope and rigor a medical school caliber course experience. This course comprises six units of content organized into 12 weeks, with an additional week for a comprehensive final exam: - Unit 1 Neuroanatomy (weeks 1-2). This unit covers the surface anatomy of the human brain, its internal structure, and the overall organization of sensory and motor systems in the brainstem and spinal cord. - Unit 2 Neural signaling (weeks 3-4). This unit addresses the fundamental mechanisms of neuronal excitability, signal generation and propagation, synaptic transmission, post synaptic mechanisms of signal integration, and neural plasticity. - Unit 3 Sensory systems (weeks 5-7). Here, you will learn the overall organization and function of the sensory systems that contribute to our sense of self relative to the world around us: somatic sensory systems, proprioception, vision, audition, and balance senses. - Unit 4 Motor systems (weeks 8-9). In this unit, we will examine the organization and function of the brain and spinal mechanisms that govern bodily movement. - Unit 5 Brain Development (week 10). Next, we turn our attention to the neurobiological mechanisms for building the nervous system in embryonic development and in early postnatal life; we will also consider how the brain changes across the lifespan. - Unit 6 Cognition (weeks 11-12). The course concludes with a survey of the association systems of the cerebral hemispheres, with an emphasis on cortical networks that integrate perception, memory and emotion in organizing behavior and planning for the future; we will also consider brain systems for maintaining homeostasis and regulating brain state.

Lehrplan anzeigen

Skills You'll Learn

Brain, Neurological Disorders, Neurobiology, Neurology

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4.9 (1,310 ratings)

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RR

Nov 25, 2016

While I greatly respect Dr. White's obvious immense knowledge of the neural anatomy, I feel taking this course did very little beyond showing me that perhaps medicine and anatomy wasn't for me.

SJ

Jun 27, 2017

I've always wanted to attend a course like this which offers such a detailed description of the fundamentals of neuroscience. Glad I found it and sure as hell recommended it to all my friends.

Aus der Unterrichtseinheit

Neural Signaling: Synaptic Transmission and Synaptic Plasticity

Let’s continue our studies of neural signaling by learning about what happens at synaptic junctions, where the terminal ending of one neuron meets a complementary process of another excitable cell.

Synaptic Transmission, part 121:29

Synaptic Transmission, part 215:05

Neurotransmitters, part 115:37

Neurotransmitters, part 222:24

Ionotropic Neurotransmitters Receptors, part 117:51

Ionotropic Neurotransmitters Receptors, part 211:43

Metabotropic Neurotransmitters Receptors and Postsynaptic Mechanisms11:40

Synaptic Integration25:04

Unterrichtet von

Leonard E. White, Ph.D.
Associate Professor

Skript

Let's look anatomically for just a moment, and consider the source

of some of these biogenic amine transmitters, beginning with dopamine.

Well, I mentioned some of the places where dopamine is released.

Dopamine is derived from cells that have their cell bodies here in the midbrain,

which is at the very top of the brain stem in a collection of

compact cells known as the substantia nigra pars compacta.

And right adjacent to that is a region called the ventral tegmental area.

Here we have cells that have their somata here and

they send axons to important parts of the brain, such as the basal ganglia,

specifically the striatum which is part of the basal ganglia.

And from the ventral tegmental areas projections into medial temporal lobe

structures such as the amygdala, as well as to this ventral and

medial aspect of the prefrontal cortex.

So dopamine is a very important neuromodulator in all of these places.

Here, just to highlight a little bit of neuroanatomy,

we have a cross-section through the forebrain as illustrated in

the upper-right of this slide, shows you about where we're looking.

And I want to draw your attention to the center of this slice.

You'll notice label number 11,

here we have this dark substance, which sits in the midbrain.

And that dark substance is in fact the substantia nigra, which of course,

is Latin for dark substance.

So here we've got the cell bodies of the neurons that synthesize and

release dopamine at some distance of their axon terminals up in

the basal ganglion and in the cortex.

And in the medial part of this region where we have dark substance,

that's our ventral tegmental area.

And that too, is a place where the cell bodies of these neurons reside that

send their axons up into structures associated with the limbic forebrain and

release dopamine there.

Well, norepinephrine is another important small molecule neurotransmitter, and

norepinephrine is derived from cells who have their home in the brain stem but

now in the dorsal part of the pons in a structure called the locus coeruleus.

The locus coeruleus is another place where we find black substance,

or actually the locus coeruleus means blue spot.

If we are lucky enough to cut a section through

the tegmentum of the pons just right,

we might see these two little spots that look sort of a deepish grayish blue color.

Those are the locations of where we find our cell bodies of neurons that

are producing norepinephrine and releasing it in various places in the brain.

Really just about everywhere in the brain and

even down into the spinal cord do these cells grow their axons.

So all of these biogenic means have in common a limited number

of cells whose cell bodies are in the brain stem that grow axons that branch and

grow profusely throughout various parts of the forebrain,

hindbrain, and even the spinal cord.

One last example is the neurotransmitter, serotonin.

So serotonin comes form a group of

cells that are found in a couple of different places in the brain stem.

They tend to be found right along the midline

in a group of nuclei that we call the seam nuclei, or the Raphe nuclei.

Raphe means seam, so

right along a seam where the two sides of the brian stem come together.

That's where we find our cell bodies that release serotonin and as I mentioned,

serotonin's a very important neuromodulator.

Serotonin appears to be a molecule that when out

of proper physiological balance can lead to various affective disorders.

Many of our drugs that we use to restore normal

health with respect to affective disorder act by

selectively blocking the re-uptake of serotonin, thereby

increasing the synaptic concentrations of that drug in important brain structures.

Okay well, there are more animations to view.

If you care to see some summary, some of the biochemistry,

and some of the molecular biology regarding

the function of these biogenic synaptic systems.

I would encourage you to view animation 6.3 and

6.5 that review the organization of dopamine and serotonin serotonin synapses.

Okay, at this point I think we're ready to switch gears just a bit and

talk about the neuropeptide neurotransmitters.

So as I mentioned, the neuropeptide neurotransmitters are larger molecules.

They're made of a number of amino acids that are covalently bonded to small

peptides.

Sometimes they can be rather short or

sometimes they can be of considerable size.

So, as you might imagine,

these molecules must be handled somewhat differently in the presynaptic terminal,

and, indeed, they are, and we'll come back to that in just a minute.

But before we talk more about how they're handled in the presynaptic terminal,

let's just make a few points about their physiology.

So, the neuropeptides mediates slower and

more long lasting effects than most of our small molecule transmitters and that's

because the neuropeptides seem to interact with metabotropic types of receptors.

And as we'll discuss these are receptors that require

cellular metabolism in order to mediate their function, and all that takes time.

So the neuropeptides mediate slower and more long lasting synaptic effects,

some of which can even go on for hours to days,

depending upon the downstream effects of the metabolic pathways that are activated.

Some of the important neurotransmitters in this category

include what's shown here in this slide.

The enkephalins, so there are a number of different enkephalins that are important.

The enkephalins are opioids that have henogesic effects in the brain and

so these bind to receptors in various places including the spinal cord.

Other important peptide transmitters are substance P,

which is very important in modulating the transmission of pain

signals in the dorsal horn of the spinal cord.

And many of our hypotholamic releasing hormones that are secreted into the porter

circulation from the hypothalamus to the anterior pituitary are neuropeptides.

As are the hormones that are released directly in the posterior pituitary

into the blood stream from hypothomlamic neurons that send their axons

into the neurohypothesis.

So these hypothalamic hormones are other examples of neuropeptides.

And lastly, let's consider the activities of some neurotransmitters that

are still relatively poorly understood, and for that reason,

we call them unconventional neurotransmitters.

Not because they are necessarily so different from our small molecules and

our peptides.

In some cases they are, but mainly because we don't yet

have a full understanding of their mechanisms of action.

And so let's begin by talking about the purinergic neurotransmitters.

So these include our purines, such as adenosine triphosphate.

So you're all familiar with molecule from your studies of cellular metabolism.

You know that ATP is the energy currency for cells, and

what you may not have known is that it actually has some

biological activity at synapses in the nervous system.

So ATP can be co released with other small molecule neurotransmitters.

Once it's in the extracellular space, ATP is typically metabolized into adenosine.

And adenosine itself can have it's own biological activity.

Adenosine tends to bind to various receptors, and

these receptors have various functions in different kinds of brain circuits.

One important circuit where adenosine is important is in the hypothalamus.

And adenosine appears to build up throughout our day and

appears to be an important trigger that leads to drowsiness.

So, the more our cells in the hypothalamus are consuming energy,

the more adenosine builds up in the extracellular fluids.

That seems to be something like

an index of our state of fatigue, and the degree of which we require sleep.

Well, one thing many of us do, I myself am guilty of this,

is that we fight this system by consuming caffeinated beverages.

And what these caffeinated beverages do is they block adenosine receptors.

So the xanthines including caffeine and theophylline, they are blocking

the receptors that are mediating this natural sense of drowsiness that will,

we think, in some way have a restorative function on brain circuits.

Another of the so called unconventional neurotransmitters that's

fairly recently been discovered are a series

of molecules that are derived from membrane lipids called endocannabinoids.

These molecules are hydrophobic, so

when synthesized they can freely diffuse across plasma membranes, and

they bind to receptors that are also bound by the psychoactive components

of cannabis, hence their their name endocannabinoids.

So these include some very interesting receptors,

such as the CB1 receptor which is present

in high concentrations in structures associated with the brain's reward system.

It's also present throughout the cerebral cortex and

in the cerebellum, in the basal ganglia.

So lots of places where we think that the drug of abuse,

the cannabinoids derived from cannabis,

have their effects on cognition and sensory and motor function.

So these endocannabinoids seem to have some interesting physiological

roles in modulating plasticity.

Especially plasticity at inhibitory synapses.

And you can read more about that in the textbook if you like and figure 6.19.

We'll come back to this when we talk about mechanisms of synaptic plasticity

in a future tutorial.

One final neurotransmitter to discuss is nitric oxide.

So this truly is an unconventional neurotransmitter in that it's a gas.

It's not a solute that can be dissolved in an aqueous medium.

It's not a peptide.

But rather it's a gas.

And nitric oxide is produced from the metabolism of the amino acid arginine,

as is illustrated here in this pathway.

So arginine Is processed by an enzyme called nitric oxide synthase,

and nitric oxide in a gaseous form is produced as is citrulline.

And that nitric oxide then is free to diffuse across the plasma membrane,

or it can interact with target structures maybe within the cell,

where the gas was synthesized.

Here in this particular illustration we're showing the activation of a guanylyl

cyclase enzyme, which results in the production of cyclic GMP,

one of the important second messenger systems we have within the brain.

Now, one of the interesting activities of nitric oxide involves its

ability to diffuse freely from, lets say a postsynaptic cell to a presynaptic cell.

So, there is ongoing interest in the idea that nitric oxide might be some kind of

a retrograde messenger that allows from signals to travel

back from a post synaptic cell to a pre synaptic site.

Of some interest is the activities of nitric oxide as a vasal dialator.

And so, this is a function that is performed in a variety of of tissues,

and that activity is mediated by a guanylyl cyclase pathway.

And perhaps it's of interest to some of you that Viagra and

other related drugs that are used to

affect erectile dysfunction function by affecting

nitrous oxide mediated vasodialation.

Similar pathways, however, are found in a variety of structures within the brain and

elsewhere in the nervous system.

Hence these drugs can often have side effects, often involve sensory processing

and we'll see why when we talk about the mechanisms of phototransduction.

And we'll discover an important role for

the guanylyl cyclase pathway within the photo receptors of our retinas.

OK, well

let's look now at a side by side comparison

the processing of small molecule transmitters and peptide transmitters.

So I would encourage you to have a look at the table that I've prepared for you,

in page 3 of your handout, which talks about the synthesis,

the packaging release, and the removal of neurotransmitter,

at synapses that use small molecules and peptide transmitters.

So with respect to the synthesis, small molecules are synthesized typically

in the pre synaptic terminal where there are enzymes that are present that

can create the active neurotransmitter right there in the presynaptic terminal.

For peptide neurotransmitters, the synthetic pathway is primarily

in the cell body where the peptide is processed like all other peptides.

Through the endoplasmic reticulum, thegGolgi apparatus,

where various kinds of post translational modifications may be performed.

Meanwhile, this peptide can be packaged into a vesicle of some sort and

then transported down the axon.

And along the way further modifications, or

perhaps cleavages of that peptide can occur.

As the initial product of the transcript is then processed and

prepared for its active function in the presynaptic terminal.

Couple of other differences to note.

Small molecule transmitters typically are packaged into vesicles

that then are concentrated right along the active zones at the presynaptic membrane.

Whereas peptide transmitters are often found in vesicles that are diffusing

around the presynaptic terminal further away from that active zone.

So consequently, the vesicles that contain the neuropeptides,

which typically are much larger Then those that contain the small molecules

are further removed from those active sites and therefore require a larger

influx of calcium in order to trigger calcium mediated fusion events.

So with a relatively modest depolarization of a presynaptic terminal

we're likely only to see the calcium mediated fusion of small vesicles

that release the small molecule transmitters.

It's only with a very large depolarization that the presynaptic

terminal is likely to release much peptide neurotransmitter because in order for

that to happen, sites well away from our typical

high efficiency active site are engaged and

those larger vesicles then fuse and release peptide neurotransmitters.

But only when that pre-synaptic terminal is flooded with calcium.

So this might be one physiological way

of holding in reserve the peptide neurotransmitters,

only when there is intense depolarization of the pre-synaptic terminal.

And lastly, considering the removal of the neurotransmitter once it's been released

the small molecule transmitters have a variety of systems.

The transmitter itself might be degraded, and

pre-cursor substances might be then taken back up into the [INAUDIBLE] terminal or

they may run through a [INAUDIBLE] cell where they may be in some storage

form before being returned from a [INAUDIBLE] to the [INAUDIBLE] terminal.

Of course, the transmitter can simply diffuse away as well.

For a peptide neurotransmitter, these substances, likewise,

are free to diffuse away, but there are also proteases that are found

here in the synaptic cleft that can cleave these peptide neurotransmitters.

And degrade them right at their region of release in and around the synaptic cleft.

So let's also take a few minutes to consider

a typical glutamatergic synapse in the brain.

So as I've already mentioned glutamate's one of the most important small

molecule in neurotransmitters that we have

it's widely considered to be the most important small molecule for

mediating fast excitatory events in the central nervous system.

So in a typical pre-synaptic terminal,

we have an important enzyme called glutaminase.

This enzyme converts glutamine into glutamate, and

glutamate Is then concentrated in synaptic vesicles,

where it's taken into that vesicle via a transporter called

vesicular glutamate uptake transporter.

So, VGLUT, for short.

So, this synaptic vesicle then, of course,

can fuse with the presynaptic terminal when calcium floods that active zone.

The glutamate is free then to diffuse into the synaptic

cleft where where it can react with postsynaptic glutamate receptors.

Now some of this glutamate, of course,

diffuses away from the synaptic cleft where there are excitatory amino acid

transporters in the glial cells that surround the synaptic compartment.

Of course,

the important glial cell that we're talking about here would be the astrocyte.

So the excitatory amino acid transporter

takes up the glutamate where it's converted back to glutamine.

So glutamine is in essence a storage form of glutamate

that can sit in reserve within astrocytes before being

recycled as needed back to the presynaptic terminal.

So there are other kinds of cotransporters that allowed glutamine to

cycle back to this presynaptic terminal where it can once again be hydrolyzed

by glutaminase in the glutamate ready for another round of synaptic release.

Okay, lastly let's just make a couple of points here in conclusion.

So we've talked about our two classes of neurotransmitters, or small molecules.

Our peptide transmitters,

we've also talked about what we've called some unconventional neurotransmitters, and

these neurotransmitters interact with two classes of receptors.

Our ionotropic receptors, which mediate rapid synaptic events

since the receptor for the ligand as part of an ion channel complex.

And there are metabotropic receptors

that require the activation of second messenger systems.

So they mediate more slowly evolving and

potentially longer lasting synaptic effects.

Our small molecule transmitters can interact with both

kinds of receptors are peptide neurotransmitters

as far as we know only interact with metabotropic family of receptors.

Now I think from this simple schematic, it should be apparent to you

that if we want to understand the post synaptic activity of a neurotransmitter,

we need to know more than simply the identity of that neurotransmitter.

It's not enough to know if it's a small molecule or if it's a peptide.

So knowing the chemical structure itself is not sufficient to understand

the physiology of the effect mediated by that transmitter.

One needs to understand something about the receptors that interact with that

neurotransmitter in question.

So in order to account for the physiological activity

of the chemical neurotransmitter you need to know the receptor.

So in our next tutorial, we're going to talk more about the structure and

function of both types of receptors,

the ionotrophic receptors and the metabotropic receptors.

And I think you'll be impressed as I am with the varsity of effects that can be

activated, even by the very same chemical signal.

So, next time we'll talk about neuro transmitter receptors.

I'll see you then.

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