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.
Neural Circuits That Govern Sleep and Wakefulness, part 2
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Medical Neuroscience
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从本节课中
Complex Brain Functions: Sleep, Emotion and Addiction
In this concluding module of Medical Neuroscience, we will consider the neurobiology of sleep and the neurobiology of emotion, including addiction. Both topics involve explorations of complex, widely distributed systems in the forebrain and brainstem that modulate states of body and brain.
与讲师见面
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
There's a couple of other key players that I want to localize for you.
If we look into the medial part of the hypothalamus, we can identify some of
these clusters of cells. Here's our Suprachismatic nucleus sitting
right about the Optic chiasm, of course. And back in the posterior part of the
hypothalamus is where we find that tubero-mammillary nucleus, just dorsal to
the mammillary body. Now, our orexin neurons are those that
are producing this peptide that are involved in promoting the wakeful state.
And the orexin neurons are found in the lateral part of the hypothalamus.
So just a little bit deep to the wall there of the third ventricle.
Now, I want to also talk about this nucleus here, the ventrolateral preoptic
nucleus. So, this is a nucleus that's found In the
anterior part of the hypothalamus. And it's very important because it seems
to interact with structures in the posterior part of the hypothalamus,
specifically this tubero-mammillary nucleus.
And the ventral lateral preoptic area, or preoptic nucleus.
Has an antagonistic effect with respect to these orexin neurons.
So this preoptic area is going to try to suppress the activity of these
histaminergic neurons among some of our other activating neurons.
So there's a bit of a push and a pull that's happening here.
With the orexin neurons providing the push signal promoting wakefulness, and
this preoptic region providing the pull signal.
Which is trying to pull the brain into a state consistent with drowsiness and
eventually falling asleep. So schematically then, here's what this
might look like. So, here's our orexin neurons that are
sending excitatory signals, activating our brain stem reticular formation
neurons that are supporting wakefulness. As well as sending projections to the
posterior hypothalamus, where they're activating those histaminergic
projections. From the tuberomammillary nucleus
supporting the wakeful state. Now, these circuits are being antagonized
by this anterior part of the hypothalamus.
This ventral lateral pre-optic nucleus, which is suppressing the activity of this
tubero-mammillary nucleus. And likewise sending signals that have a
suppressive influence over our cholinergic neurons and our adrenergic
neurons and our serotonergic neurons of the brain stem.
So this transition, then, between being vigilant, being awake, being attentive,
and being a bit sleepy and being a bit drowsy.
Is likely playing out in the posterior hypothalamus, depending upon the balance
of these influences. Whether the sleep promoting system Is
winning or is the vigilance promoting system.
Now before I say a little bit more about this, I do want to share with you an
image that was taken by a student of mine just a few months ago in the brain
anatomy lab. And it's a very unusual look at this
beautiful. Structure right here, the locus
coeruleus. So thanks to Jonathan Wineholt who took
this picture, what I had a student do, actually not Jonathan but another
student. We were dissecting some human brains as a
way of learning human neuroanatomy. And I asked the student to make a
midsagittal cut with a large knife through this brain.
And the student was just a bit off the mid line.
But that turned out to be really fortuitous.
Because look at what we found when we looked into the brain stem, following
this parasagittal section. We found this beautiful band of dark
substance in the dorsal lateral tegmentum of the pons.
And what we're looking at here is a trail of pigment that is present in the cells
that produce norepinephrine. So this is, in fact Are Locus Serillius
which is a Latin term meaning blue spots. So, this is the, the blue spot in the
brain, or this is the dark substance. We also have some dark substance here on
the medial edge of the ventral tegmental layer and substantia nigra compacted
com-, complex in the midbrain. So we're actually seeing the dark
substance in two places here, in this Parasagittal preparation.
So thank you to Jonathan for sharing this picture with us and perhaps you'll have
opportunity one day to see the blue spot for yourself in the human brain.
So let's get back to talking about this balance between the sleep-promoting
systems and the wakefulness-promoting systems.
So one of the key factors in promoting a transition from being awake to being
asleep is the activation of this ventral lateral preoptic area of the
hypothalamus. It turns out that one substance that is
activating this region is the substance, Adenosine.
And sleep researchers tend to be really excited these days about finally
beginning to understand how Adenosine seems to be operating in promoting a
transition toward sleep. Of course, as you know, Adenosine is the
a in ATP, Adenosine Triphosphate, which is the main molecule that carries energy
in our brain cells. So as that phospate group is cleaved
energy is released, and that energy can be used to support a whole host of
metabolic function within brain cells. Well, as it turns out, we think, as our
brain cells are active during the day, and energy is being consumed at a higher
rate. Then ATP is being broken down into
Adenosine diphosphate, and eventually Adenosine monophosphate, and then finally
free Adenosine is available and is released from cells, and begins to
accumulate in the extracellular spaces. Well in the region just in front of the
hypothalamus called the basal forebrain, there are nuclei there that seem to be
sensitive to these rising levels of Adenosine.
So as Adenisone rises in this region of the basal forebrain, it drives activity
That is exciting these cells of the ventral lateral preoptic area.
So the basal forebrain then seems to play an important role in driving this sleep
promoting system that's coming out of the anterior hypothalamus.
Leading to a suppression of the posterior hypothalamus as well as these brainstem
nuclei that are otherwise responsible for maintaining.
alertness in the conscious state. And Adenosine has been conceptualized as
being a thermostat, of sorts, that is sensitive to the energy that's being
consumed by neurons. So as energy is being depleted by these
brain cells Adenosine is accumulating, signalling the body to drift off into a
state of quiescence, that is to falling asleep.
And as we progress through a typical night's sleep, adenosine levels fall
again. So this has led to the hypothesis that
adenosine is a kind of energy thermostat. In the basal forebrain region that is
indicating the expenditure of energy over a very long time scale, the time scale of
the daily rhythm. And this accumulating extracellular
Adenosine then, might be one of the proximal factors in promoting a
transition from wakefulness towards sleep.
Now, it's quite interesting that of course human cultures for thousands of
years have discovered that Xanthines like caffeine and Theophylline can block the
activity of Adenosine on the basal forebrain region.
Adenosine binds to Adenosine receptors, and caffeine and theophylline block these
receptors. So while Adenosine is accumulating the
impact of that accumulating Adenosine on the basal forebrain is mitigated by the
consumption of these caffeinated substances.
So those of us that find ourselves quite addicted to caffeine are trying to fight
our energy thermostat and I suspect in the long run that's probably not a, a
very wise lifestyle choice. So perhaps a little moderation is in
order here probably is in my lifestyle for certain.
[SOUND] Okay. Well, let's now turn to a bit of a closer
look at the rhythms that are generated at the neuronal level that are reflected at
the macroscopic level in our electroencephelographic depiction of
brain waves. So these rhythms reflect a bi-stable
condition of our thalamocortical projection neurons.
So these thalamocortical projection neurons basically exist in, in one of two
physiological States. they may be at times in an oscillatory
state, or they may be tonically active. And as it turns out, this oscillatory
state is the state that we find these cells in as we transition to deeper and
deeper levels of non-REM sleep. The active state of body and brain is
when these cells are then depolarized out of this oscillatory mode and are in a
more tonic, active state. Where they can faithfully transmit
information from their input sources through their thalamic relays to the
cortical regions that they innervate. Here's a look at these neurons in, these
two states. So, when an animal is asleep.
And we look at the recordings of membrane potential from a thalamocortical cell.
We see that these cells are oscillating. In a fairly slow rhythm there is a slow
depolarization envelope that hits threshold and then fires a series of
action potentials. And then that leads to a deep
hyper-polarization. So this is the oscillatory state.
The membrane potential is hyper-polarized.
And that hyper-polarization triggers a slow depolarizing envelope that is
attributable to the activation of a calcium ion channel.
And so this depolarizing envelope is actually a calcium spike, although it's
not particularly spiky. Because it has such a slow time course.
But as this depolarizing envelope proceeds, eventually a threshold is
reached for the activation of our much faster voltage gated Sodium and Potassium
channels. So when that threshold is reached,
Hodgkin Huxley style action potentials fire.
And that leads to a barrage of activity, a little burst of activity, that rides on
the top of that depolarizing envelope. And after that brief barrage of action
potentials, then the membrane potential hyper polarizes again beginning yet
another cycle. So this oscillatory mode is what explains
this slow wave hyper-synchronous behavior that can be observed in thalamocortical
systems while we fall into deeper levels of sleep.
Now, this hyperpolarized state is induced [SOUND] by withdrawal of these brain stem
inputs that are otherwise promoting depolarization.
So a withdrawal of cholinergic and adrenergic inputs to these thalamic
neurons causes them to slip into this hyperpolarized state.
Where this burst generating mode begins to take hold of the membrane potential of
these cells. And when these cells are oscillating,
they are not responding to the inputs that they might otherwise convey onto the
cerebral cortex. So this oscillatory mode is a means of
physiologically disconnecting the thalamus from the outside world.
And we think this is quite important because it helps us to not be distracted,
not be awakened, not be aroused by stimuli that's failed to reach some kind
of threshold of activation. So, obviously, that would be consistent
with, maintaining a sleeping condition even with some, lower level degree of
stimulus in the environment. Now, suppose there is a very strong
stimulus in the environment. That may be enough to sufficiently drive
afferent activity in the thalamic neurons.
To depolarize them out of this oscillatory mode.
Or, it might be sufficient to activate the brain stem systems that promote the
waking state. Through one means or another,
depolarizing these thalamocortical neurons will shift them out of their
oscillatory mode into a tonic firing mode.
And we see that here with this gradual depolarization of the membrane potential,
and in this instance, it was induced by activating brain stem inputs from the
cholinergic nuclei and from the locus coeruleus, and after these neurons have
been depolarized. Now, they can respond to sensory stimuli.
So this now is a barrage of action potentials.
That is driven by the presentation of a sensory stimulus to this sensory
thalamocortical neuron. So, the brain stem activating systems
associated with the cholinergic and the adrenergic populations are those that are
really critical. For inducing this state change in
thalamocortical neurons from this oscillatory mode to this tonic firing
mode. The oscilltory mode is a mode where the
thalamus is disconnected from the outisde world, and the tonic firing mode is when
the thalamus is now engaged and ready to faithfully transmit signals that it
receives. Through the ascending sensory pathways
that are running through the thalamus.
