Today's episode is all about excitation, also
known as excitatory neurons. Excitatory neurons
are part of this push -pull system of excitatory
and inhibitory neurons. Of course, excitation
is activation or start or go signals. We've recently
covered a few episodes on the inhibitory side,
the inactivating. or stop signals. Those are
episodes. Episode 76, parvalbium interneurons
and the autistic phenotype. Remember, parvalbium
interneurons are the most common inhibitory type
of neuron. These are very fast acting and often
the autistic phenotype has a deficiency or a
lack of in key areas such as the anterior insula.
the ACC, the dorsolateral prefrontal cortex,
and the thalamic reticular nucleus. Episode 82,
sonic hedgehog and inhibitory neurons in autism.
Episode 83, thalamic reticular nucleus or the
TRN, sensory gating and autism. In addition,
we have episodes four and five. a two -part series
about just general excitation and inhibitory.
The reason is this. The recent episodes are zooming
in to cover the specific cells and their roles
within the autistic phenotype. There is a significant
battle between this excitation and inhibition
imbalance. Excitatory Neuron are primarily pyramidal
neurons. And they release glutamate, the brain's
main excitatory neurotransmitter, to activate
postsynaptic neurons via AMPA and NMDA receptors.
Remember the spatial relationship of AMPA and
NMDA on the postsynaptic area. of the synaptic
cleft. These neurons drive neural activity and
promote information transmission and are critical
for sensory, cognitive, and motor functions.
Remember, overall, the human central nervous
system, the brain, has three main types of neurons,
sensory neurons, interneurons, and motor neurons.
In the autistic phenotype, excessive excitatory
activity contributes to an elevated excitation
inhibition ratio. And this leads to sensory hypersensitivity,
of course, cognitive deficits. The primary one
here is a lack of adaptive responses, not being
able to adapt properly or with a large toolbox,
if you will. in the social world. And also repetitive
behaviors. This black and white, these rigid
thinking, the fixated interests that are so called
abnormal in intensity or focus. This EI imbalance
contributes to these things. Overall, I don't
know, I can't comment on if the Autistic Phenotype
has an abundance of excitatory neurons. and or
a lack of inhibitory neurons. Now I know this,
the data are impressive on this. And based off
of the Reza Shadmir episode about the cerebellum
and the parv albium data, there are a lack of
inhibitory neurons, especially the parv albium
interneuron and the purgenji cells of the cerebellum.
There are indeed. a lack of those. I am unsure
if it's enough, if that's adequate enough to
cause this imbalance. Because another region
of interest is this, that hypo -connectivity
with distal connections of the brain, such as
the superior colliculus to the frontal eye fields
or the dorsolateral prefrontal cortex, there's
distal connections in the human brain and the
autistic phenotype struggles with that as well.
So the main cell type here in the excitatory
neurons is pyramidal neurons. This is characterized
by its shape, large triangular and extensive
dendritic trees and long axons for long range
connectivity. Now if you're wondering why it
is called pyramidal neurons it's because they
are it's nothing creative. It's nothing special
here. They just look like a pyramid. These excitatory
neurons act on those AMPA receptors and NMDA
receptors. This is glutamate. And those are both
ionotrophic receptor types, very fast. They're
faster than metabotrophic, which is glutamate
receptors. Mglu are one through five. These are
more modulatory. Now you might ask, and you ought
to ask, What are these excitatory neurons? How
are they different than the excitatory neurons
of neuromodulators such as acetylcholine and
dopamine? Remember dopamine has two receptors
that are excitatory and three receptors that
are inhibitory. And of course we have excitatory
dopamine and inhibitory dopamine. These are a
little bit different. Glutamate transmits information
in a fast like a light switch type of activity
here. It just it's instant. Neuromodulators determine
the processing. They modulate the excitability
to keep firing or keep paying attention and these
happen seconds to minutes versus the one millisecond
to 10 milliseconds of the AMPA and NMDA receptors.
The modulators are like a volume control. Or
if you have a adjustable light switch, we can
determine the lighting. The modulators are state
setting, determines your brain state, and determines
attention, motivation, and salience. So really
the process is these excitatory and inhibitory
neurons acting fast, within 1 to 10 milliseconds.
And then neuromodulators are on the scene within
10 to 30 seconds. And then, if we really want
to get into it, hormones are activated about
30 seconds on scene. Okay, with the pyramidal
neurons, there are little subtypes here. Layer
2 and 3 pyramidal neurons facilitate cortico
-cortical connectivity. So for example, visual
cortex 1 to the dorsolateral prefrontal cortex.
It's one of the most distal connections in the
brain, from the very back of the brain all the
way to the front of the top. That's the dorsolateral
part. And then layer five and six pyramidal neurons.
These project to subcortical structures such
as the thalamus, the striatum, thalamic reticular
nucleus and so forth. hippocampal pyramidal neurons,
or in CA1 and CA3, similar, very similar to the
inhibitory neurons that we discussed. This is
critical for memory. And we also have granule
cells. These are dentate gyrus of the hippocampus
cerebellar cortex and excitatory inputs to inhibitory
neurons. Remember, excitatory neurons and inhibitory
neurons can act on each other. The synaptic properties
here, the high synaptic plasticity via NMDA -dependent
long -term potentiation. These are huge for learning.
We'll cover learning shortly. And long -term
depression. This is modulated by BDNF. We'll
talk a little bit about brain -derived nootropic
factor in a bit. some brain regions associated
with the pyramidal neurons, the cerebral cortex
of course. Now pay attention to this because
these are very similar. They are identical to
the inhibitory neuron episode. So the dorsolateral
prefrontal cortex, the ventral medial prefrontal
cortex, the orbital frontal cortex. the anterior
cingulate cortex. Those are all very popular
in the podcast. We've discussed each one of those
regions. And the sensory cortices, primary, the
visual cortex one, and the subsequent layers.
Somatosensory cortex, remember S1. And the primary
auditory cortex, A1. We've discussed V1, S1 and
A1 and the inhibitory neuron episode. The insular
cortex as well, the anterior insula especially
and the posterior insula. The insula is a very
popular region of mine and of the podcast. Very
important. It's very privileged. And the temporal
cortex, especially the superior temporal gyrus.
Remember the Decoding the brain. How reading
works in autism and dyslexia. We talked about
the STG in quite detail. Inferior temporal cortex.
Huge for object recognition. And then the hippocampus.
The CA1 and CA3. And the dentite gyrus. And then
the amygdala. The basolateral amygdala. is heavily
populated with excitatory neurons and the cortical
amygdala, more for social behavior. Now, hard
stop here. The days of saying this region is
responsible for this, this region equals this
action, this behavior, this feeling, et cetera,
are over. Neuroscience has switched off of that
for great, great reason. It's more about neuro
correlates, networks. pathways, connections,
and so forth. Oftentimes even, such as this amygdala
example that we're using. Yes, it's fear, but
it's also the opposite of that. It is not about
the region. It's about the network and connections.
The amygdala is often the biggest misnomer, especially
with this so -called fear center. That term oversimplifies
its complex role in emotional processing and
does a disservice to its broader functionality.
And this is what we're going to cover right now.
It is a huge misnomer. While it's true that the
amygdala is critical in detecting and responding
to threats, rapid processing sensory cues to
trigger fear responses like an increased heart
rate or freezing. It is not solely detecting
Fear. This misnomer stems from early neuroscience
research, particularly studies on fear conditioning,
which highlight its role in associating stimuli
with danger. However, the amygdala's involvement
spans a wide range of emotional and cognitive
processing, making the so -called fear center
tag misleading. It's more accurate to view the
amygdala as an emotional hub. Hub is a very good
term and it's evaluating the significance of
experiences and coordinating the brain's response
to both positive and negative stimuli with fear
being just one piece of that puzzle. And remember
everything we've discussed recently about brain
waves sometimes called frequencies or oscillations.
The amygdala's functions are very diverse and
they encompass emotional processing, memory enhancement,
reward evaluation, and social behavior. The amygdala
assesses the emotional weight of stimuli, whether
it's a joy for something you like or you want,
you need, you love, or the thrill of a potential
reward. or some sort of social connection. And
this is integrating sensory input with internal
states, like mood or hunger. For instance, it
activates during rewarding experiences, such
as eating or social bonding. And it's interacting
with the brain's reward system, including the
ventral striatum, which in large part, the nucleus
accumbens. The nucleus accompanies the ventral
striatum in its very large brain region and dopamine
pathways. The amygdala strengthens memories tied
to significant events, both positive and negative.
And it makes these moments like remembering a
pleasant first thing, first experience of a certain
stimuli or a near -miss accident more vivid.
It kind of stamps these. In addition, the amygdala
decodes social cues like facial expressions to
gauge trust or affection. And it also collaborates
with regions like the prefrontal cortex and hippocampus
to regulate emotions and contextualize the experience.
One thing that really throws this misnomer gives
it strength, I should say. is the so -called
low road versus high road. And this is very true.
If you see a snake and you instantly jump back,
you're startled, you're alert, so forth. That's
the amygdala kind of lighting up because the
visual sensory makes a quick stop at the amygdala
for these things. And that's the low road. But
then eventually you think, oh, not a venomous
snake. that's not a copperhead that's a water
snake and then that's the high road kind of providing
context based off of memory based off of the
living organism really to say no need for startle
no need for this fear and by the way a copperhead
and water snakes are very similar they have this
black shape The Copperhead, this shape is in
the shape of a Hershey Kiss, a triangle. And
the Water Snake, it's more of a tornado, so it's
a upside down triangle. Or even sticking to the
theme of the episode, we could call it a pyramid,
based off of the pyramidal neuron. Hershey Kiss,
Copperhead. Tornado, Water Snake. Okay, we were
talking about brain regions, and I need to pivot
back. It's hard sometimes. So we finished up
the amygdala there. And also the striatum, the
caudate, and the putamen. So that's the dorsal
striatum. Remember the basal ganglia, the input
centers of the basal ganglia. That's our go -no
-go area. It's modulating response types. And
also the ventral striatum. that we just mentioned,
the nucleus accumbens. Pyramidal neurons are
dense in these three regions. The thalamus, of
course, the thalamus. Relay neurons and the lateral
geniculate nucleus, so remember vision, you should
know that's vision. The ventral basal complex,
which is VB, we'll talk more about that momentarily.
And the somatosensory. In addition in the thalamus,
the medial. Geniculate nucleus. This is auditory.
And the medial dorsal nucleus for cognitive and
emotional processing. And the cerebellum for
those granule cells. And this is the excitatory
inputs to purgenji cells. Okay, I know that's
a lot of nomenclature, a lot of dense neuroscience
and brain regions. But they're all very relevant
here. They're all important. if you wanna understand
certain phenotypes, like the autistic phenotype.
So the receptors, let's touch a little bit more
on the receptors, AMPA. These are very fast excitatory
transmissions, such as I was touched, and they
use sodium, potassium, and they are activated
one to five milliseconds. The NMDA receptors
use sodium potassium plus the calcium. These
are critical for synaptic plasticity to long
-term potentiation and long -term depression.
Remembering the texture of what was touched.
ANPA will say, I was touched. NMDA will say,
oh, I recognize that texture. I know what touched
me. and NMDA are slower. They open at roughly
10 milliseconds and stays open for longer, 50
to 200 milliseconds. And also the M -glutamate
receptors, M -Glu -Glu receptors, one through
five. This modulates excitability and plasticity
via G protein coupled signaling. These are metabotropic.
receptors. They are slower than the two previously
mentioned ionotropic receptors. And some interactions
here. These excitability receptors receive inhibitory
inputs from GABAergic interneurons, the parvalbium
interneuron, the somatostatin inhibitory neuron,
and the basal active intestinal peptide, the
calbindian, in the chalretinin and the purgenji
cells, all of those inhibitory neurons that we
previously discussed. This is via GABA -A, B,
and C receptors. A general role here for these
excitatory neurons and receptors to drive neural
activity for sensory processing, especially visual
cortex 1, somatosensory cortex 1 and auditory
cortex 1 and for cognitive functions especially
in the dorsolateral prefrontal cortex for emotional
regulation some regions of interest here are
the anterior insula and the amygdala and the
motor control remember the striatum and the cerebellum
they also facilitate synaptic plasticity for
learning and memory, huge. And they generate
gamma oscillations from the 30 to 80 Hertz range.
Remember, these are activating, telling us to
go. In coordination with parvalium interneurons.
In the autistic phenotype, there's an excessive
excitability, excitatory activity in the sensory
cortex. especially the visual cortex one, the
somatosensory cortex, and the auditory cortex.
We've covered this in great detail. This is due
to brain -derived nootropic factor -driven synaptic
enhancements and reduced inhibitory control.
And this elevates that gamma power, and it drives
sensory hypersensitivity. This impaired EI imbalance
in the dorsolateral prefrontal cortex and the
anterior insula reduces gamma synchrony and contributes
to cognitive and social deficits. Especially
remember those distal connections. It's a big
mismatch, a timing mismatch. Overactive corticostriatal
thalamic cortex circuits especially the orbital
frontal cortex in the striatum amplify repetitive
behaviors remember the basal ganglia is involved
there so what is the neurobiology and the purpose
this evolutionary aspects of excitatory neurons
information transmission is huge synaptic plasticity
These so -called network activations. This is
now and the future of neuroscience. Networks.
And the thalamic reticular nucleus interaction.
So excitatory inputs from cortical layer visual
cortex 1 pyramidal neurons to the thalamic reticular
nucleus modulate sensory gating and oscillatory
activity. It has to be a healthy balance here.
Just think about this push -pull tactic. So what's
the difference between typical and the autistic
phenotype with the excitatory neuron functions?
In large part, it's the get up and go, the activation
versus inactivation, orchestrating which regions
to turn on in addition with those neuromodulatory
cells. It's all a network here, an orchestra.
modulating movements and understanding, processing,
understanding your environment and what you're
going to do when you encounter these things in
the environment. And also with the brainwaves.
Remember the different brainwaves here. Each
wave range has different functions that has a
lot to do with brain states, bodily states. The
autistic function here. Let's start with the
sensory cortices. V1, S1, and A1. So the hyperactivity.
You can all understand the hyperactivity. Excessive
excitatory activity due to the enhanced pyramidal
neuron firing and the reduced parvalbum and somatostatin
inhibition. This must be a healthy balance. You
have to activate and inactivate. Activation and
inactivation happen simultaneously. An elevated
gamma power. Increased gamma power, especially
in that 30 to 80 Hertz, and V1, S1, and A1 is
very much a huge thing with the autistic phenotype.
This hijacks the sensory processing. What are
you paying attention to in the environment or
even within yourself? This is huge. This is why
the autistic phenotype has that attention to
detail. Remember the tree bark example and the
visual thinking. I believe episode two of visual
thinking. Think about a tree. Do you see the
tree or do you see specific details about different
trees? And in large part this is a source of
the visual thinking as well. This imbalance of
excitatory and inhibitory especially those early
connections. We get stuck. There's so much to
process right there. The rate of information
coming in is so fast. But then those distal connections
are huge. This so -called higher order regions
of the prefrontal cortex and so forth. Reduced
activity and synchrony because of this imbalance
of EI. I can't overstate this enough. If you
go from point A to point B, and let's say there
are five stops, that you have to make to reach
your destination. The autistic phenotype, let's
say the first two stops, we get there fast. So
fast versus the typical. But the final destination,
achieving and reaching that final destination,
the typicals will get there faster because there's
the disconnection. It's about the overall point
A to point B. How we get there differs. For the
autistic phenotype, it's skewed to the early
connections. We get there so fast. But the subsequent
stops. Especially, you know, to the prefrontal
cortex. You know that's a major region for how
we evolve and executive functioning. We get there
slow. And just think about neuroplasticity and
how we store memories and expectations. How do
you think this is going to build up with experience
and over a lifespan? Do you think this is going
to be stored as pleasant memories? Because mostly
what we're talking about is the social environment.
Internally, all good. No problems. It's actually
a huge benefit here. Remember, the biology that
gives us autism allows us to be comfortable within
ourself. That's the huge source or the top source
of the accelerated learning. We give ourselves
a chance. There's no internal conflict or barriers.
So some roles in learning with the excitatory
neurons. In large part, it has to do with the
synaptic plasticity. Remember, the brain doesn't
want to work. It just wants to respond. It responds
based on what it knows, what kind of connections
are being made and strengthened within each of
us. And that will be privileged. The brain doesn't
want to utilize other connections because that's
work. You might think about how change is hard
for the human being, and indeed it's true, but
think about it from the synaptic view. Look,
go inside the brain in the central nervous system
and view it from that perspective. this will
allow it to make better sense. Whenever we repeat
things, the so -called cells that fire together
wire together and the strengthening and the growth
of synoptic connections, that's the preferred
choice for the living organism. And then if you
add in the brain waves, if it's one trial learning
or gamma or high gamma, it's strengthening these
connections faster. That's why if you almost
get into an accident, a near -miss accident,
that's really heightened and it stamps your memory
much more than the previous time you drove to
work and there was no accident or close call.
The role of the brain -derived neutropic factor,
BDNF, enhances NMDA receptor function. This is
in large part the driving mechanism behind this.
BDNF is so huge, especially in the critical period.
Whenever children can just learn multiple languages,
like passively, with no problems, no disruptions.
In large part, BDNF is modulating that. It allows
it to happen. And if you think about the autistic
phenotype, altered plasticity, there's this so
-called hyperplasticity. because of the excessive
BDNF driven long -term potentiation especially
in V1, S1, and A1. This enhances sensory learning
leading to superior detailed oriented learning
like visual pattern recognition but it overall
reduced flexibility. In the hippocampus overactive
CA1, CA3 pyramidal neurons Due to that reduced
somatostatin and peripheral albium inhibition,
impaired pattern separation. This creates a rigid
memory encoding. Remember, these are all the
same areas that we discussed in the inhibition
episodes. Drosolateral prefrontal cortex impairment,
a reduced EI imbalance in this brain region impairs
working memory and associative learning. And
this contributes to that cognitive inflexibility
as well. The dysfunction in the thalamic reticular
nucleus, an impairment of parvalbian inhibition
in the visual and somatosensory and auditory
sectors, allows for excessive sensory input back
up to the cortex. Remember the thalamic cortical
pathway, enhancing sensory learning but overwhelming
cognitive circuits. In the limbic sector of the
TRN has a deficit because of the reduced dorsolateral
prefrontal cortex excitatory activity. This appears
attention and dependent learning. In the autistic
phenotype some strengths here is enhanced sensory
learning in those early visual, somatosensory,
and auditory networks. This is superior attention
to detail. Some challenges, though, are impaired,
creating inflexible, the lack of adaptive responses,
and leads to context -dependent learning. Just
tell us. Just be specific type of thing. So also
think about repetitive behaviors here and social
deficits as well. and OCD -like behaviors. OCD
and the autistic phenotype share some very similar
neural circuitry. Overactive excitatory inputs
in the corticostriatal thalamic cortex circuit.
Due to the reduced inhibition control, this amplifies
habitual learning and drives repetitive patterns.
Something as similar as tics, tourettes is over
excitation. We've talked about stereotypy. It's
a misnomer as well. It's like, it's defined.
If you look up the definition of stereotypy or
stereotypy, it will say purposeless behavior.
But there is very much a purpose of why these
repetitive behaviors and stemming and OCD like
tendencies, tics, tourettes, there's a purpose.
There's a reason. these things are happening.
Humans just define things so loosely without
even considering. So let's wrap up with the push
-pull analogy here. The goal signal explanation
of this push -pull. Excitatory neurons act as
the brain's goal signal, and this drives neural
activity to initiate and propagate information
processing. Glutamate releases via AMP or NMDA
receptors, and this depolarizes post -synaptic
neurons. While increasing, they're firing probability
and promoting, one, sensory processing, cognitive
processing, emotional processing, and motor output.
V1, S1, and A1 so visual, tactile, that touch,
and auditory stimuli. Cognitive processing, especially
in the prefrontal cortex. Pyramidal neurons support
attention and working memory. The emotional processing
centers. The basolateral amygdala is huge here
and the anterior insula drive emotional responses.
What are you paying attention to? There's a reason
why the insula is part of the default mode network
and the salience network. Motor output. The dorsal
striatum and even the ventral striatum with reward
learning. Then the cerebellar. These are motor
movements. Remember the dorsal striatum is our
input area and this will regulate and determine
action selection. In typical brains, this goal
signal is balanced, acting as a stop -slow signal.
You have limitations on how fast you can go.
In the autistic phenotype, that excessive goal
signal and the BDNF -driven excitatory enhancements
and the reduced inhibition amplify everything.
The 2003 paper from Rubenstein and Mike Merzenich,
who studies neuroplasticity, is a good foundation
to start with with this EI imbalance. An EI push
-pull analogy here is the push, the excitation.
Pyramidal neurons in the cortex and the thalamus
push neural activity forward, driving sensory
cognitive and emotional processing. The pull
system here, however, the inhibition, those inhibitory
cells and the purgenji cells pull this back.
It's a brake system. Collectively, they're working
as bumpers on, let's say, a bowling alley. And
this is all one, depending on the context and
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to the podcast, listening to the episode, please
feel free to leave a review or rating. In podcasting,
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