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.
Neurotransmitters, part 1
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Medical Neuroscience
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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.
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Leonard E. White, Ph.D.Associate Professor
Department of Neurology, Department of Neurobiology, Duke University School of Medicine; Department of Psychology & Neuroscience, Trinity College of Arts & Sciences; Director of Education, Duke Institute for Brain Sciences; Duke University
Welcome back to my home. I'm out in my yard on a, kind of a muggy
gray day. it's been raining so the air feels a
little bit like it might start raining on me at any moment now.
So, we'll see what happens, but let's keep going.
So we're here today to talk about neurotransmitters.
So this true facts are second core concept in the field of neuroscience
again continuing on in our thinking about the important means by which neurons
communicate using electrical and chemical signals.
So now we're going to focus on what exactly those chemical signals are.
So our learning objectives today are that I want you to be able to name the major
small molecule neurotransmitters and neuropeptides in the central nervous
system. And briefly state the functions of each
and I want you to think with me about the factors that determine the effect of
neurotransmitters on postsynaptic neurons.
Alright, well let's begin by reviewing what we talked about last time.
About the organization of chemical synaptic transmission, and this slide
gives you again, an overview of the processes that are involved in chemical
synaptic transmission, beginning with the steady state, where we find in the
presynaptic terminal a variety of organelles, and of course our presynaptic
vesicles that are loaded up with neurotransmitter ready to go.
And what happens then with the arrival of an action potential is a wave of
depolarization spreads along the preterminal membrane which eventually
reaches voltage gated calcium channels. And those channels open calcium rushes
in, which is the key triggering event. Which leads to the fusion of the
presynaptic terminal membrane and the membrane of the synaptic vesicle.
So that happens as the snare complex which is present out here.
Twists and tugs and pulls those membranes together once calcium associates with
synaptotagmin. And as those membranes begin to fuse they
form what we call a fusion pore and that allows for neurotransmitters then to
diffuse out of the synaptic. Vesicle into the synaptic left, and from
there the neural transmitters can associate with receptors for those neural
transmitters in the postsynaptic side of the synapse.
And as receptors and transmitters interact typically ion channels open and
close. that could lead to the generation of wave
depolarizaion in that postsynaptic process.
And maybe even with enough summation of inputs that are doing the same thing at
the same time, there could be an action potential generated in that postsynaptic
cell. Meanwhile, the membrane of the vesicle is
recycled back for further activity. And this involves the coating of the
vesicle membrane with a protein called clathrin and the association of clathrin
with other molecules that facilitate the pinching off of that vesicle membrane and
then it's trafficking back into the pool of vesicles that are ready to be filled
again with their neurotransmitter and reenter this vesicle cycle.
Okay, well let's let that suffice as a brief review of chemical synaptic
transmission. Again I would refer you to the animation
associated with the textbook animation 5.2 on chemical synaptic transmission.
Which will review all of these processes in a nice, short succinct presentation.
Alright, well what were here to talk about today is neurotransmitters and
neurotransmitters come in two broad kinds of categories based on their structure
and these two categories of neurotransmitters interact with different
kinds of receptors. So we have two broad classes of
neurotransmitters based on the size of the molecules.
One category we call, small molecule neurotransmitters for obvious reasons,
and then to contrast those small molecule transmitters we have neurotransmitters
that are actually small peptides. And so these peptides of course are
comprised of amino acids that are covalently bound to one another and
sometimes these peptides can be quite sizable.
So small molecule transmitters and peptide transmitters.
So these two classes of transmitter bind to two classes of receptor.
One class of receptor we call ionotropic receptors, these are receptors where the
receptor site is actually a part of an ion channel.
And that ion channel can open or close when the transmitter binds to the
receptor. So these ion channels are called
ligand-gated ion channels, with the ligand being the neurotransmitter.
The other type of receptor that we'll consider today are called metabotropic
receptors and these receptors activate second messenger system.
So there are metabolic steps involved and mediating the effect of the
neurotransmitter once it binds to it's receptor.
Now, our small molecule neurotransmitters can actually interact with both of these
classes of receptors. Both the ionotropic receptors and the
metabotropic receptors. So right away I want to emphasize to you
that if we want to understand the activity of a neurotransmitter, we need
to know something about the receptors that it interacts with.
And the activities of neurotransmitters, even though the very same cells can be
remarkably diverse depending upon what kinds of receptors were expressed on that
neuron. Our peptide neurotransmitters, as far as
we know, as far as I know, only interact with metabotropic receptors.
So as we'll come to see these metabotropic receptors mediate a slower
and potentially longer lasting effects in post synaptic neurons.
So, we associate our small molecule transmitters primarily, with quick
actions and our peptide transmitters generally speaking with more long lasting
and slowly evolving actions. Okay, well let's begin with survey of
some important small molecule transmitters.
Now, for those of your following along in the reading the reading here in chapter 6
goes into more depth than what we'll cover.
so I want you to focus on the level of knowledge that I've given you in the
tutorial notes and the level of my discussion with you all today.
So, let's begin by thinking about these small-molecule transmitters and get a
broad functional sense of what these molecules are.
So, many of them are amino acids some of the amino acid transmitters that are
important in brain and spinal cord function are shown here.
They include amino acids such as glutamate potentially aspartate.
certainly gamma-aminobutyric acid, or GABA for short, and glycine.
So these molecules mediate rapid synaptic effects when they interact with their
ionotropic receptors. As I mentioned, they may also interact
with metabotropic receptors. So, the small molecule transmitters can
also have longer lasting effects, when those particular kinds of receptors are
bound. Now, here we're illustrating some of the
important small molecule transmitters that you'll want to know about.
And perhaps the most important of them all is glutamate.
So glutamate is typically considered the major excitatory neurotransmitter in the
central nervous system and as you see here it is an amino acid.
So short carbon skeleton with the amino group attached to the side, opposite the
carboxyl group. So glutamate is involved in various
aspects of cellular metabolism but it also is concentrated in synaptic vesicles
at the terminals of neurons that use glutamate as a neurotransmitter.
Now, this is such an important molecule that we've prepared some animations that
talk about the processing of this. molecule as a neurotransmitter, so I
would encourage you to pause just a minute and view animation 6.2 on the
website that supports our textbook. You can navigate there yourself or click
on the hyperlink in your tutorial handout.
Well next lets consider acetylcholine. So we are deviating just a little bit
from the flow of the handout but that's okay.
Acetylcholine is another small molecule transmitter, its not an amino acid but it
is a small molecule. And acetylcholine has very important
activity both within the central nervous system and outside of the central nervous
system. Outside of the CNS, it's the major
excitatory neurotransmitter of our somatic motor neurons.
So, this is the neurotransmitter that's released on muscle fiber leading to the
contraction of muscles. It's also a major excitatory
neurotransmitter in autonomic ganglia and it's also the neurotransmitter of many
post ganglionic parasympathetic fibers. Within the brain itself, it seems to have
an important modulatory role that may be important in various cognitive functions
such as attention. Just as an example of how one such small
molecule neurotransmitter might be processed, let's take a closer look at a
cholinergic synapse, and so we have this illustrated here in figure 6.2.
And so, within the presynaptic compartment, we've got the metabolic
machinery that's necessary for producing acetylcholine.
In this case, acetylcholine is synthesized by an enzyme called choline
acetyltransferase from acetyl-CoA, one of the products of oxidative metabolism and
choline, a dietary compound that's important for various aspects of
nutrition and brain health. Well, acetylcholine is synthesized in the
presynaptic terminal packaged into synaptic vesicles, and then released in a
calcium dependent fashion. When acetylcholine is in the synaptic
cleft it can interact with post synaptic receptors which can be either of the
ionotropic or metabotropic variety. And once acetylcholine has been released
into the synaptic cleft, it can be degraded by an enzyme called
acetylcholinesterase. And when that happens, the choline
portion of the molecule is taken back up in to the presynaptic terminal and
recycled. To learn more about the function of a
typical cholinergic synapse and how all this works, you might want to view
animation 6.1 on our website. Now, before moving on to the biogenic
amines, let me just back up a moment and talk about the other important amino acid
neurotransmitters that we skipped over, namely the two at the bottom here, GABA
and glycine. So GABA is short for gama-aminobutyric
acid and it's a metabolite of glutamate so glutamate is in the bio synthetic
pathway for GABA. Glycine is a different amino acid.
Now, both of these amino acids typically have inhibitory activity in the mature
nervous system. We'll come back and say quite a bit more
about GABA as we go. But for now, let me just highlight that
GABA is the single most important transmitter in the brain that mediates
synaptic inhibition. Glycine is a very important
neurotransmitter. Especially, in the spinal cord where it
likewise mediates synaptic inhibition. Glycine also plays an important role at
synapses that release glutamate, where glycine serves as a cotransmitter whose
binding is important for the activity of one type of receptor for glutamate.
Okay, so now we're ready to move on to another class of small molecule
neurotransmitter. These are the biogenic amines and these
include molecules such as dopamine, norepinephrine, epinephrine seratonin,
otherwise known as indoleamine and histamine, based on yet a different
carbon ring structure. So these are all amine molecules that are
linked to some kind of a ring type of structure and they all have biological
activity in the nervous system that tends to modulate the activity of
neurocircuits. So unlike molecules like Glutamate and
GABA, that mediate rapid synaptic effects.
That appear to convey information, as information flows in neural circuits.
The biogenic amines, rather, modulate the way those circuits function.
And we'll talk more about them, when we see them in context, in structures such
as the basal ganglia of the forebrain. but it's worth emphasizing here that
these substances are very important in motivation and rewards systems, such as
the compound dopamine. Dopamine's also critical for modulating
movement in circuits such as the basal ganglia.
And it's involved in activation of circuits in the prefrontal cortex.
This is very important and helping to mediate various aspects of cognition.
Likewise norepinephrine is also very important in cognitive functioning.
It seems to be a part of what it means to pay attention is to have a heightened
release of norepinephrine, along with other molecules such as acetylcholine.
Another important small molecule transmitter among the biogenic means is
serotonin. And together with dopamine, seratonin and
dopamine together seem to account for many of the diagnostic categories that we
encounter in psychiatry and the human behavioral sciences.
In fact most of the drugs that are prescribed to treat psychiatric illness
act on modulating the activities of dopamine and serotonin synapses in the
brain.
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