For today's episode, we will cover a special
inhibitory neuron called the Parf Albium Interneuron.
We will cover a recent article by Fujima Etta
just released in late August 2025 in Cell Press,
a top journal for medicine and neuroscience titled
Parf Albium Interneurons in the insular cortex
control social familiarity and emotion recognition
Now if you know about cell press They have many
different types of journals. This one's called
cell reports However with all of these journals
Cell press really has a huge benefit in my opinion
because they release a graphical abstraction,
which is easy to follow, kind of a graphical
summary of the article, and some highlights.
Three to four, typically four bullet points.
It is almost like a cover letter for the article.
I love this page because it also provides room
for notes. I'll just read the highlights, the
four bullet points from this article now. A subset
of Insular parvalbian interneurons exhibits increased
activity during social interaction. Second one,
inhibiting parvalbian interneurons prevents the
loss of preference for familiar peers. Third,
inhibiting parvalbian interneurons impairs the
preference for stressed peers. And finally, the
fourth. Parvalbian interneurons modulate pyramidal
neuron activity related to social target preference.
And just a side note on the pyramidal neurons,
these are excitatory. So we have a dance here
between inhibitory, the parvalbian, and the pyramidal,
the excitations. We will recap several critical
areas here. The medial prefrontal cortex, the
insular cortex, the default mode network, and
remember the inhibition problem with the autistic
phenotype, the excitation, and inhibition balance.
In large part, the parvalbium interneuron is
helping this. It has a role in this. With autism,
there's high excitation and or low inhibition.
And for those really dedicated here, this cell
type has roles in the basal ganglia. We've covered
the basal ganglia in several, maybe four, five
episodes. Huge problem with the autistic phenotype.
And we will once again get into the saying at
all article released last year from UCLA on six
weeks old. These are human infants. six weeks
old study. We will parse this out and add layers
to this even more. Because something autism research,
in my opinion, fails to do is expand on these
good articles that are released and are meaningful.
What are we going to do with these articles now?
And finally, we will have a brief recap on a
protein, CNT, NAP2. which is heavily involved
in autism research and plays a big function here
with developing the autistic phenotype. We've
covered this in episodes four or five and with
Dr. Hannah Stevens. But first a word about Daylight
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for a 10 % off discount. Okay, the medial prefrontal
cortex. Remember, it's medial, meaning middle.
So evolutionarily, it came on board before the
lateral or basically before the outer surfaces,
the sides and the top of the prefrontal cortex.
Remember the human head, our brain above the
eyes. If you draw a line back from the eyes to
the back of the head, the occipital lobe, our
heads extend up and full like no other species.
So the medial prefrontal cortex, it is a huge
area for the internal calculators that we discuss.
It includes decision making, it considers risk
versus reward and future planning, conflict monitoring,
and error detection. A huge way the living organism
learns, grows, and evolves is updating from errors,
making errors, and then correcting them. This
is huge here in the medial prefrontal cortex,
which is basically adaptive responses. We have
a whole episode on this allowing the living organism
to adapt, shift, utilize healthy skills in real
time. Remember, The autism and medial prefrontal
cortex, whenever we are making healthy choices,
when we are utilizing our skills as a living
organism, the medial prefrontal cortex and specifically
the ACC anterior cingulate cortex lead the way.
They orchestrate all of these downstream movements
and behaviors that control even thoughts and
feelings. When we do not adaptively respond,
Our lower brain area overtakes the medial prefrontal
cortex. It kind of shuts it out, pushes it away.
So with adaptive responses, this is huge in autism.
Also, social cognition, which will be covered
in the main article for today, and self -referential
thinking, self -referential thoughts. That intense
dreamlike state autistics have, a specific region
of the ACC, which is in the medial prefrontal
cortex. The ACC is just a little subdivision
here. More on that in a future episode, how this
area is huge for those dreamlike states and visual
thinking. So you ought to be able to see some
emotional regulation. also happening here in
this medial prefrontal cortex area. So let's
discuss the insula, the insular cortex. It has
several subdivisions as well, subregions. Specifically
for today, we'll talk more about the anterior
insula. Now remember, the insula is a central
hub for analyzing emotional brain states, thoughts
and feelings even, bodily signals. those physiological
responses like heart rate and how you're breathing
if you're sweating how your gut feels it's receiving
all of that data as well and it's also incorporating
the environment what is going on on the outside
the interior insula integrates entire receptive
signals with those emotional and cognitive information
that contributes to these subjective experiences
it's involved with things like disgust or empathy,
and even some anxiety. Whenever those sub -regions
overtake the medial prefrontal cortex, the insula
will register that. Those physiological responses
happening in real time will be salient. And if
you remember the salience network, the insula,
especially this anterior part, is heavily involved
in the so -called salience network. which is
huge in that UCLA study and is huge in everybody's
life. An interesting consideration is the interior
insula also registers social cues specifically
with trust and fairness. Remember Katie Asher
coming on when Houston, she says that Houston
can detect evil at high rates and with high accuracy.
This is part of intuition. Autistics have an
outstanding intuition because of these brain
regions that we're discussing today and the anteroceptive
functions. The anteroceptive functions is a good
way of thinking about this. What is happening
on our insides? Okay, we should talk about the
parvalbumin interneurons. Remember, basically,
in the central nervous system, there are three...
main types of neurons, sensory neuron, motor
neuron, and interneuron. So the par of albium
interneurons can be seen as abbreviated as PVIN
in a lot of research. They are found in various
brain regions, including the cortex, these areas
that we're discussing today, the hippocampus,
which is a large part from memory, and the basal
ganglia. So with the inhibition, of course, they
are GABAergic, G -A -B -A GABA. What's interesting
about these P -V -I -Ns is the morphology and
they're often so called basket or chandelier
type cells, which means they have extensive axonal
arborization, which aids in the synapsis. These
parvalbium cells provide a strong inhibition
If you think about the level of strength or if
you want to layer these or rank these with excitation
cells or GABAergic cells, these parvalbiums are
strong and they are fast spiking with rapid action
potential in the gamma oscillation or the gamma
waves. This is as fast spiking as you can get.
This is because It provides precise timing and
neural responses. It synchronizes the excitation
inhibition. It helps modulate and control behaviors.
So of course there are some space and time domains
here because the living organism needs to adapt,
respond, and move throughout its environment
with great efficiency for those survival instincts,
for those goal -directed instincts. And these
PVINs are really, really, really zooming in and
showing how this is being conducted in our biology.
It's very, very fascinating. Okay, let's go into
that study. So the methodology here is very important
to look at when you're parsing out scientific
literature. So the researchers use microendoscopic
calcium imaging and chemogenetic manipulation
in mice. Yes, this study is going to be done
on mice. In neuroscience, there are kind of manipulations
that a model that people can follow. So their
animals, their subjects are very similar from
study to study, supposedly. The calcium imaging
enabled real -time observations of the neuronal
activity during social interactions, while the
chemo genetic tools allowed for selective inhibition
of the PVINs and that allowed them to assess
their functional role. Very fascinating. So the
study found that the PVINs with the social and
emotional processing are essential for encoding
social familiarity. So distinguishing family
versus Novel conspecifics. Remember these are
mice. I'm reminded of our oxytocin episode with
the two different types of oxytocin. Magnocellular
and parbocellular. And how each one of these
types of oxytocin kind of helps with the parental
bonding versus the peer -to -peer bonding. This
is exactly that. The study also shows emotional
recognition. So, responding to a stressed peer's
emotional state and a specific subset of these
PVINs show increased activity during peer interactions.
And this is highlighting their role in processing
social and emotional cues. Everything that we
just kind of outlined before we get into the
study is kind of showing that with the medial
prefrontal cortex, the ACC, the insula, and I've
added in the oxytocin now. Very, very fascinating.
Very, very much aligned with the autistic phenotype.
So some of the behavioral effects of these PVIN
whenever with these inhibition cells. So they
disrupted the mice's ability to reduce preference
for familiar peers and increase interactions
with stressed conspecifics. And this indicates
that the PVINs regulate context -dependent social
behaviors. Context -dependent here is so good.
And this modulates pyramidal neurons. We've discussed
pyramidal neurons during the spindle neuron episode.
So this interaction with PVINs in the pyramidal
neurons is specifically in the anterior insula.
allows the living organism to maintain a proper
excitation inhibition balance for adaptive social
exploration. I love this stuff. Stuff like this
is why I do the podcast. PVINs also dynamically
adjust for the pyramidal responses to ensure
appropriate neural circuit activity. These PVINs
are in large part disorchestrating. And it's
allowing the living organism to detect social
salience, more of that salience, and processing
emotional states. So good. Dysfunction in this
balance impairs the ability to prioritize novel
stimuli or respond to emotional cues that social
cues, such as the stress in others, and providing
a cellular mechanism for the social cognition.
deficits. Okay, the Sang et al article once again.
Salience Network connectivity is altered in six
weeks old infants at heightened likelihood for
developing autism. Now sometimes in autism research
there are high likelihood groups and atypical
likelihood groups. That's what this is saying.
This was released in April 2024. This was done
on 53 infants, 24 of which are high likelihood
for autism due to having an older sibling with
an already autism diagnosis, which is very questionable
even. It's hard to parse that out. And 29 at
typical likelihood with no family history. And
they used resting state functional magnetic resonance
imaging. RS fMRI at six weeks of age during natural
sleep. The focus here was on the salience network
connectivity, particularly the interactions with
sensorimotor regions. Now the sensorimotor regions
is at the top middle of your head. So if you
think about those distal connections sometimes
even with the midbrain, the mesencephalon or
these subcortical areas. That's a large distance.
A large part of the sensory motor region involves
sensory processing and movement. And then the
prefrontal regions, which includes the medial
prefrontal cortex. So the behavioral assessments
here, because they're just six weeks old at 12
months, included the autism observation scale
for infants, AOSI, and the early social communication
scale. infant toddler sensory profile. This is
helping evaluate the likelihood of and the connection
of the autistic phenotype to these subgroups
the likelihood versus the typical. So just right
away the key finding here is infants at high
likelihood for autism show stronger salience
network connectivity with those sensory motor
regions compared to the typical developing group
that showed stronger salience network connectivity
with the prefrontal regions including, you guessed
it, the medial prefrontal cortex. So there's
a trade -off here they're suggesting that there
was an inverse relationship between the salience
network connectivity to sensory motor and prefrontal
regions and the high likelihood influence with
the stronger sensory motor connection had weaker
salience network to prefrontal connectivity.
In addition, they found that the salience network
connectivity patterns for these at six weeks
old predicted behavioral outcomes at one year
old. And the stronger salience network sensory
motor connectivity is associated with increased
sensory over responsiveness, which is very common.
You can see this with the Autistic Phenotype.
See Autism and Sensory Processing, the two episodes
on that from Spring of 2025. In contrast, the
stronger salience network to the prefrontal connectivity
with specifics to the medial prefrontal cortex
predicted better social attention skills, such
as just initiating joint attention. And this
is all relevant for a future episode where we
parse out the precuneus and dive a little bit
deeper into visual thinking and the default mode
network. This is providing a bit of a foundation.
So tying in previous research on this salience
network kind of dysfunction with the autistic
phenotype. This is consistent and A 2013 study
reported hyper -connectivity with the salience
network in children with autism and achieved
78 % accuracy in classifying autism versus typical
based off of this salience network pattern. In
addition, a 2016 study linked increased salience
network connectivity with the sensory processing
areas And a different study in 2024 also found
the reduced salience network connectivity between
a rostral prefrontal cortex and the left cerebellum
and autism, alongside increased connectivity
between the right supramarginal gyrus and the
temporal regions, which linked these changes
to deficits in self -awareness and emotional
processing. Some other worthy mentions here with
the anterior insula. A 2010 study found that
reduced anterior insula activation correlates
with alexithymia. Alexithymia is the inability
to define, recognize your fillings. And this
is kind of common with the autistic phenotype.
Hyper -responsiveness to adverse stimuli was
also found in the insula cortex, suggesting altered
sensory -emotional integration, which is potentially
driven by these PVIN cells that we've discussed
today. The PVINs in the insula cortex, so reduced
PVINs in the insula cortex is observed in autism
mouse models. for instance with the CNT -NAP2
knockout studies. And this leads to impaired
inhibition control, which disrupts social processing,
which is very much in line with the Fujima study.
So since we mentioned it, this CNT -NAP2 is very
worthy of mentioning here. This organizes neural
circuits, most specifically at the synaptic level.
And also remember in previous episodes, episode
four or five, Neurorexin and Neuroligin, those
pre and post synaptic proteins and genes. CNT
-NAP also is involved with cell adhesion with
neurons and glia. And it regulates migration,
dendritic arborization. Remember some density
issues for the autistic phenotype. Specifically,
two areas of the dorsal striatum. The input area
of the basal ganglia, our no -go area. In autism,
the dorsal striatum has a lot of dendrites. More
ability to activate and be overwhelmed. Dr. Hannah
Stevens studies this. And also, the dendritic
issues with the thalamus. Remember autism, sensory
map, and serotonin. The thalamus in the autistic
phenotype typically isn't pruned correctly. CNT
-NAP2 also, and this is huge, balances excitation
and inhibition. This is huge in autism. Remember
the Rubenstein and Merzenich. paper in 2003 this
paper was released it's it's highly cited like
3200 citations and mike merzenek is a it's kind
of a leader for neuroplasticity how living organisms
are constructed what makes us who we are now
something relevant here because we mentioned
the oxytocin connection or the similarity let's
just say i don't know if it's related and this
ability to understand social cues and have social
familiarity with family versus peers. The medial
prefrontal cortex roll with social cognition.
Remember I mentioned this. There are consistent
findings with a reduction of PVINs in a hypofunction.
PVINs in the medial prefrontal cortex with autism.
A 2017 post -mortem study, these are excellent
types of studies, report 38 to 70 percent reduction
of PVINs in the prefrontal regions in autism,
which correlate with the social deficits. Now,
38 to 70 percent reduction is a wide range, but
significant in these mouse models. Remember,
we can standardize kind of these behavior models.
We can manipulate animals to have similar deficits,
be it autism or mania, depression, etc. In autism
mouse models, there's a PVIN hypofunction in
the medial prefrontal cortex that contributes
to rigid thinking. Okay, that's huge in autism
and often kind of hard to observe from the outside.
These autism diagnosis, these assessments, have
a hard time picking that up. And also impaired
social behavior. However, optogenetic, remember
Carl Dysaroff, optogenetic stimulation of these
medial prefrontal cortex, these PVIN cells, enhances
sociability. In other words, they can kind of
rescue these social deficits. And lastly on the
theory of mind think. Remember Sir Simon Barron
Cohen released this in 1985 and it kind of provided
a foundation, a direction forward about how we
should perceive the autistic phenotype. However,
there's a lot of errors with that. There are
a lot of errors. If you read the Canter paper,
those case studies They knew exactly what was
happening in the environment. And they were mostly
young. Boys. 3, 4, 5 years old. Remember the
girls were a little bit older. 7, 8, 9 or so
forth. But they knew exactly what was happening.
I don't want us to underestimate, overlook, the
interoception here of the autistic phenotype.
And this intuition. This ability to process sensory.
including within the self, including being able
to recognize what is happening. This is a trade
-off here. The sensory trade -off versus the
social trade -off. The autistic phenotype is
very comfortable within themselves. This is a
large part what is happening. The biology that
gives us autism allows us to be comfortable within
ourselves. This has massive benefits for learning
and understanding Do people understand that?
We are going to dive into this in great detail
in a future episode with the visual thinking
Because these regions are involved and how autistic
brain is similar to AI how there's massive amounts
of catalogs for different categories Massive
amounts of information being absorbed. This is
the autistic phenotype. This is what autism is.
If you're listening to the podcast, listening
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