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PROFESSOR: We were talking about the Papez circuit and
structures of the limbic system.
And we're going to come back to these in a little while.
But the limbic system and these
slides is in the midbrain.
The limbic midbrain areas you should be familiar with now,
central gray and ventral tegmental area.
And then we move forward, brain and hypothalamus.
Out in the hemispheres here, we're at the medial side, also
ventral, hippocampal formation.
This is retrosplenial cortex behind the corpus callosum.
It's a continuation of the cingulate cortex.
And this is the entorhinal area, which is a major route
into the hippocampus.
And we keep going forward.
Now, we're in the amygdala there.
It's in front of the ventral end of the hippocampus.
Whereas up here dorsally in the red, we have hippocampus,
the medial pallium.
It happens to be below the corpus callosum.
But you can imagine how if you followed this surface around,
it's continuous with this.
And then it's curled around there.
Sort of like the hem of a skirt there.
The callosal fibers felt develop later.
And they just happened to go through right there between
the cingulate and most of the hippocampus.
Then down here, we have hypothalamus again.
And going a little more forward in front of the
hypothalamus, we're in the so-called basal forebrain.
Just the rostral continuation of the hippocampus.
On the midline, it's become septal area.
And above the corpus callosum, it's cingulate gyrus.
Going the other direction, this is part
of the basal forebrain.
But out here, it's olfactory cortex.
As we have out here, too.
Just happen to have it on the other side.
Now in this diagram, it shows transcortical pathways to the
hypothalamus.
So it's showing something a little bit different.
We start with primary sensory areas of cortex.
They are connections.
And these are only the major connections.
There are longer connections going transcortically also.
But here, we're just grouping different cortical areas.
This is just an introduction to what we'll be dealing with
when we come to the neocortex.
So we start out with the specialized cortex, idiotypic.
Each looks different from the other.
They each have their own typical nature.
This is the primary sensory and the motor areas.
And from there, we connect with association areas that
are specific to one modality.
Specific to the motor area, specific to visual or to
auditory or to somatosensory.
And then the higher order association areas, they get
input from different unimodal areas.
So they're getting multimodal input.
This would include language areas, for example.
It is those areas, the seat of highest cognitive functions in
humans, those are the areas that connect to the paralimbic
areas, including the parahippocampal areas, the
cingulate gyrus.
And then they connect with the amygdala and hippocampus, as
well as some other areas that are part of the limbic system.
And these are closely tied to the hypothalamus.
Now that kind of progression, you will get to know as we
continue with this.
So now I want to ask this question.
How does the hypothalamus influence the neocortex?
And what kind of influences are we talking about?
First of all, the various limbic areas do project to the
dorsal thalamus, which as we know is the
gateway to the neocortex.
That's how the neocortex gets it sensory inputs.
That's how it gets inputs from the cerebellum and the corpus
striatum by way of the thalamus.
But all the MD, the medial dorsal nucleus, gets input
from limbic structures, including olfactory cortex,
which is where we encountered it before.
And it projects to the prefrontal cortex, this
orbital prefrontal area.
Now, the hypothalamus has other the ways of influencing
the neocortex.
It causes a gating of information that's going
through other thalamic areas.
And those circuits are a little bit complex.
I've outlined them a little bit in the--
I'm not used to this tablet PC yet.
And then if you look at the diagram of the Papez circuit,
there are circuits that involve multiple synapses that
reach the cortex through the Papez circuit here, from
mammillary bodies to anterior thalamus to cingulate, which
then has transcortical connections to
the association areas.
And it also has a multiple synaptic route from the
hypothalamus through the nearby septum to the
hippocampus and so forth.
And then finally, we have axon systems, we call them the
widespread or diffuse axon systems, that project without
much discrimination between different areas, to many
different cortical areas, like the basal nucleus, that
nucleus that degenerates in Alzheimer's disease.
It's found in the basal forebrain.
It uses acetylcholine as its transmitter.
And the axons go over the whole neocortex.
And there's also more recently discovered projections from
specific hypothalamic cell groups, similar to structures
in the brainstem for the caudal.
They use norepinephrine and serotonin.
They project very widely over the cortex.
So they have some kind of modulating influence.
Not only in sleep and waking, which of course is the most
obvious change in brain state that we experience, but many
other states as well.
And when we talked about states of the brain, I pointed
out the combination and the effects of these different
widespread systems.
You can get very many different general states of
the whole nervous system.
So here's a picture of the tweenbrain, the
hypothalamus down here.
And here I've put in colors, the dorsal thalamic cell
groups that project to the neocortex.
There's the geniculate body, LP, the ventral nucleus
getting somatosensory.
The auditory would be just behind this.
But there's the MD, on the other side of the lamina,
where we find the interlaminar nuclei, the old thalamus.
So there it is.
And the medial part of that gets input from the
hypothalamus, from olfactory cortex, from the basal
forebrain, from the amygdala, various structures of the
limbic system.
When we talk about mental state, we know a person's
mental state, his attitudes, his emotions can influence the
endocrine system.
That happens by way of the hypothalamus.
It's the major controller of the pituitary.
So when we're anxious for example, we secrete more
adrenocorticotrophic hormone.
More cortisone is circulating in our blood.
We know the hypothalamus influences mental state in
other ways.
For example, in neurosurgical procedures, if the person is
conscious, which they often are in neurosurgical
procedures, you get pretty drastic
effects on mental state.
Teuber, the founder of this department, used to like to
talk about a patient that he knew about, that he dealt with
a number of men who had various injuries in the Korean
War and some from World War II.
And he discussed one of these patients that had a fragment,
a shell fragment in the third ventricle.
So here's the third ventricle.
And the thalamus is oriented in this way.
The shell fragment would float there, in the
cerebral spinal fluid.
And when he would move around, it would cause some
stimulation, just by mechanical means.
There's the nearby hypothalamus.
And it was very common for that man to experience the
effects of irritation of the hypothalamus.
And he would start crying.
And when he first started experiencing this, he would
tell the doctors that it's something in me making me cry.
He said, I don't feel sad.
But it's crying in me.
But over time, it was very interesting, over time as he
experienced this more and more, he identified with that
state more and more.
And he really did feel sad.
And he did really feel upset.
Now, that tells us something perhaps about the nature of
identity and our identification with these
physical states.
That's a way that our higher functions can influence the
control of these portions of nervous system activity have
over our behavior.
We use the term autonomic nervous system in contrast to
the somatic nervous system.
And clinicians often call the somatic nervous system, the
voluntary nervous system, to distinguish voluntary and
involuntary.
And the problem with that is that even the autonomic
nervous system activities, we have some
voluntary control over.
We know this mainly because people, through training, can
gain a lot more control over it.
The most well-know and astounding, and many people
don't believe it, but I've read enough articles on it and
I have one book about this, if any of you are interested,
where certain yogis, not only Indian yogis, but others as
well, and also not all in India, some of them are
Tibetan, they gain a lot of control of their autonomic
nervous system.
They can control their heart rate.
They can even control body temperature.
Sometimes they can change the body temperature in one limb.
So this indicates that this is limited.
Well, how could that happen?
Well, we know the connections are there.
But they're not strong.
If you look at the nervous system connections for
reaching the motor cortex, it's pretty easy to understand
what's behind voluntary control of a hand movement or
something like that.
Of course, you can argue but what do we
even mean by voluntary.
It arises someplace in the brain, usually from the
motivational system.
But when it comes to the hypothalamus, the connections
are weaker, from the neocortex to the hypothalamus.
Nauta talks, in the readings that I've placed on the list,
about the relative importance of the more longer pathways
influencing autonomic nervous system and
the less direct pathways.
He argued for a greater importance of the short
connections, even though there are some long connections that
have evolved.
And let me just describe one experiment that illustrates
the functional effects of that.
Rudolf Thauer did a pretty interesting experiment,
interesting in several different regards, involving
lesions that affected hypothalamic outputs.
He did this in rabbits.
Rather than just cut off the hypothalamus from the more
caudal structures, and I talked before about, remember
the cat experiments where they separated the hypothalamus
from the midbrain.
And they could eliminate that connection.
And they could still, after a period of recovery anyway,
they could stimulate the midbrain and still get the
attack behaviors, the predatory attack.
Just from electrical stimulation,
they could that mood.
Well, Rudolf Thauer did a much more drastic experiment.
He placed a wire loop just caudal to the hypothalamus.
And then he had the wires protrude from the skull.
So he could pull the wires in very small amounts.
And if he pulled it all at once, he was all of a sudden
cut off all the connections, all at once between the
hypothalamus and the more caudal part of the brain.
If he did that, it was difficult even to keep the
animal alive.
He would totally lose his motivation.
He wouldn't initiate any behavior.
He lost much of the control of his autonomic nervous system.
Temperature regulation was terrible.
But he did the experiment then in a different way with some
of his rabbits.
He would pull it just a little bit at a time.
And every time he would do a little bit, he would cut off
more of the connections.
But the behavioral effects of each small increase in the
lesion were not very great.
And the animal would recover.
He kept doing that.
Each time the effect was small, even when he had almost
cut all of it.
And then he would finally finish it.
And the effect still was small.
And the animal would recover.
That effect in neurology is called the partial lesion
effect or multiple stage lesion effect,
where you do a lesion.
Can you think of an example that a doctor might encounter
fairly frequently that would show this effect for multiple
lesions, where you're going to get less of a behavioral
effective of the lesion?
Yeah?
AUDIENCE: Like a
neurodegenerative disease or something.
PROFESSOR: It could be a nerve degenerative disease.
What else?
AUDIENCE: A tumor growing.
PROFESSOR: A tumor growing.
Exactly.
Even when neurodegenerative diseases usually
happen rather slowly.
In Parkinson's disease, people lose more and more of their
dopamine cells.
If they lost 80% of those cells, or let's say 70%.
If they lost 70% all at once, it would cause a drastic
effect on the corpus striatum.
And they would show all kinds of Parkinson's symptoms.
But people experience the loss of those cells, of the
dopamine cells in the
substantia nigra, very gradually.
So you don't start seeing Parkinson's symptoms until
they've lost about 80% of those cells.
And we'll come back to that when we get to the more
specific discussion of the striatal connections.
So that's what we're dealing with here.
It shows that it's not those long connections of the
hypothalamus that are so critical.
It's many, many short connections at all levels of
the autonomic nervous system.
And yes, you lose some higher control when you cut off all
the connections.
But if you do it gradually, you're going to get the
smallest effect.
And the animal functions pretty well and maintains a
lot of his motivational functions.
And people that study the effects of brain and behavior
need to know about these things if you want to
understand the nature of lesions,
how they affect behavior.
Remember, we talked about the diaschisis effects of lesions.
And that's really what we're dealing with here.
Let's just review a couple things.
Hypothalamic control, the two divisions of the pituitary.
This is the Brodal picture I used before.
You see that a little better?
So here's these two nuclei in the hypothalamus that send
their protein production down the axon to a synaptic-like
structure that ends on blood vessels.
It's secreted.
This is the vasopressin or
antidiuretic hormone and oxytocin.
What does oxytocin do?
Anybody?
AUDIENCE: Does it like cause oxytocin release?
PROFESSOR: Yes.
It actually has two different functions in women.
It causes milk secretions.
That's the milk let-down reflex.
It's a neural, hormonal reflex.
The stimulation from the nipple has
to reach these cells.
Both of these groups secrete both of the substances,
although one is specializing more in one,
and one in the other.
And that releases the oxytocin and causes the milk let-down.
And what's the other function?
And these do interact a little bit.
Not too much.
The other function?
AUDIENCE: Bonding.
PROFESSOR: It is known to have these effects too.
This is a very interesting one that we know less about.
Well, what's the other one I'm thinking of?
AUDIENCE: I was going to say emotions.
PROFESSOR: Contraction of the uterus.
A commercial name is Pitocin.
But it's oxytocin.
It's the hormone oxytocin.
And that's how they induce labor,
injections of this stuff.
But this is when it happens naturally.
It happens through these cells.
And this just shows the bloodstream
there and the capillary.
And here's the anterior pituitary, which is a
glandular structure that does not get innervated.
There are no axons coming in there.
But there are blood vessels coming from this capillary bed
in the median eminence region of the hypothalamus.
And there axons are terminating on those blood
vessels too.
They're coming primarily from the arcuate nucleus.
But there's others too that are secreting releasing
hormones that cause release of substances like
adrenocorticotrophic hormone or gonadotropins into the
bloodstream.
Here, I'm just reminding you when we first encountered
these pathways of the limbic system, we were calling them
the medial forebrain bundle.
I followed it from the limbic system structures, including
the hippocampus here, the basal forebrain.
They're also coming from hypothalamus.
And here are all these axons.
They cover all this region.
That's medial forebrain bundle.
And where are they ending up?
They're ending up here in the ventral tegmental area and in
the central brain.
The other one coming from the neocortex and corpus striatum.
And I show that here.
The fibers from the corpus striatum and from the
neocortex coming into the more lateral forebrain bundle.
We just call that the internal capsule, fibers from the
cortex coming through the striatum and then down to the
brain stem and spinal cord.
So there are the limbic structures of the midbrain and
the tweenbrain.
And remember with hypothalamus, we also include
epithalamus there.
Often it's called the habenula in mammals and
non-mammals as well.
And this is a finding of a number of studies that show
specificity in the midbrain system.
This is just the central gray region of the midbrain.
They've eliminated the rest of the midbrain.
Here's the ventricle, the hole in the middle here, with the
cerebrospinal fluid.
In front of this would be the tweenbrain.
This is all midbrain.
And they're showing that different regions within the
central gray control different kinds of functions.
Defensive behavior, effects on blood flow in different parts
of the body, on the lateral region here.
Also you can get effects on hypertension, rapid heartbeat,
and so forth.
So there is autonomic effects and behavioral effects.
And then there's also been discovered a sexual column.
You produce sexual motivations from stimulating that area.
That wasn't so surprising considering Rudolf Thauer's
results, where he had separated the hypothalamus and
he could get animals functioning so normally.
They had to have representations.
The same things that were in the hypothalamus, they had in
the midbrain too.
So why do you need a hypothalamus?
For a number of reasons.
Hypothalamic neurons are responding to substances in
the blood, like body temperature.
So you've got better temperature control if you've
got a hypothalamus.
And you have a lot of ability for endbrain structures to
modulate by their connections from the limbic structure to
the endbrain to the hypothalamus, which then
influences these lower levels.
So you lose a lot of that if you get to the midbrain.
But you still have a lot of brainstem inputs to it, so the
animal can still function pretty well.
Even though Rumi wrote about religious attitudes, I like
his poetry and relevance to neuroscience too.
So we're going to continue with this now by talking more
specifically about hormonal influences on brain
development and brain function.
We'll talk a little bit about sexual differentiation of the
hypothalamus.
And though I'll focus on humans, a lot of the studies
have been done in the rodents, and in birds as well.
Some of these studies have been applied in recent years
to studies of sexual orientation, sexual
attraction.
And then the studies of bird song, which I mention when we
talk about the auditory system.
We'll now focus on hormonal and other determinants of bird
song and the brain structures controlling it.
That includes cycles of neurogenesis in the adult
bird, neurogenesis and cell death.
Also there's evidence for estrogen actions.
The original studies focused on testosterone effects.
But then now estrogens affect development as well.
And there's some evidence that they act through affecting
trophins, these growth hormones.
We call them the trophin family.
And there are trophin receptors.
Some of that work has been done with organotypic
cultures, including cultures of cortical tissue and
hypothalamic tissue.
We know the dopamine system is affected by such steroids.
Though some of that, it's not too well know
exactly how that works.
I also want to mention at this point that there's other
hormones besides sex hormones.
I'm focusing on the sex hormones.
But thyroid hormones for example are important in brain
development.
There's pretty strong changes during a normal pregnancy of
effects on thyroid function, increased blood concentrations
of T4-binding globulin.
There's increased demands for iodine to
produce the thyroid hormones.
And we know the thyroid is stimulated by chorionic
gonadotrophin.
Gonadotrophins are produced by the chorion, which is the
outermost membrane of the placenta.
And that hormone is used in treating some dysfunctions
involving the gonads because of their stimulatory
properties.
Did I mention this before, the effects of pollutants?
But these polychlorinated biphenyls, for example in
dioxin, they're pollutants that cause brain abnormalities
because they bind to thyroid receptors,
thyroid hormone receptors.
Because they're structurally similar to thyroid hormones.
And that was the finding that led a student of mine, Eric
Montie, to begin his studies of sea mammals, because he was
interested in the effects of these pollutants getting into
the ocean and affecting brain development in
developing sea mammals.
And he's branched out to include other kinds of
pollutants that effect for example the
California sea lions.
But these pollutants come from natural sources, from algae in
the California shores.
And these are just references for that stuff.
And now, there are three papers, or I guess two in the
literature already and one being
published from Eric's work.
And there's actually other papers too.
But there's three that I'm one of the co-authors.
When you talk about sexual orientation, whether you're
going to grow up preferring the opposite sex or the same
sex, people always are interested in well, how much
are genes influencing it, how much are hormones influencing
it, how much is the environment influencing it?
The environment includes the way your parents treated you.
And of course, these things are studied
with animals as well.
So that's the question I'm asking.
And I put this paper, I found it.
Some of you might have seen it earlier, because it was down
on the imported documents.
But he reviews studies that show pretty strong support for
both genetic and hormonal influences.
But the social influences, in spite of many studies that
have tried to demonstrate them, don't show much.
There's very little support for that.
It's almost all genetic and hormonal.
Neurologists and psychiatrists have collected data on various
human pathologies that show very strong sex differences,
both neurological and psychiatric disease.
That can only be if the brains are different.
So just without even studying the brain's morphology or
molecular biology, we know the brains have to be different.
Because here I've put the percentage of female to male
in these various diseases.
Look at anorexia nervosa or bulimia,
these eating disorders.
Anorexia, 93% female; only 7% male.
And there's more references than this.
But this is the ones I took from the Swabb paper.
One type of schizophrenia, a schizophrenia that occurred in
children born during this period, a particular period in
Dutch history, 72% of the schizophrenics that came from
that period were women.
Many more women are anxious as well or depressed, as you see
at least in statistics collected down.
I think it's still true.
But now, everything below that line, males are more down.
And they're even from the first one, severe mental
retardation, much more common in males.
Autism more common in males, stuttering.
Schizophrenia is actually more males than females.
This was one type of schizophrenia.
That just indicates the diversity of types of
schizophrenia.
So when you group them all, environment that
there's more males.
Dyslexia, sleep apnea, and Tourette's syndrome, all have
more males than females here.
All of that indicates differences in the brain.
So let's talk about now one of the major effects on brain
development is gonadal hormones.
And I want to just answer these two questions.
When are the sex differences in gonadal hormones at a peak
in human development?
And that occurs in three different areas.
One is early in gestation.
And that's when the gonads are forming.
So without the hormonal differences, the fetus would
grow up looking like a female.
But with testosterone early on, testosterone from the
testes, you get the male genitalia forming.
And again, they peak perinatally.
And then they're not so different
anymore until puberty.
Now if we look at the differences in the brain, one
of the first areas that were clear in the brain was the
sexually dimorphic nucleus in the anterior preoptic area of
the hypothalamus.
And there were studies done plotting the cell number in
that sexually dimorphic nucleus as a function of age.
Here's the age line, age after conception.
So there's birth, right there.
And you can see that the differences didn't really
become clear until after age four.
So even though, way back here, at the beginning, in that
first half of gestation, this period, the hormonal
differences were great.
No varying differences yet in the early period.
No differences, even though here at birth the hormonal
differences were considerable again.
And they're not going to be really
different until this region.
This is puberty, in here.
And yet the differences are appearing before puberty.
So what does that say about what's affecting the brain
differences?
Well, maybe we focused a little too much just on the
hormonal differences.
Although this of course doesn't prove, because the
hormones acting in this period could still be producing the
later morphological differences.
I just want to point out one of the problems that some of
the early studies were simply getting sections of the brain
in humans and looking at relative volume of different
cell groups.
And the problem with that is with humans, you don't get
good fixation normally.
I mentioned this once before I think.
So there are various kinds of tissue decay going on, various
amounts of time before the tissue is fixed.
And of course the nature of the fixative used, the speed
at which it gets into the tissue, it's
going to vary a lot.
So the only way to really overcome that is if you can
identify in a cell stain, in spite of the degradation of
the tissues, if you can identify the cells, you can
count cells.
It's not easy to do.
It's a lot of work.
But now with more automated methods, they can do that a
lot faster.
So they're able to collect more data.
What's the other method?
Don't use post-partum.
Use living brains.
Use imaging methods.
The problem there is resolution.
There is work going on here, in this department.
Alan Jasanoff is doing that, in improving the resolution of
imaging methods.
So we're still not close to what we can do with
histological methods.
I will probably make a trip to Florida this summer to work
with Eric Montie, that I do this work in sea mammals with.
Because I want to be able to see the actual brain.
He has the brain of the sea lion now that they did the
imaging when the animal was alive.
And I want to see the actual sections.
See the cell stains.
And then we can get more data.
But I do think, and I'll mention that again here, they
are getting more and more data relevant to the same questions
now, from the imaging methods.
So I want to talk about other cell groups besides the
sexually dimorphic nucleus, the anterior hypothalamus.
And then I want to ask if it's different in heterosexuals and
homosexuals?
The role of the hypothalamus in sexual orientation has been
a big question in this field.
A few years ago, in rats, there was a study of the
nucleus we've mentioned before when we talked about the
visual system, the suprachiasmatic nucleus, known
to be involved in controlling circadian rhythms.
And here's a drawing of the human hyopothalamic region.
This is the optic chiasm.
And right above the chiasm, you have the
suprachiasmatic nucleus.
And this particular component here, this is rather anterior.
And this nucleus runs considerably more
posterior than this.
But there's one particular subnucleus within that, the
vasopressin containing subnucleus.
And that nucleus has been found in rats
to be sexually dimorphic.
That's where it was first discovered.
Then it was found likewise in humans.
And here is the sexually dimorphic nucleus we first
talked about.
And here is another one.
And this one is interesting, because it's also different
between heterosexual and homosexual men.
And so that's just one of the morphological studies.
A lot of this work was initiated actually by a gay
man who is well-known in neuroscience.
We all like him a lot.
He was here in Boston for a long time.
And then he moved out to California.
If you look in the literature on sex differences in the
brain, a lot of the early studies were done here in
Boston by this fellow.
Now, that section is right at this level, between
levels two and three.
So here we're in front of the optic chiasm.
Here we're behind the optic chiasm.
There's the optic tract there.
So that's the level we're at in the brain.
So what we'll talk about next time is we're going to talk
about canary brain and how it changes from season to season.
What's involved with that.
Initially, we thought it was all hormonal.
But now we know that experience also plays a major
role in these morphological differences.
So we'll take it up from there.