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.
Repair and Regeneration, part 1
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Medical Neuroscience
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The Changing Brain: The Brain Across the Lifespan
This module represents another turning point in Medical Neuroscience. Now that we have surveyed human neuroanatomy and our sensory and motor systems, we are ready to take a step back and consider how this magnificent central nervous system came to be the way that it is. We will also learn how the brain re-wires itself across the lifespan as genetic specification, experience-dependent plasticity and self-organization continue to interact, re-shaping the structure and function of neural circuits throughout the central nervous system.
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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
Before we talk about the response of the brain to direct injury of itself let's
just touch briefly on the mechanisms by which peripheral nerves respond to
injury. Well this is the good news part of the
story of regeneration of nervous tissue. With damage to a peripheral nerve, the
axon that has been injured has a significant capacity to regenerate.
And to reestablish a functional connection with the target of that axon.
So typically this is a process that unfolds in a sequence.
following an injury to a nerve, so for example we imagined there may be some
kind of surgical or traumatic injury to a peripheral nerve.
be it a spinal nerve or a cranial nerve. And what we see is a degeneration of the
distal portion of the axon. However, the entire nerve typically is
not lost. Rather the macrphages invade the region
and consume the debris in the wake of the injury.
but the schwann cells then, will proliferate.
And the proliferation of these schwann cells basically establishes a channel,
through which a regenerating axon might locate it's target.
And reestablish a functional connection. But along the way the schwann cells
really are the key mediators of regeneration and regrowth of this injured
axon. Because the schwann cells begin to
produce growth promoting substances. These growth promoting substances can
influence the expression of growth related genes in the cell body of these
neurons. And that can then induce the formation of
a growth cone. Which can then respond to local signals
that are produced by the schwann cells and laid into the extracellular matrix.
And thereby a growth cone can be reestablished, it could become modal, and
it could recognize adhesion molecules. And it could respond to other kinds of
inductive signals that are produced by these schwann cells that are now
proliferating. And reestablishing this channel through
which this growth cone can eventually find it's peripheral target.
Now once the growth cone does make it to the target.
Be it a muscle fiber or a ganglionic neuron in the case of preganglionic
visceral motor neuron for example. we have the capacity to reestablish a
synaptic connection. Now, this typically is not done with
perfect fidelity, so that the connections are never 100% of what was there
previously. And often the rules that shape the
connections, in the developing embryo, are recapitulated.
But perhaps not with the, uh,exact degree of precision, that was once possible.
So, as a consequence, one typically doesn't see full functional recovery with
peripheral nerve injury. I know in my case I have had some return
of sensation in the cutaneous surfaces. but I remain somewhat impaired in certain
motor functions involving the lower right regions of my face.
So at least following my injury to the mandibula division of trigeminal in some
branches of the facial motor nerve. I'm still awaiting the restoration of, of
full function of course, doing everything I can to rehabilitate this process.
But nevertheless, I think the realistic expectation is that the process of
re-innovation at best will be incomplete. Now, we are talking about the changing
brain across the lifespan. And, unfortunately, as we age, the
likelihood that we will encounter some kind of an injury.
That, changes the, the structure, or the integrity and the function of the nervous
system, is, is increasing. So, we're going to turn out attention now
to the way that the central nervous system responds to injury.
And as we'll see despite its best attempts to do so
There are active mechanisms that limit the regenerative capacity of the brain
and the spinal cord following injury or disease.
Well, there are essentially three ways that the central nervous system can be
injured. They can be injured through trauma, they
can be injured through hypoxia or ischemia.
That denies the brain of the oxygen or the blood flow that's necessary for full
neural functioning. And the brain can degenerate, under the
conditions that are consistent with a neurodegenerative disease.
In each if these three categories of central injury, there is often the acute
risk of the loss of neurons, right at the time of injury.
And this happens basically because of, of two considerations.
the first is excitotoxicity. And as you may remember from unit two in
the course, excitotoxicity refers to the destruction of neurons due to the release
of glutamate. And the interaction of glutamate with its
receptors that set off a sequence of events that leads to the lysis of cell.
So neurons can be excited to death by an elevated concentration of glutamate in
the extracellular fluids. Well, this can happen during acute injury
to the nervous system Because as brain tissue is damaged the
glutamate that 's found within cells is now released to the extracellular fluids.
But also there is typically an increase in electrical activity, which leads to an
increase in the synaptic release of glutamate.
So the direct release of glutamate from damaged cells, together with the synaptic
release of glutamate. Elevates this neurotransmitter to levels
that interact with the receptors on surviving neurons
To the point where dangerously high levels of intracellular calcium can
become establish in the postsynaptic neurons.
And with dramatically high levels of intracellular calcium, well beyond what
is physiological for inducing long-term potentiation for example.
These pathologically high levels of calcium can trigger a sequence of events
that leads to the programmed cell death of neurons.
This is a phenomenon that we call Apoptosis.
And we know more now about what these pathways are.
So as calcium enters through typically NMDA receptors for glutamate as well as
other signalling molecules related to damage to cells, to hypoxia, to stress.
even to the withdrawal of growth factors following injury.
these factors can interrupt the normal function of this signal called Bcl-2.
So when Bcl-2 is blocked, this allows a sequence of events to unfold.
That lead to the activation of this important enzyme, Caspase-3.
Caspase-3 is what can trigger this downstream set of mechanisms that leads
to program cell death. This involves the condensation of
chromosome, the fragmentation of DNA, and the destruction of nuclear membranes.
Now, lets consider what happens to these neurons that are just on the margins of
the injury. So we can consider this to be like the
shadowy margins of the infarcted brain tissue, following lets say a stroke of
traumatic brain injury. In fact we sometimes call this region of
tissue the pernumbra. So the penumbra means shadow.
The penumbra is a region of brain that has been stressed by the injury.
But these neurons have not necessarily been pushed into excitoxicity or
apoptosis, program cell death. So these neurons will survive but perhaps
many of their axons have been severed. And the question is what will happen to
this neurons? Do they have capacity to regenerate new
connections and restore some functional capacity.
Well, there is a mixed answer to this question that we're beginning to
understand. And part of the reason why the answer to
the question is mixed is that, it may depend upon where the axons are growing.
The axons that are trying to grow back through white matter have a much more
difficult time with regrowth and regeneration.
Than do the axons that are spreading out in the horizontal dimension within gray
matter itself, such as the cerebral cortex.
So let's first consider what's going on within the white matter.
Where the axons that might have supplied a long pathway such as, the corpus
callosum, or the corticospinal tract. Are going to have a very limited
capacity, to regenerate, and regrow, a normal axonal connection.
So let's think about why that might be the case.
So imagine that we have, some neurons in the cerebral cortex, that are extending
axons into some white matter structure. And if there's some region of injury now,
that affects these cells, so there's some injury to neurons within this region.
One of the most dramatic reactions that will happen around the margins of this
infarcted tissue, is proliferation of glial cells.
In fact, the proliferation is so intense that this local volume of brain becomes
congested by these glial cells and their processes.
And it's not just a physical congestion. But it's also an exuberant production of
chemical signals that have a negative effect on the growth potential of their
surviving neurons. Indeed if we look at what happens
following an injury within a white matter structure of the brain or the spinal
cord. What we see is a rather dramatic
reaction. first involving the infiltration of
microglia that will phagocytize the cellular debris.
Astrocytes become activated, and might likewise migrate into the area, and then
the oligodendrocytes themselves will proliferate.
And together these glial cells will form a scar of tissue.
That continues to produce substances that have a suppressive effect on the
development of a modal growth cone in the activation of growth promoting programs
by this injured neuron. So there are a variety of molecules that
are expressed by these glial, some of which are especially important and are
expressed by the oligodendrocytes themselves.
And among these molecules are integral membrane proteins such as this molecule
right here, this OMgp. Which stands for Oligodendrocyte-myelin
glycoprotein. And this integral membrane protein, MAG,
Myelin-associated glycoprotein. And then this intriguing protein that you
can read about in the textbook if you like called Nogo-A.
And what these integral membrane proteins seem to be doing, is inhibiting the
expression of growth promoting programs by injured neurons.
Now, in addition to these Integral membrane proteins.
There are secreted ligands that will interact with a variety of receptors,
that are expressed on the membranes of the axon.
And a growth cone that may be attempting to regenerate.
And these Ligands interacting with their receptors, seem to promote the collapse
of that growth count, and, and active inhibition of growth.
So one of the problems for the central regeneration of axons within compact
white matter within the brain and spinal cord is this active suppression of
growth. That's mediated via the signals that are
expressed on the surface of glial cells. So, once might imagine a variety of
strategies to try to overcome this. Either by suppressing these signals
through immunotherapy, or other kinds of pharmacological, therapy.
One might imagine providing a permissive environment.
That would provide a route for the regenerating axon to avoid this plethora
of signals that will actively suppress the growth and elongation of a
regenerating axon. Well, there are a variety of strategies
that have showed some limited success in animal models.
Unfortunately, we have yet to see dramatic success in any human studies.
But with ongoing study and ongoing discovery I think there is potential to
develop strategic interventions. That will overcome these intrinsic limits
on the capacity of central axons to regenerate.
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