Last week we considered the importance
of glutamatergic excitatory long-range projections.
We thought a little bit about how sensory information
came from the periphery and reached the neocortex
where it's believed that sensory percepts are generated.
The transmission of information turned out to depend upon
glutamatergic synapses,
and different brain areas were linked together
by long-range axonal projections.
So for example, there was an axon
that went from the skin to the brain stem
and would signal touch.
And there was another set of cells in the retina
that send long-range axonal projections
that release glutamate in the thalamus.
to signal sensory information.
And so you can imagine an easy scenario
where excitatory volleys of action potentials,
and sequential brain areas become activated, fire action potentials
in the downstream neurons, that then channel down axons
and then release glutamate upon another downstream target.
And that's easy to see how sequential steps of excitation
are useful for propagating sensory information.
It turns out that long-range GABAergic projections
are equally important in the brain,
and that's what we'll study in today's video.
So some parts of the brain like the neocortex
only have local GABAergic neurons,
ones that have a short axon
stretching maybe for a few hundred microns,
at least, predominantly.
However, other brain regions that also have GABAergic neurons in them
send long-range axonal projections out of that brain area,
and they then inhibit other nuclei in the brain,
and that's what we'll be studying today,
the long-range GABAergic projection neurons.
We're going to focus on three examples
of GABAergic projection neurons
that are present in the mammalian brain.
We'll discuss the neurons in the reticular nucleus of the thalamus.
They provide an interesting feedback inhibition to the main thalamus
and presumably are involved in filtering sensory signals
getting to the cortex.
We'll also discuss striatal projection neurons,
part of the basal ganglia, that are thought to be involved
in goal-directed motor control.
And finally, we'll discuss the GABAergic Purkinje cells
the sole output of the cerebellum
and how that's involved in sensory motor tuning.
We'll begin by thinking about the reticular nucleus of the thalamus.
And we'll consider it in the context of a sensory system
that we've already discussed.
The one that brings tactile information
from the whisker hairs on the snout of a rodent,
and bring it through to the somatosensory barrel cortex.
So the signalling pathway begins at the periphery,
we have whisker hairs that are embedded inside follicles,
movement of one of these whiskers, activating mechano-gated ion channels
causing an action potential to propagate down
the sensory neurons of the trigeminal nerve.
They release glutamate in the brain stem, in the principal trigeminal nucleus,
some of these neurons will fire an action potential,
that again, propagates down the axon and releases glutamate now
in the thalamus.
Some of the thalamic neurons then, will sense that glutamate,
depolarize and then in turn, fire an action potential
that then conveys the sensory information to the primary somatosensory cortex.
This is where we have this nice organization
of these dark stained structures here that correspond in a one to one mapping
with the layout of the whiskers on the face of the animal.
Now if we zoom in on this area in a little bit closer detail--
and that's what we see here,
we see again, the thalamic nucleus here,
the so called ventral posterior medial nucleus of the thalamus
that sends the axons up here,
and they then, innovate individual layers for barrels.
On their way, these thalamic neurons send off collaterals.
So the axon branches here, in a specific region here,
a new area for us called the nucleus reticularis.
And here, this is full of GABAergic neurons
and these GABAergic neurons cause a feedback inhibition
upon the thalamus.
Let's take a closer look at how that works.
We imagine the ventral posterior nucleus here,
shaded in red.
It contains a highly organized somatotopic map of the whiskers
so in the same way that the neocortex
has a map of the whiskers that is anatomically identifiable,
the ventral posterior medial nucleus of the thalamus
also has an anatomically identifiable whisker map.
And so for example, our C2 whisker representation here,
is found in the thalamus in the form of a C2 barreloid.
So the deflection of the C2 whisker causes some neurons here
in the ventral posterior nucleus to find action potential.
That action potential propagates down the axon of the thalamocortical neuron
towards the primary somatosensory cortex.
And that's where sensory percepts are thought to be generated.
On the way, it sends off axonal collaterals
that also release glutamate, but now, onto the GABAergic neurons
that are present inside the nucleus reticularis.
So an NRT neuron here will receive a glutamatergic input
when a VPM cell fires.
If sufficient amount of excitation comes from the VPM
the nuclear reticularis neurons, or at least some of them,
will fire action potentials in turn.
That then means that the axon of the nucleus reticularis neurons
becomes relevant,
and the axon comes back and in part, will innovate
exactly the area from where it received excitation.
And so there's a feedback inhibition
right onto the cells that initially were excited.
And so in the VPM, from this action potential,
we'll see a hyperpolarizing IPSP.
And it's a fast GABA(A) mediate inhibitory postsynaptic potential.
And so for now, imagine what's happening,
in general at the VPM
in terms of a deflection here that a whisker sensory input
that causes a depolarization action potential firing in the VPM cell.
And then, we'll have the nucleus reticularis
that then in turn, provides feedback inhibition
so we'll get an inhibitory postsynaptic potential here
from the VPM in terms of the membrane potential fluctuations.
And what this inhibitory postsynaptic potential does
is that it prevents action potential firing
outside a very narrow time window.
This IPSP very rapidly comes back
and inhibits the main thalamic projection neurons.
And that means that the timing of the action potentials
coming out of the thalamus,
have to occur with exquisite millisecond precision,
presumably providing important temporal information
for the primary somatosensory neocortex.
If this neuron was depolarizing more slowly,
and was trying to get to threshold,
it simply wouldn't make it.
because the IPSP would come in and curtail it.
And so only neurons that are strongly excited
fire action potentials.
And so there's a selection for the most active cells,
to propagate action potentials to the cortex,
and the ones that are less active, will be inhibited by
the rapid GABAergic feedback inhibtion.
In addition, the GABAergic neurons that are in the reticular nucleus
don't just provide feedback inhibiton
on to the location of where the excitation came from,
but much more broadly.
And so there's a surround inhibition that will then inhibit neurons
both sitting nearby in other whisker representations
but even in different thalamic nuclei.
And so there's a competition as it were,
for the flow of sensory information to the cortex
that in part is regulated by the nucleus reticularis.
The second long-range GABAergic projection
that we should consider, is from the basal ganglia.
In particular, we'll consider the striatum and substantia nigra
which are important components of the so called basal ganglia,
an interconnected set of brain nuclei.
And first, just to locate ourselves,
where we are on the brain,
we're going to look at the same slide as we were looking at before,
where we have the somatosensory thalamus,
we have the GABAergic reticular neurons,
we have the primary somatosensory cortex,
and of course, we have here,
our axons that go from thalamus to cortex.
In between, is a large area of the brain here
called the striatum.
And the striatum is full mainly of GABAergic projection neurons.
These GABAergic projection neurons receive the inputs--
the excitatory inputs,
from the cortex and also from higher thalamic areas.
So they won't get it from the DPM nucleus of the thalamus,
but from second order thalamic nuclei,
they also provide excitation onto these striatal projection neurons.
And so there are two major excitatory inputs
that arrive onto these striatal projection neurons.
The striatal projection neurons then project out of here--
by definition it's a projection neuron,
and they're GABAergic.
And this red blob here is suppose to indicate
this area of the striatum that sends the axons
out of the striatum
and innovate an area of the brain called the substantia nigra.
And in particular, they inhibit neurons
in the substantia nigra pars reticulata.
The substantia nigra pars reticulata also has GABAergic neurons in it
and they're also GABAergic projection neurons.
In fact, these neurons are tonicaly active,
so at rest, these cell here,
are firing action potentials at a high rate,
and they're inhibiting brain stem motor areas,
and so they prevent the animal from moving.
If neurons in the striatum become active,
these striatal projection neurons
will inhibit the substantia nigra pars reticulata
and then will allow these motor nuclei to become active
and drive movement.
And so there is a so called direct projection
of these GABAergic neurons that inhibit substantia nigra
and that in turn disinhibits motor neurons function
and that then allows goal-directed behavior.
The striatal projection neurons
received one further very interesting input
and that's the dopaminergic input also from the substantia nigra,
but from a different part of the substantia nigra
called substantia nigra pars compacta.
That's where the dopaminergic neurons of the midbrain are,
and by far, the largest majority of the axons--
the dopaminergic axons,
from the substantia nigra compacta innovate the striatum.
So this is a hot spot for dopamine in the brain.
And that dopamine is a very interesting signal
it's involved in reward signaling,
and motivating goal-directed behavior.
And indeed, the major function supposedly,
of the basal ganglia is to control goal-directed behavior.
The dopaminergic innovation of the striatum
occurs with volume transmission,
so the swellings along the dopaminergic axons
don't have tight postsynaptic appositions,
but rather they release a dopamine into the extra cell space,
the dopamine diffuses into the extra cellular space,
and it targets two major sources of receptors,
D1 receptors and D2 receptors.
And these it turns out, are expressed
on different types of neurons.
So there are two different GABAergic striatal projection neurons,
ones that express the D1 receptors,
and these indeed turn out to be the so called direct path
that inhibits the substantia nigra pars reticulata,
and form the goal pathway that tries to drive action.
The D2 spiny projection neurons,
the ones that express the D2 receptors,
form the so called indirect path,
where they inhibit the globus pallidus,
and the globus pallidus then in turn,
inhibits the substantia nigra pars reticulata.
And so here we've got two negative signs,
here we have just one negative sign,
and so this is a pathway that prevents movement,
a so called no-go pathway,
and so we have two different pathways,
a D1 direct projection from the striatal projection neurons
that enhances action,
and we have a D2 pathway that tries to prevent
movement of the animal.
And what's interesting about the way that the dopamine signal works,
upon the D1 and D2 receptors,
is that it has different forms of synaptic plasticity.
And so of course, the main inputs
that these striatal projection neurons get,
are glutamatergic inputs from the thalamus and cortex,
that's true of both the D1 and the D2 spiny projection neurons.
But the plasticity that occurs at these synapses
is quite different comparing the D1 and the D2 expressing cells.
Dopamine is released as a reward signal.
So when the animal is expecting reward,
then dopamine is released into the striatum
and it is thought to act as a reinforcement signal
that's useful for learning and synaptic plasticity.
It tries to encourage the animal to do what it's doing
because of this reward that's expected.
And that then enhances plasticity here
in the D1 goal pathway,
and it seems to have the opposite effect
on the D2 no-go pathway.
And so there's an interesting way, in which dopamine seems to be involved
as a rewards signal in terms of learning and synaptic plasticity
and seems to be one that enhances
the goal-directed actions of an animal
that lead to reward.
Obviously, a very interesting and useful learning signal.
The other reason to be interested in dopamine,
is that it has an important and major role in brain diseases.
And in particular, in Parkinson's disease
it seems to be the generation of the dopaminergic neurons
that seem to be the major cause of the symptoms of Parkinson's disease.
And the major symptoms of Parkinson's disease
are things like bradykinesia, slowness of movement,
and that might then be, because of a deficit here
in the D1 go pathway
where there's sort of a lack of self-motivated,
goal-directed movements
and that lack of dopamine might then be one of the causes
of why bradykinesia comes about in Parkinson's disease,
where the dopamine signal is missing.
The third long-range projection neuron that we'll think about,
are the Purkinje cells of the cerebellum.
And the cerebellum, this area here shaded in red,
in Latin cerebellum means "little brain",
and in some respects, it really is a bit
like a miniaturized version of the big, main brain.
And so the cortex sitting around here,
has projection neurons that are glutamatergic
and they then project and excite, deep brain areas.
In the cerebellum, there's also a cortical structure,
the cerebellar cortex,
that's where the Purkinje cells are located
and these are GABAergic neurons
and they inhibit the deep cerebellar nuclei.
And so that's interesting that we have the main, big brain
that has the cortex and cortical projection neurons
that use glutamate to excite other areas,
and we have the little brain, the cerebellum
that uses GABA
in terms of the GABAergic projection neurons
that leaves us and inhibit deep cerebellar nuceli.
And the cerebellum is thought to be involved
in sensory motor learning,
and also higher cognitive functions.
It receives sensory information
both from descending and ascending pathways,
and it uses that sensory information to find true motor output.
The cerebellar Purkinje cells are among the most beautiful
of the neurons in the mammalian brain.
They have these elaborate dentritic arborizations here,
you see in this drawing from over 100 years ago,
by one the heroes of neuroanatomy, Santiago Ramon y Cajal,
who used at that time, a new staining procedure
invented by Golgi,
and he studied many of the cell types of the mammalian brain
in exquisite detail, and indeed predicted
many of the circuit wiring diagrams of the brain
about how information would flow
from one brain area to another.
And here, he's drawn two Purkinje cells next to each other
with that elaborate dendritic arborizations
so these are the largest dendrites
that are present in the mammalian brain.
Here's a descending axon
from where it will project to the deep cerebellar nucei,
and release GABA,
and inhibit those deep cerebellar nucei.
And these Purkinje cells seem to be useful integrators
where they coordinate their sensory motor actions
of the mammalian brain.
So in this video, we've seen that some
GABAergic neurons have long-range axonal projections.
And in particular, we've considered three types
of long-range projection GABAergic neurons.
We've thought about the thalamic reticular neurons,
that have a role in feedback inhibition in the sensory thalamus,
and they probably have an interesting role there
in gating and filtering the sorts of sensory information
that are relayed to the neocortex.
We also discussed the GABAergic projection neurons
of the basal ganglia,
in particular the striatal projection neurons
that inhibit the substantia nigra,
and there, they're thought to have an interesting role
in goal-directed motor control.
And finally, we talked about the GABAergic Punkinje cells
that form the sole output neurons of the cerebellum,
where they inhibit the deep cerebellar nucei
uninvolved in fine tuning motor action.
And so, not only long-range excitatory neurons
have important roles in brain function,
but long-range GABAergic neurons
also play a significant role in governing the action
of the mammalian brain.