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THURSDAY, April 1, 2004

Session 2: Neuroscience, Brain, and Behavior I: Brain Development in Children

Thomas M. Jessell, Ph.D., Professor of Biochemistry and Molecular Biophysics, Columbia University, and Investigator, Howard Hughes Medical Institute

CHAIRMAN KASS:  Session 2 of our meeting, Neuroscience, Brain, and Behavior I: Brain Development in Children.  From reproduction and the beginning of bodily life to the brain and the functions and flourishing of mental and emotional life.  Everyone senses the great excitement of neuroscience and modern psychology, methodical investigations by the mind of the mind to increase the human understanding of the human, prospects for addressing mental illness and aberrant behavior, and improving our abilities to make the most of our native mental capacities.  Everyone also vaguely senses that those exciting new discoveries might be accompanied by new ethical, social, and philosophical challenges precisely because these studies touch so directly on many of the powers and activities that make us who we are: awareness, memory, imagination, desire, motivation, thought, feeling, and moral judgment itself.

The Council is interested in learning about the developments in neuroscience and psychology present and projected that might raise significant ethical and social issues either because of the technological interventions to which they might lead, or because of changes in human self-understanding that they might invite.  In our Beyond Therapy report, we explored some of the psychotropic drugs that alter behavior, memory, and mood, in the service of goals beyond therapy.  But we sense that this was just one of a number of challenging issues that might emerge from this field.  At the last meeting we got a beginning in this area with introductory presentations from Robert Michaels on neuropsychiatry, by Jonathan Cohen on brain imaging and reward and decision, and you'll recall that we decided at that meeting before proceeding further to find out which aspects of this large domain were most worthy of our attention, that we should try to learn something about just the foundations, about normal brain and mental development, especially in children.  So today and the rest of today is about those foundations, the scientific foundations of normal brain and mental development in infants and in children.

The questions behind these discussions are really these.  What can neuroscience and developmental psychology tell us, either now or soon, that might be relevant for understanding how best to raise flourishing children and adults?  What can neuroscience and developmental psychology tell us that might be relevant for understanding and preventing disordered or dysfunctional children or adults?  But the explicit discussion, as opposed to these larger questions, the explicit discussion will be the science itself, neuroscience in the morning, psychology in the afternoon, and at the end of the day we'll have a chance to take stock of what we have done and how far we have come.

It's my great pleasure to welcome Dr. Thomas Jessell who is Professor of Biochemistry and Molecular Biophysics, the Center for Neurobiology and Behavior, and Howard Hughes Investigator, at Columbia University.  He is a distinguished researcher in the field of brain development.  It's a great pleasure to welcome you to the Council.  Apologies for detaining you, and we very much look forward to your presentation.  Dr. Jessell has asked me to announce that he would very much welcome our interruptions if we have questions or things on clarity.  He wants to make sure that we're following.  Dr. Jessell, the floor is yours, and thank you again.

DOCTOR JESSELL:  Well, first I would like to thank Dr. Kass for this opportunity to participate in this discussion of brain science and its relation to behavior.  And just to echo these comments that I really would encourage interruptions, comment, dissent, clarification.  If I lapse into jargon, then please bring me back to clarity.

Perhaps in the light of the first session this morning, an interesting place to start this discussion is in fact early in embryonic development, because it's at a relatively early stage in development that nervous systems form, that nerve cells are generated, and that those nerve cells begin to acquire identities that drive the subsequent formation of connections within the developing brain.  And one of the things that I'd like to suggest or argue in my comments this morning is that to a large extent the precision with which those connections form governs the intrinsic behavior or repertoire of any organism, whether it be a child, any type of mammalian organism, even lowly invertebrates.  Behavior is in large part dependent on the nature of the circuits that exist within those nervous systems. 

Now that is not to say that the wiring diagram, if you like, of the nervous system is the only determinant of behavior.  I think we've understood for many years that this provides an architectural substrate upon which environment and experience then mold those connections and refine those connections to produce the full, rich repertoire of behaviors that any given organism is characterized by.

So one of the things I'd like to discuss this morning initially at a relatively reductionist level is really to review what the field in general has learned about the nature of brain development during embryogenesis and postnatal development.  What is the relationship between genes, neurons, circuits, and behavior?  What are the molecular determinants that begin to establish the structure of the nervous system?  Then discuss the interplay between these genetic programs and environmental influences.  When does the nervous system cease to develop, if you like.  When is the pattern of connections established in a way that cannot be changed?  And our views on that have also changed rather dramatically over the last 10 to 20 years.  So we're dealing with questions of plasticity of the nervous system in relation to circuits and the way that those circuits influence behavior.  So these are all normal developmental processes, if you like, and perhaps if we have time at the end I will turn to the way in which those normal developmental processes become subverted in brain disease, in various types of neurological and psychological, psychiatric disorders.  Now those are very large problems, so I think at best I will be really scratching the surface on some of those later issues.

So just to put things into a general context.  Now, I hope that everybody can see some of these images, because some of my comments will really be dependent on them.  And those on my left are in danger of being attacked by this laser pointer, but I think we're working at the moment.  So what you are looking here is in very superficial terms the process of human brain development as a function of the nine months of gestation.  And so somewhere within the third to fourth week, the nervous system begins to form.  So cells in one of the major germ layers of the embryo, the ectoderm, make a decision that they're going to acquire neural character as opposed, for example, to acquiring the properties that eventually give rise to skin.  So the first steps in the formation of the nervous system occur at a surprising early stage.  And then as you can see because this is drawn relatively to scale, what happens over the subsequent eight months of embryonic development is a process by which the nervous system at least in large part accumulates large numbers of cells.  So the nervous system is exceedingly small at these early stages, but as you can see, by the time an embryo is born at nine months of gestation, there is a very highly organized nervous system which is much, much larger than the anlage that was seen at three to four days.  And so what we're really looking at at this period, and this process continues, not just in embryonic life, but in postnatal development.  Neurons continue to be added. 

So in a sense what the field of developmental neuroscience at these early stages has been trying to address are two basic questions.  So one of these relates to numerology.  So these are estimates, but the human brain is thought to contain some 1011 neurons.  This is a staggeringly large number of neurons.  And it also contains, and again this is simply an estimate, at least 1,000 different classes of nerve cells.  So by comparison, with most other tissues and organs in the body, the extent of cell diversity inherent in the nervous system is observed at a much more extreme level than in the liver, or in the heart, or in other tissues.  And so one of the major questions is to understand how during development the nervous system controls the number of nerve cells that are produced. 

And the other thing that this image shows is that not all nerve cells, once they're produced, are the same.  Individual nerve cells have discrete functional properties, and some of those functional properties are inherent or derived from the fact that the morphology, the shape, the structure of those nerve cells is markedly different.  So on the right-hand side of the screen here we're looking at one nerve cell that is found in a part of the brain called the cerebellum that is involved in motor control and many other functions.  And you can see that that cell, that neuron, looks very different from a neuron found in the retina that is involved in visual processing.  So one of the things that development does is ensure that not only do you generate very large numbers of neurons within the developing human brain, but you make these neurons different from a very early stage in fundamental structural ways that presumably influence their later functional properties. 

And I'll talk a little bit about what we currently understand about how these two problems of generating neurons and making neurons different are achieved at a developmental level.  Now these neurons don't exist in isolation.  The functional property of the neuron is dependent on that neuron becoming incorporated into a functional neural circuit, a network of neurons interconnected in different regions of the brain such that the combined activities of many neurons in different parts is necessary to produce a given behavior.

So the problem becomes even more complicated at this point.  So if we look at a typical region, for example the cerebral cortex, what we're seeing here is a complex, dense mesh work of neurons.  And this has been appreciated from classical anatomical techniques for the last century or more.  So each of these individual neurons as you can see from their morphology is subtly different from their neighbors.  One of the questions is how do these differences in morphology, these differences in structure, relate to the types of connections that they produce. 

So the two general questions that I want to begin to address, at least in the first part of my comments, are really going to be the issue of the impact of genes and genomes on neurons, on neuronal identity, and the way that those neurons begin to assemble interfunctional circuits.  So if you like, this is a reductionist view in which many aspects of brain organization are achieved through a genetic program to result in a wiring diagram of the brain.

So how are neurons generated?  This is perhaps the fundamental problem, the event that has to proceed if all other aspects of circuitry and behavior are going to be achieved.  And this is a problem that has been appreciated for, again, almost a century.  But it's only very recently that we have any molecular understanding of the way in which a cell in a primitive ectoderm acquires a neuronal property.  And this is a process that is reiterated many, many times to produce this vast diversity of neurons that exists in the human brain.

And so if we look from classical studies by Pasko Rakic and others, what we're looking at here is a small region of the developing brain, in this case a region of cortex.  And so in this region what you can see is a layered, a striated structure here.  One particular region called the ventricular zone, which you can't really see properly here, is the site of the precursors that will give rise to nerve cells.  These are neuro-precursors if you like.  They're stem cells in a particular context of neural development.  So these cells lie at one side of this epithelium, this sheet of neural cells.  And those cells divide under tightly controlled programs.  And the process of division here will determine whether that precursor cell continues to remain a precursor cell with a capacity to divide further, or whether that cell will leave the cell cycle and acquire so-called post-mitotic neuronal property.  One of the characteristic features of neurons is that once they're generated, they never undergo further divisions.  So this is a crucial event in determining the number of cells that populate the nervous system to determine how many of the precursor cell population remain, and how many post-mitotic non-dividing neurons are produced.

And the classical view until a few years ago had been that these cells divide in this restricted germinal or ventricular zone, and then they migrate through a complex process series of cellular events away from this germinal zone into their eventual settling positions in other regions of the nervous system.  And one of the ways that they're thought to undergo this migration process is along a series, if you like, of tram lines, or structural elements called radial glial cells which act as conduits for this migration process.  So really there are two processes going on here at these very early stages.  The process of cell proliferation coupled with the decision to give rise to a neuron, and then the migration of the neuron along these processes. 

Until very recently, and part of the reason I'm mentioning this, is to indicate that some of our thinking on these processes, even though the problem has been identified in classical terms.  Some of our thinking and some of the information is really very, very recent.  So much of what I'm saying is really a current 2004 view of these processes.  But this is still a field that is in a state of considerable flux.

So the classical view, which is shown on the left-hand image here, is that neurons achieve their final position within the nervous system through this migration.  They ensheath, they intertwine around these radial glial cells, and that's the way they move.  But the radial glial cell and the neuron have been thought of distinct cell types with no relationship.  What we now know from work in the last five years or so from many people is that this is certainly true, but this is an oversimplification, because it turns out that the radial glial cells, these structural elements, not only serve as a scaffold for neuronal migration, but they also represent in many ways the precursors of neurons themselves.  So the radial glial cells have a dual role.  They not only generate neurons, but they then act as a scaffold.  And I'll just give you one example of this new view.  So here we're looking almost in real time at one of these radial glial cells.  You can see its processes spanning the length of the future cortex.  And if we follow that cell in real time, although I'm showing it in a series of static images, what you can see is this cell divides at around Time Zero.  And then there are two cells.  And as we follow with time, one of the progeny remains in the ventricular zone, presumably to remain a precursor cell, but the other cell begins to migrate along this structural element.  And by using various genetic markers, some of which are not showing actually on this slide here, what we can see - there's a slight technical problem here, because this cell would be labeled Red with a neuronal molecular marker.  So this type of real-time imaging here is showing that radial glial cells are in fact the precursors of neurons.  So this is a piece of cell biology that has emerged over the last few years that has radically changed the way that we think about neuronal production in the developing brain.

So can we move then from this cellular description of where neurons throughout the central nervous system, throughout the brain, come from, into a molecular understanding of this decision.  What are the genes that determine whether a cell remains proliferative, or whether it exits the cell cycle and acquires a neuronal fate?S  And over the last decade there have really been very substantial advances in understanding the nature of genes that drive this neuronal differentiation process.  And one can show that some of these genes are sufficient when expressed in a proliferative cell to produce the neuronal phenotype, to produce the neuronal fate.  And I'm showing you one example of this.  The nature of the genes don't really matter here.  But what we're looking at is a top-down view of an early vertebrate embryo.  And so this has a left side and a right side.  And on the left side, if we concentrate on, for example, the image in Panel B, you can see a few blue dots here.  Those are the neurons that have been generated under a normal developmental condition.  And you can see that there's a sea of non-neuronal tissue in which are interspersed individual nerve cells.  So in this experimental situation, a single gene that is one of these genes that promotes neuronal formation, has been introduced into these precursor cells, and the consequences for neuronal production have been examined.  And what I hope you can see is that to the right of this dotted line there is a vastly greater number of nerve cells that have been generated as a consequence of introducing that one gene.  So neuroscientists now are beginning to be able to control this early decision as to whether to give rise to a proliferative cell or whether to generate a nerve cell.  And these are genes that are operating in the embryo normally, and this is part of a genetic program that in a sense is determining the fact that the human brain has 1011, not 1012, not 1010 neurons.  So there's a tightly orchestrated genetic program that ensures the production of neurons.

This image indicates, at least with this sort of color-coding, that all neurons are the same.  So there are really two problems here.  One, as we saw, to generate large numbers of neurons.  But the second is to make those neurons different.  And so if we consider that the human brain at the time of birth contains some 1,000 different cell types, how are those different cell identities?  They're all neurons, but each of them acquires a characteristic identity that suits its particular later function.  How is that diversity of neuronal identity controlled?  So if there are 1,000 different classes of neurons, does that imply that there must be 1,000 different signaling mechanisms that are operating with one pathway of signal, one signal per neuron, which would provide extreme constraints on the number of genes necessary to generate this diversity.  Or has the nervous system evolved more efficient ways of generating diversity from a relatively small number of signaling systems.  So as a generality in the nervous system, as in the embryo as a whole, the way in which cells acquire their different identities is through the intersection of two different pathways. 

The fate of no cell in the nervous system is really preordained from an early stage.  So there is no such thing as a central nervous system homunculus.  Cell identities are acquired because of their position in an early developing neural epithelium.  And what their position really is doing is defining the environment to which that individual neural precursor cell is exposed.  So if you're in one position you're exposed to a different set of signals then being in a different position.  So really, neuronal generation and neuronal identity involves the intersection of environmental signals with programs of gene expression that are going on within the nerve cell itself.  And it turns out that this vast diversity of neuronal identities, 1,000, 2,000, whatever that number turns out to be, is generated through a surprisingly small number of environmental signals, where those signals operate in combinations.  So the nervous system has evolved efficient ways of using a small number of signals to generate this vast degree of diversity. 

And I just wanted to give you one principle by which diversity comes, how you can generate many different cell types, neuronal cell types, from just one signal.  And it turns out that some of these signals, which are secreted proteins produced by one cell which influence neighboring cells, have been termed morphogens.  So what we're looking at here is an early primitive region of the nervous system.  This particular region is going to give rise to the spinal cord, but if you looked in the brain, you'd see a very similar morphology. 

So this is the nervous system.  These are non-neural tissues.  There are localized sources of these secreted factors in non-neural tissues.  You can see by the shading of the color blue here which represents a site of gene expression.  And one of these proteins, which has been known as Sonic Hedgehog for various reasons, is a secreted protein.  That protein functions as a morphogen.  So what a morphogen is is a protein that can induce or change or compose different cell fates as a function of the different concentrations of that one substance that a cell is exposed to.  So the exposure of a naïve precursor neural progenitor cell to a low concentration of this factor will induce one neuronal fate.  But as you double the concentration of that factor, that same recipient cell acquires a different fate.  And so in this way, one single signaling factor, by acting at different concentrations can induce different classes of neurons.  And so for example, the local source of this factor establishes a concentration gradient throughout the early nervous system, the neural epithelium.  And in this particular example at least five different classes of neurons - their identity doesn't really matter - are generated in response to this one factor through twofold differences in concentration.  So this type of mechanism is used again and again in the nervous system.  In some cases it's concentration, in some cases it's the convergent exposure to two different signals that results in differences in identity.  But numerically, a relatively small number of these signals imposes the vast degree of neuronal diversity that we see within the nervous system.

So I want to switch now.  And you'll see that this is going to be of necessity a relatively superficial overview of all of these processes away from generating neurons.  Let's assume that you have generated vast numbers of neurons in the early nervous system.  How do those neurons begin to form connections?  Because one of the things that these early programs achieve are neurons with distinct identities.  And in reality, what the identity of a neuron does is enable it to extend a long process, kind of an axon, from the site at which it's generated into the vicinity of its target cell.  So neurons need to connect.  And so in some cases - and I'm going to show you an example from the visual system throughout some of these comments - you can see that the distance over which a nerve cell has to project in order to connect to its eventual target is very considerable.  Some several orders of magnitude longer than the diameter of the cell body at that cell itself.  So here we're looking at a sort of schematic view of some aspects of the visual system.  These are the eyes.  And in the retina there are neurons which process visual information, process light, convert light into electrical signals.  And the job of these retinal neurons is to take that information that is arriving from the environment, from the periphery, and to transfer that information into higher centers in the central nervous system.  And in many ways it does this by extending this long process called an axon from the site at which the cell is generated into its eventual target regions.  And then once it reaches that target region, it then has to choose particular sets of target neurons with which to form connections.

So there are many challenges here for a developing neuron in order to be able to establish an appropriate wiring pattern.  For example, if you focus on this retinal neuron, it has to make a decision to leave the retina, to extend this process out of the retina, along the optic nerve.  It then has to make a decision as to whether to cross, as most axons do, or stay on the same side of the brain.  So there are important guide post or path-finding decisions.  It then has to reach an appropriate position within its target region.  And then it alters trajectory, and then reaches an appropriate depth within the target region.  So all of these are different environmental problems that the developing neuron has to negotiate in order to reach its target.  And again, over the last several years we've begun to understand the complexity of this organization, again, has been appreciated for over a century.  But what we haven't known are any of the mechanisms, the molecular mechanisms that ensure these precise patterns of connectivity.  And the last 10 to 15 years has revealed almost a greater degree of molecular information than is currently processable.  But I want in very brief terms just to go through some of the thinking about how neurons, once they have acquired an identity, begin to be able to connect with target cells.

So the business end of the neuron is a sensory motor apparatus which is called the growth cone.  So the neuronal cell body gives rise to a long axon.  And at the end of that axon is a highly motile cellular structure, the growth cone.  And so what we're looking at here are various views of growth cones.  So the axon would then move out of below the screen and some many yards away would be the cell body.  But what you can see is that the growth cone which really senses information in the environment and converts that sensory information into a direction, into a vector or trajectory, is a highly organized structure.  And the general view is that the ability of the growth cone of the neuron to navigate this complex terrain en route to its target depends on the expression of a variety of receptor molecules which are sensing information in the environment, mediating that information through these receptors and converting that into directed behavior. 

And so what this involves, both the reception of information in the environment and the conversion of that into a motor response.  The growth cone has to crawl physically through a variety of substrates.  So in this process of extension of the axon, there is a highly complicated cellular machinery that is occurring where, for example, the actin cytoskeleton is tightly linked to these receptors on the cell surface.  So that information from the environment is converted through the actin cytoskeleton into directed movement.  And we're beginning to understand a great deal about the way in which neurons, growth cones, use their cytoskeletal, use their structural properties to influence their direction of growth.

The other thing that we've begun to understand is the nature of the environmental symbols that influence the behavior of axons, behavior of growth cones.  Now I'm going to show you an example from an isolated in vitro experiment that the assumption is that same mechanisms are going on in the developing brain in situ.

So what we're looking at here in this panel is the axon of a growing neuron and here is the growth cone.  You can see that this is a highly elaborate process, the small protrusions called Filopodia that if this was a real time image are constantly changing, constantly moving.  These are the sensory apparatus.  This is the sensory apparatus that is looking for cues in the environment.

We know a lot about the molecules in the environment that influence the structure and the direction of axon growth cone movement.  So the details of this don't matter, but we now understand many, many classes of molecules that are distributed at key points along the trajectory of a growing axon and that influence direction directly by impinging, by imposing, changes in shape and motility in the growth cone.

So what we're looking at in the bottom panel is the exposure of the same growth cone to a protein that we know guides axons and the way that it guides those axons is by inducing a very dramatic collapse of this complicated cellular structure.  So essentially it prevents growth cones and axons from moving in that direction because the growth cone is necessary for motility in a directionally sensitive manner.  This will then prevent growth continuing in this direction and then the axon will move off in another direction.

Some of these molecules influence guidance if you like in a negative, repellant way.  They form no-go zones in which axons are simply incapable of moving.  Others act in a more positive way.  That is they act as lures or attractants to direct in a positive way axons towards a particular target.  Through the combination of these negatives factors and positive factors, it's thought to guide axons from the site in which the neuron is generated in a set of complicated steps to the vicinity of its targets.  So this have been a very dramatic advance in understanding as we will see later on and may have implications in therapy in the context of regeneration in the adult state.

Once an axon through these guidance mechanisms has reached the vicinity of its target cell the next challenge it faces is actually to select which of the small subset of neurons it's going to form stable connections with.  There may be 1,000 different potential target neurons for that one neuron, one axon, to connect with.

How does it choose which of those 1,000 neurons it's going to form a stable association with?  Now this is an area that even though has been the subject of intensive study is still relatively poorly understood.  It's only in the last five years or so that we have any understanding in the central nervous system in the brain of the mechanisms for forming functional synaptic connections because communication between nerve cells depends on the formation of these functional connections.  There are many problems inherent in this process of recognition of how you recognize the target cell to form connections.

So in various schematic ways, there are sort of where type questions.  That is this is one target cell.  This in-growing axon has chosen to form a connection on that one target cell, but not on a neighboring cell which would be off the screen here.  So that is the first type of question.  Which cell do you choose to form a connection with?

The second type of question which is very important for the function of the neuron is where do you form the connection.  Do you form the connection close to the cell body of that target neuron or do you form because neurons are such highly polarized structures way out from the distal processes of the so-called dendrites of the neuron?  So there are questions of sub-organization as well as which cell you choose.

Frankly we don't have a good understanding in molecular terms of how these processes operate even though we do know that there's a high degree of stereotypity of selectivity in those processes.  So what the field currently trying to understand in a way that I think will eventually be important for understanding how circuits control behavior and how those behaviors are eroded in disease is understanding the biochemical mechanism that is essentially a recognition process between the arriving neutron, the pre-synaptic neuron and its pos-synaptic target.  We have little information yet on the nature of the molecules that drive this process.

But interestingly and I'll come onto this later, the few molecules that have been implicated in this process are known to be mutated in certain forms of human neuro-developmental disorders.  So it begins to suggest that actually understanding the machinery of synaptic connectivity may say a lot about the normal and pathological function of the human brain.  I'll elaborate on that point.

So the final step in this brief overview of the wiring diagram in the brain occurs after neurons have made connections with their target cells.  You might imagine that this is the end of the process.  Once you have generated the neuron, you've managed to reach the target region.  You form the connection with the target cell.  The job of development is done.  But it's very far from done.  As we'll see, there are many processes that have to operate.

One of those processes relates again to this basic problem I started with of numerology.  That is in order for a circuit to function appropriately, there has to be a precise matching of the number of neurons that are generated in one region and the number of target cells or target neurons that are found in a completely different region.

And one of the very surprising things that emerged some 50 years ago is that the nervous system is extremely wasteful in the generation of neurons.  In fact in most regions of the nervous system, two to three-fold more neurons are generated than are eventually incorporated into functional circuits which would seem a wasteful process.

But one of the rationalizations of that process has been that perhaps one of the things that permits one to do is to achieve numerical matching between two sets of interconnected neurons.  If you generate neurons in larger numbers, those that are generated in excess become dispensable and can be eliminated.  There is a lot of evidence, cellular and molecular evidence, that this type of process occurs and this is generally known under the term of neurotrophic factor hypothesis.

The basic idea that seems to operate is that you have a restricted target cell and many neurons that have the potential to innovate that target cell.  But what happens again and again during brain development is that only a small set of those neurons that are originally generated eventually form stable connections with that target cell.  The reason at least that this occurs in part is that one of the things the target cell is doing is communicating back to the neuron.

There is a two-way process of communication and the target cell is producing factors that support the survival of the neuron and it's producing those factors in limited amounts and limited availability.  So in a sense, this target cell produces only half as much of this survival factor as is needed to support the entire compliment of neurons.  As a consequence through a competitive process, only perhaps 50 percent of those neurons that are alive in the vicinity of the target cell form stable connections.  What we'll see in the next section is that this process of competition, excess production and competition, is really paramount in linking the genetic programs of neuro-wiring to experience and activity in the way that experience and activity sculpt these basic projections.

Without going into details, we know the basic elements of this competition, target-celled derived support factor hypothesis.  In many cases, we know the nature of the molecules that promote cell survival.  One of the dramatic advances in all biology over the last 10 to 20 years has been the appreciation that in fact the default state of most cells in the body is not to survive, but to die.

There's an intrinsic death program that is inserted into every cell.  Cell survival really only is permitted under conditions in which that intrinsic death program is suppressed and is subverted and the first inkling of that information in fact derived from these sorts of experiments in the nervous system.  So we know the nature of these neuronal survival factors and we know a lot about the biochemical mechanisms by which they promote cell survival.  This is the first example really in a normal developmental epoch of ways in which competition and interactions between cells shapes this genetic programming of the wiring diagram.

I'm going to move now unless there are questions or comments that I could elaborate on from this simplistic but nevertheless I think valid idea that genes in large part program the basic wiring diagram of all nervous systems from invertebrates to vertebrates, from mouse to man.  Many basic aspects of the connectivity are programmed in a way that involves serial developmental decisions to give this basic neural blue print.  But at that point, the precision of connections, which connections are maintained, which connections are reinforced, which are eliminated then begins to be impacted in an extremely profound way by environmental signals.

So I want to begin to talk now about how activity of nervous systems, how the experience and the environment shape these connections.  Again I'm going to use the classical example which emerged from studies by Hubel and Wiesel in the 1960s and the 1970s focusing on the organization and structure of the visual system and the influence of environmental deprivation on the structure because I think that there are many, many examples of this general paradigm but that the first realization came from these classical cellular and physiological studies.

We're now back in the visual system.  These are the eyes.  This is the optic nerve projecting to a set of relay nuclei to a second order neurons in the thalamus and those thalamic neurons then relay visual information from the eye via this one relay station to the cortex.  So most vertebrates can extract information from the visual world and use two eyes to do that.

How does the brain extract information from the left visual field, the right visual field, keep that information separate as it begins to form these projections, form these connections, and where is that information integrated?  One of the important things that occurs is that you keep the information from the left eye and the right eye separate at many of the early processing stages in the developing brain.  What you can see is as one traces through and then looks in higher magnification, that an input from say the right eye here will eventually project to a region of cortex that is spatially distinct from that region of cortex that receives information from the left eye.

What the great discovery of Hubel and Wiesel together with Vernon Mountcastle in the somatosensory system was that the cortex is basically organized in columnar fashion.  Information doesn't arrive in an indiscriminate, anatomically mixed fashion.  Information from the two eyes is physically separated.  One can see that physiologically as Hubel and Wiesel first saw that but you can also see that anatomically.

For example, if we provide a tracer into one eye such that that tracer is incorporated through all of the neurons that form that right eye circuit, you can then see the consequence of the projection of that right eye in relation to the unlabeled left eye.  So that if we look here, this is a cross section through a mammalian cortical structure.  This is true of humans.  This is true of primates.  This is true of cats, many mammalian organisms.  What we are looking at are the terminal fields of axons that receive information let's say from the right eye.  They would be shown as these light patches here.

What you can see is the cortex consists of the mosaic of light and dark patches which is a reflection of information coming in from the right eye as opposed to the left eye.  This is a relatively mature state.  This is what 13 week post-natally in this cat experiment here.

But what is interesting is if you look at a much earlier but still post natal stage, what you can see on the top here is that these stripes or banded patterns don't exist.  What the implication of that is is at this early developmental stage information from the left and right eyes is arriving in the same spatial region within the developing cortex.  What you can see is that over the intervening 11 weeks of post natal development in a so-called critical period, the information, the axons from the left and the right eyes are segregating to form these distinct domains.

This is a process of development of connectivity that is occurring in the post-natal period which then follows most of the earlier embryonic patterning mechanisms that are described in the first section.  What is particularly dramatic about this sort of structural organization of visual input is that it's critically dependent on visual experience.  An early set of classical experiments looked at the consequences of eliminating visual input into one of these eyes and examining anatomically and physiologically the consequences for the structure of the brain.  What happens if you deprive one eye of the normal sensory information that it receives?  And you see very dramatic changes.

So we are now going to switch orientation and we're going to be looking at top down images of the brain, of the cortex with sections or slices cut through in this plane.  What you see here is in the top panel - I hope you can see that from the back - that you have again these alternating stripes, so-called ocular dominance columns of left eye, right eye where the width of each of these stripes which is an anatomical representation of information coming from the two eyes is roughly equally proportioned, that equal black stripes and white stripes here.  This is a diagram showing this mosaic of information.

What you can see in these intervening panels is that structural reorganization of information in the brain in the cortex has a consequence of monocular sensory deprivation, depriving one eye of visual input.  For example here, and it really doesn't matter, what you can see in this case is if the eye that was represented by these dark stripes was deprived, you can see here that there's a massive over representation of the structure, the inputs, from the eye that is still receiving visual information.  The white patches greatly exceed the dark patches.

Conversely if you design the experiment in a different way and you deprive the light patch eye, you can see that the dark patches prevail.  This is very dramatic evidence that visual experience produces a structural change in the brain.  One of the things that one can now begin to understand is the nature of the process by which environment and experience produces structural changes in the central nervous system in the cortex.  This is just a diagram of what we were looking at in real images before.

Early on the information from the two eyes is essentially overlapping over this post natal, critical period.  The information gets segregated into distinct ocular dominance columns in the developing cortex.  And that under conditions where sensory information is eliminated from one input, then the other input predominates.  So these are gross structural changes in the organization of the brain that are the consequences of presumably the inability of experience and activity of those neurons to maintain a spatial territory.

You can actually see this influence of experience and the environment at the level not of just domains of the cortex but individual neuronal branching patterns and morphologies.  These are just four diagrams showing essentially the normal change in development of an axon, a nerve that is going to innovate the cortex and the consequence of deprivation.

On the left-hand side here, we've traced the terminal projections of one of these axons arriving in the cortex conveying visual information in a young post natal animal.  You can see that the region of space or cortex occupied by this axon that it's relatively broad that the density of terminals of branches in any given region is relatively small, relatively low.

Now as the animal matures under the consequences of normal visual experience you can see that there's a dramatic change in the shape of that projection.  A much smaller region of the cortex is now innervated, but that region that is innervated now receives a much higher density of axonal branches and synapses.  So this is the process of post natal structural reorganization that is occurring.

We know that this structural reorganization is again dependent on experience upon sensing the visual world because if we deprive one eye then you can see that at the level of an individual neuron those structural changes are very dramatic.  The neuron has few axons, few terminals.  We are seeing this level of structural reorganization in the nervous system as a consequence of visual experience at many, many levels.

Here we're looking - and I'm going to emphasize this point because I think it's one of the major features in the way in which environment, the experiential world influences the structure of the mature nervous system - at the level of the axons that are arriving in the cortex, but we can also see this at a finer level of resolution if we look at the target neurons that are going to receive that information.

I'll do this first.  Here is one of these cortical neurons.  The cell body, it has a very extensive set of processes called dendrites and the synaptic input, the information that is coming into this neuron is occurring on a series of very small micro structures that come out from one of these dendrites which are so-called dendritic spines.  The spines here, these protrusions, are really the units of synaptic information.  Each of these spines is going to be occupied by an incoming synaptic terminal.

We know that some of the same activity experience dependent changes that I was showing you in the previous slide at the level of the pre-synaptic terminal also influenced the dynamics of these spines.  Whether these target neurons have many spines, have few spines, these are very dynamic cellular structures which come and go as a consequence of activity.  Both on the pre-synaptic input side and the post-synaptic target side, experience and activity in the circuit is having an dramatic impact on the structure.

This information all of which is derived initially from the visual system raises the question of whether this is something special about the way the visual system works, or whether in fact all sensory systems are subject to the same structural change in organization of the brain as a consequence of sensory information coming in from the environment.  There are many, many examples as one moves out of the visual system that the same thing is true.  I'll show you just one example from the auditory system.

This is again a slightly varied organization here, but we're now looking at a map of a region of auditory cortex.  This is the region of the brain that processes normal sound, auditory information.  The wonderful thing about the auditory system as opposed to the visual system is that sound is tuned according frequency.  Different regions of the auditory cortex are tuned to optimal frequencies.

There's a so-called tonotopic map.  Different sound frequencies get projected to different regions of the auditory cortex.  By applying a single sound you can make that region of the cortex that receives that particular sound frequency.  That's what we're looking at here in an early post natal rat in fact this is.

Now the relatively large region of cortex associated or devoted to that particular tonotopic frequency.  If we look some 34 days later, the region of cortex that is devoted to that same sound frequency has reduced in a very dramatic way.  This looks a lot like what we saw in the visual system.  We know that auditory experience, the sound that we experience, over that critical post natal period has a dramatic influence on how this auditory, tonotopic map forms.  Because if we now apply to an experimental situation, apply in a sense a white noise preventing the auditory system from extracting normal variation in sound frequency, then applying this distracter noise  produces a very dramatic slowing of the normal maturation of this cortical map.

We're now looking at the same map here but under conditions in which a distracter noise had been applied.  You can see that not only does deprivation of visual information but deprivation of important auditory information erodes the normal formation of the structure of the brain, the structure of the cortex.   You see this same information, this same principle, occurring in all sensory systems.

What this means I think is that during this critical post natal period information coming from the environment and from the visual senses, the auditory senses, the tactile senses and the somatosensory system, taste, smell, all of this information is converging on the central nervous system and providing these structural refinements in the basic wiring diagram that are essential for accurate perception of the environment, accurate performance of motor commands in response to that information.  This I think highlights what we've known for many years that this critical post natal period is essential for the appropriate structural information within the nervous system.

CHAIRMAN KASS:  This sounds as if this is mostly a certain kind of openness is then restrained and pruned and that there's a greater sort of amorphousness which then becomes more specialized as a result of this experience.  Have I gotten that particular point right first?

PROFESSOR JESSELL:  Yes, perhaps the easiest way of showing it is just to go back to this image which is essentially a pruning image.  What is happening at these post natal stages in development is that the map is roughly correct.  So visual information is coming into the visual cortex and not to the auditory cortex.  But the fine details of the working of those cortical structures is not sufficient to achieve this rough map.  You have to proceed.  You have to achieve a precise map.  That precision is achieved by this pruning process.

So in a sense what we're looking at here as you go from young to mature is the pruning of one neuron.  That has functional consequences because then you achieve a much greater degree of point to point precision in connections. This pruning process is activity, is experience driven.  Without that experience, without the range of information coming in from the outside world, this pruning process fails to occur.  We can see that at the single cell level and we can see that at the level of the auditory example.

CHAIRMAN KASS:  May I just follow up?  Would there be - I don't even know what I'm asking here, but is there something that you could call pre-natal experience that is at work even before?  Sound I suppose is still transmitted intrauterinely.  Visual would be a different matter.  But do we have environmental and "intrauterine" experiential things that are already doing this or does the major effect take place after birth?

PROFESSOR SANDEL:  And what about the Mozart effect?  Even if that's not true, would that be an instance of this?

PROFESSOR JESSELL:  Yes.  I haven't mentioned it and stressed the post natal period, but there is strong evidence that this activity-driven wiring of the nervous system occurs during fetal development as well as post natal development.  There is very strong evidence in one of the articles I distributed.

Carla Shatz is one of the people who has really provided some of the strongest evidence that in fetal development the retinal ganglion neurons that are first arbiters of processing of visual information  are firing in patterns during embryonic development that is thought to be important for setting up perhaps the first aspects of organization superimposed on this basic genetic wiring program.

That is certainly true for the visual system.  I think there is good evidence that is true in the auditory system.  Whether it's true in some of the other sensory systems, the evidence is less.  So this process even though it's been most heavily studied at a post natal period for reasons of accessibility probably is beginning during the embryonic stage and when it begins you can put limits on to in the nature of the basic connections that have to be formed before the information from the environment can even reach relevant areas of the cortex.  But it's a relatively early process.

DR. ROWLEY:  But if I can follow on with that.  It was my impression from reading Carla's article that what's formed are some of these intermediate connections or the way stations or the relay stations rather than the specific connection with the fine processing neuron in the cortex.


DR. ROWLEY:  In her example in the visual cortex.  So you set up the systems that are necessary already before birth so that these intermediate processes that connections have been made and then the pruning of the final one is what's then done after birth.

PROFESSOR JESSELL:  Yes, that's absolutely correct.  The system that Carla is looking at which is shown on this slide back here, I've been concentrating on the cortex which is the final target.  Carla has looked at this intermediate thalamic relay station because those are the targets of retinal ganglion neurons that are spontaneously active during fetal development.

I suspect that wherever you look you will find evidence that the activity experience dependent structural changes traditionally this has been looked at first in cortical structures.  We now know it's true in subcortical structures in the thalamus.  I suspect even at the level of the first sensory relay station, perhaps even in the retina itself, activity is having an influence in terms for example of the morphology of neurons or fine details.  I suspect that this is happening in a very pervasive manner and where you look depends on what type of experimental system accessibility of that particular region of the nervous system.

PROFESSOR SANDEL:  You've been speaking about the plasticity in the early post natal period.  Do we know when it stops?


PROFESSOR SANDEL:  When experience dependent changes no longer affect the structure of the brain?

PROFESSOR JESSELL:  That's the next section.  So maybe I can come onto that.  Yes.  The answer is that if you'd asked me this or asked the field this ten years ago, the idea would have been that this critical period closes at some point two to three months after birth in an experimental animal. It perhaps closes in the first several post natal years in the human infant.  What we now know is that to some  extent that process of plasticity persists throughout adult life.  I'll give you some examples of that.  Probably I think as a generality the nervous system is most plastic at early stages and plasticity is essential for connectivity in the way that we've seen in an immediate post natal period.  But there are striking functional elements of plasticity albeit at a reduced level even in the mature organism.

CHAIRMAN KASS:  Dr. Jessell, would you like to complete the presentation?  We can take questions then.

PROFESSOR JESSELL:  If they are burning questions, now is a good point.  We've reached the end of this stage.

CHAIRMAN KASS:  Bill Hurlbut and then Gil.

DR. HURLBUT:  In saying that there is a longer phase of plasticity at some point whether now or in your further presentation, can you talk about the possibility of actual revisions like the slide you showed Mike Merznich's information?  I know Mike is very interested in revisions of neural process.

PROFESSOR JESSELL:  Yes, I will comment on that perhaps in this context of the adult stage and what some of the Merznich observations, some of those implications are.  Yes.

CHAIRMAN KASS:  Gil, very briefly.  Then I think we should let Dr. Jessell complete.

PROFESSOR MEILAENDER:  Yes.  Whether I can make sense of this question or not I don't know.  I don't belong to the party of rationality.  But could you or would you use in describing this process of development a word like optimal?  Is there an optimal point anywhere along the way?  Or is that not the kind of word that you would use?  Is it just a process that you describe in which one couldn't find a place to use that sort of word?

PROFESSOR JESSELL:  I think what we've learned is that development as I'm describing it is a process of gradualism.  That there is constant change as a consequence of influence of the environment.  To use the word "optimal" presupposes to some extent that we know how the circuit should function in all its aspects.  What we see are erosions of performance in behavior that presumably can be linked to changes in circuits.  So that is suboptimal.

What the optimal wiring of these circuits are I think we don't understand.  So dramatic perturbations I think we can interpret.  As we'll see, maybe it's a matter of give and take that in considering for example the plasticity of the adult nervous system.  One is balancing two forces.  One is that you want some constancy in connections because that constancy allows you to perform at a high cognitive level.  Learning and memory are thought to be encoded at least in part in the constancy and the strengths of individual connections.  So constancy there is a desired attribute perhaps something approaching optimal.

On the other hand if you think about regeneration of the nervous system under conditions of lesional injury, then the nervous system, that constancy becomes a liability in terms of the ability to reform connections.  Where optimal is along that sort of line, I don't know and I don't think anybody perhaps knows at this point.

I'd now like to come onto the question that we were just discussing which is over what period does plasticity really persist.  Is there as classically viewed a critical period and once you reach the end of that critical period in post natal development, the wiring diagram of the brain is fixed and activity simply operates on the structure that exists without having the ability to change it further?  Work from Michael Merznich and many other people I think has very dramatically changed our view of the extent of plasticity in the adult brain.

What I was going to do is to talk about three aspects of this balance between constancy or stability and change in an adult context in three different sections.  One comes back to what we were talking about earlier in terms of just the generation of neurons.  The second is the reorganization of circuits.  The third is the regenerative capacity of the nervous system as a function of age.

One of the dogma that has been overturned in the last 10 to 15 years relates not only to the reorganization of circuits but to this idea that neurons are born early in development and then once they're born the nervous system has acquired its mature cohort of neurons and there's not much you can do to change that situation.  I think that now we know that that is not the case and that there are certain privileged sites within the brain that are capable of new neuronal production even in the adult stage.  This obviously has many implications in a clinical, in a therapeutic way.

If Rusty Gage who I think was due to be here, he would expounded on this view because he's been one of the major contributors.  But in his absence, I'm going to really review very briefly some of the evidence that I think provides persuasive evidence that at least in the mammalian brain although I think whether this is really true and the extent to which it's true in human brain is still a matter of debate that in the mammalian brain, in mice and many experimental animals, neurons are produced in the adult nervous system, in the adult brain.

But they are not produced everywhere.  There seem to be two privileged sites where neurons can be produced.  One of those is in a region in the forebrain in the subventricular zone.  The details really don't matter, but many of these neurons will then migrate into the olfactory bulb, one of the regions that is involved in processing sensory information.  It's been known for many years that neurons that convey odor perception from the external world turn over even in the adult state.  These are the primary sensory neurons.

What has been appreciated more recently is that they are target neurons, the neurons that have to receive that incoming odor information also turn over at some rate.  So the olfactory system for whatever reason and one might speculate on that is a privileged site within the human brain in which neurons are constantly being replenished.  What impact that has on one's ability to respond to odorant information to pheromone information, the environment, is something that could be discussed.  What this shows very clearly is one site in which neurons are produced in the adult brain contravening existing dogma that had persisted for many decades.

There is also a second site and so far only a second site of new neurogenesis and that is found in a cortical structure called the hippocampus.  This is an area which has been implicated in many interesting cognitive functions, learning and memory  amongst them, but also mood and emotional disorders.  It's very clear here that there is a small group of precursor cells that in the adult animal in just the same way that we've seen in the embryonic period of neurogenesis, there are progenitor cells which make the decision whether to leave the cell cycle and become post mitotic neurons in the adult.

You can visualize them with various molecular tricks.  What people now think that at some slow rate these neurons are produced.  They begin to acquire all the hallmark structural features of neurons and there is some, albeit weak, evidence that these neurons can actually contribute, reconstitute themselves, into functional neural circuits although I think it remains unclear as yet what the functional consequence or contribution of these adult generated neurons is.

But this has been a very surprising set of observations that initially met with some resistance and then some over enthusiasm and interpretation.  But I think that it's now clear that these two regions of the adult mammalian brain can produce new neurons.

There are further implications of this observation in terms of plasticity of the mature brain  because the production of neurons for example in the hippocampus in the adult brain doesn't proceed at a constant rate.  It itself, this process of neurogenesis, can be influenced by environmental stimuli.

Rusty Gage is one of the people who've show that rearing experimental animals in deprived or enriched environments can have a relatively significant impact on the rate of new neuronal production in this region of the hippocampus.  One of the experiments that Gage performed is to rear mice in a relatively deprived experimental laboratory environment or to give them enriched environments or environments in which exercise and motor systems are activated at a much higher level.

You won't be able to see this because of this technical problem, but maybe if we concentrate of the middle panels here, each of these black dots represents that region of the hippocampus where new neurons are produced and each black dot is a newly generated neuron under these control conditions and under conditions of exercise or an enriched environment.  Here you can see that stimulating the environment of the animal produces a significant increase in the rate of new neuronal production.  Again this is a much later example of the way in which an animal's environment influences plasticity in the mature state.

DR. ROWLEY:  I was wanting to ask you to define more precisely the age both of the animals and of the equivalent age in humans.

PROFESSOR JESSELL:  Yes.  In these animals, these are mice in this case.  You can see the same thing in experimental rats.  These are so-called mature which would be two to three to four months of age, something like that.  The issue with humans is, I think, at a more fundamental level and there are people more expert than I who could address this as to whether the same process that we see in lower mammalian species occurs in a significant way in the adult human brain.  I think that is a matter of debate.

It's clear that there are progenitor cells that are proliferating in the adult human brain.  The question as I understand it is whether those progenitor cells produce, overt fully authenticated post-mitotic neurons in the human brain at the rate that they do in the lower mammalian brain.  This phenomenon can be seen at six months of age in mice.  This is a very robust phenomenon.  It's not the trailing edge of a developmental process.  I think new neurogenesis is really occurring at a relatively constant level probably until middle age for the mouse.  But again there are fundamental issues as to what extent - and maybe other people will have views on this, to what this really occurs in the human brain.

So one form of plasticity change in the human brain as a consequence of the environment is seen through simply modifying the environment.  But there are also experiments which suggest that pharmacological intervention can also influence the rate of neurogenesis in the hippocampus at least in experimental animals.

Eric Nessler and Ronald Dumond, some years ago, not too long ago, came up with a very striking observation that anti-depressant treatment using a serotonin uptake inhibitor, Fluoxetene, has a dramatic effort on the rate of neuronal production in the hippocampus in this same system.  I've just taken one image which is exactly the same type of experimental approach. Under the control conditions, there are relatively few of these black dots.  You probably can't even see them there.

Under Fluoxetene treatment, then the rate of neurogenesis increases in the hippocampus.  This suggests that clearly these drugs have behavioral consequences and raises the question of whether some of the behavioral consequences of mood-altering drugs are in fact a consequence of changes in the rate of new neuronal production.  Clearly these drugs may have many effects.  So this could be an incidental rather than a causal influence.

My colleague at Columbia, Rene Hen, has performed an interesting series of experiments recently that were reported in Science last year which actually while not proven at least keep open the idea that adult neuronal production is in fact perhaps a causal contributing factor to changes in the behavioral consequences following serotonin uptake inhibitors.  This is a very active field at the moment, but I think it have many people galvanized about thinking not only about natural experiences but also the way in which pharmacology and drug treatment influences this aspect of brain plasticity and behavior.  This is a recent set of observations so the consequences of this I think remain to be discussed and thought about.  This is one example which really takes the information.

DR. HURLBUT:  Those studies are on mice.

PROFESSOR JESSELL:  These are on mice.

DR. HURLBUT:  And are these mice that are in any sense depressed so to speak or are they in an enriched environment?

PROFESSOR JESSELL:  Yes.  There are a behavioral assays that the Hen group have done in particular where they've used certain behavioral, open field trial responses.  It's a complicated issue.  One of the things that the Hen study tried to do is actually prevent adult neurogenesis and then ask about the behavioral consequences of Fluoxetene administration.  One of the ways they tried to do that is to irradiate the hippocampus, killing the progenitor cells, preventing neurogenesis and they have some behavioral evidence that many of the behavioral consequences of Fluoxetene treatment are belated as a consequence of irradiation.

That raises all sorts of additional questions about whether irradiation is specific and whether you can contribute the effects of irradiation to the loss of neurons and whether the behavioral parameters being measured in mouse really are a reflection of the state of elation or depression as viewed in a human.  I think all of these are open questions and hopefully will emerge with further studies.

DR. HURLBUT:  So essentially you are saying that there is to date no evidence that an otherwise normally functioning enriched mouse would have increased rates of neurogenesis under an SSRI.

PROFESSOR JESSELL:  I think many of these things are suggestive correlations at the moment that drugs and environmental experience that change the behavior of the mouse change neurogenesis.  The Hen experiment to my knowledge is the experiment that most closely links causality or implies causality in the process, but I think Hen himself would not argue that that case has been proven at the moment.  I think there are experimental designs that will emerge over the next two to three to four years that will establish causality or not.  Then I think things become interesting.

This has been plasticity in the adult context viewed from neuronal production.  There is extensive evidence that aspects of circuitry are also plastic beyond the traditionally viewed critical period.  We've discussed the Merznich type of experiments and Michael Merznich has been the person who has promoted this idea most persuasively.  It again comes back to mapping in regions of the cortex, particular regions of a peripheral sensory receptive field.

Merznich has done this to a great extent in the somatosensory system where individual regions of the body surface can be mapped to particular locations in the somatosensory cortex.  Then the basic gist of these Merznich type of experiments is to change the level of information that is applied to that peripheral receptor field by training in way or another and ask in a mature central nervous system in the mature brain whether the cortical representation of that peripheral receptor field changes using physiology and to a lesser extent using anatomy.

Then there are striking examples that the cortical representation of a given receptor field for example on the digits in a primate, in a monkey, changed dramatically as a function of training.  So here is the receptor field on the digits of a monkey.  This is the normal region of cortex that receives that information.  This darkly shaded area represents the normal area, the normal region of cortex, that receives information from those three receptor fields on the digits.  After training you can see a very significant expansion in the area of cortex that processes that information.

This is a functional reorganization of the nervous system as a consequence of experience or training.  It raises the issue of what is the structural basis of this.  Is this a structural reorganization in the way that we've seen at earlier stages of development in the visual system or is this really a functional reorganization?  Are some synapses normally just not operative and sitting there in a quiescent state?  But upon training, these synapses suddenly start to work?  So at a physiological level, you see a change in the map.  These are questions that I think are currently being examined.

The extent to which this clear and established functional reorganization which is the important thing reflects a structural change or reflects changes in the efficacy of synaptic communication between neurons.  Merznich's group has some evidence for structure, but whether structure accounts for all of the dramatic changes in mapping of sensory inputs I think remains to be seen.  Nevertheless this very clearly, I think, shows that there can be reorganization of circuits as well as simply the generation of neurons at a much later stage in an adult stage.

Then finally I want to deal with, if you like, the flip side of plasticity in the adult nervous system.  The ability of the nervous system to adapt to a changing environment probably is a good thing.  It allows you to optimize perhaps circuitry in relation to particular environmental conditions.

But one of the things the nervous system is not good at doing is reorganizing in the wholesale way so all of the processes I described at early stages in development, the extension of axons, the ability to form connections, the ability to refine those connections in a very dramatic way, decrease dramatically with age.  One of the major problems from a clinical perspective is the relative constancy here.  I've focused on examples were things can change.  Neurons can be produced.

But by and large, the mature nervous system is a relatively static structure.  This has dramatic consequences following damage or injury to particular regions of the nervous system.  In one well-talked about example in spinal cord injury, one of the reasons that people with high spinal cord injuries recover so poorly is because of a poor regenerative capacity of the nervous system.  This is if you liked limited plasticity.  Damage to a particular region, all of the descending fibers from the brain that are necessary to activate the motor system to restore motor control, the extension of those processes across a lesion or scar region is extremely poor at the moment.  This again has been appreciated for 100 years.

Over the last ten years I think partly through work on developmental mechanisms, there is now some hope that plasticity in this context can be enhanced dramatically by changing the environment in which regenerating axons are trying to grow.  One could view this in two ways.  One is that perhaps the failure of adult neurons to extend axons effectively to recover function is an intrinsic property of those neurons.  They just somehow with age lost the capacity to grow axons.  That probably is not the case.

A major influence on the inability of axon regeneration is nothing to do with the neuron itself, but is the fact that the environment of that neuron is now extremely non-permissive for axon growth whereas at an earlier stage in development, it was highly conducive to growth.  The last five years or so has seen very dramatic advances in understanding the molecular basis of that non-permissive adult environment.  It turns out that many of the supporting glial cells in the nervous system - we focused here on neurons - in particular a class of cells called oligodendrocytes express proteins on their surface that will inhibit axon regeneration.

Since most axons are trying to grow in the mature central nervous system in the highly myelinated oligodendrocyte rich environment, the reason they don't grow well at least in part is because oligodendrocytes with maturity acquire proteins that inhibit axon regeneration.

Again the details don't matter, but this slide is really just to show that there are now some molecular reality to proteins that are expressed on the myelinating oligodendrocyte and receptors expressed on the sensitive neuron.  Many studies now are underway to try and eliminate thes proteins and see whether that has the ability to enhance some regeneration.  This is viewed from a clinical perspective to recover motor function for example in cases of spinal cord injury, but I think it has interesting implications because it comes back to this issue about what is optimal in terms of stability and plasticity in the mature state.  If you could find ways of allowing perhaps in order to maintain faithful function of neural circuits, you have to find a way to cement them in place.

The downside of that fixation process is the inability to recover function from more dramatic traumas to the nervous system.  What happens if we can now unleash plasticity to a much greater extent than had previously been possible?  What will be the consequence in terms of other aspects of nervous system function, cognitive processes?  Will one generate complete disorder?  Will animals become more intelligent as judged by behavioral methods under conditions where they can reorganize circuits in the mature state?

I think these are issues that one is only just beginning to scratch the surface with.  With the technical abilities that come in part through molecular biology over the last five years, one will likely be able to manipulate circuitry in the adult central nervous system in a much more profound way than has been possible for the last century.  Thinking about how one then designs, at least initially experimental tests to examine the consequences of reorganization in the mature state, I think is something that needs considerable thought.  The last thing I want to do is if I still have five minutes.  I can stop at this point.

CHAIRMAN KASS:  Why don't we stop and take a few questions if that's all right?



DR. ROWLEY:  I'd like to hear the rest of what's been prepared please.

CHAIRMAN KASS:  Okay.  All right.

DR. ROWLEY:  We all can have a shorter lunch.

PROFESSOR JESSELL:  This will be two minutes so hopefully it won't impose too much.  What I've talked about so far has really been normal developmental processes, the influence of environment and genetic programs and predetermination on the structure and function of the nervous system.  But this has as we've begun to talk about in regeneration  a clinical consequence.  One of the other things that has emerged I think from understanding normal molecular genetic programs that have developed is that those processes are likely to be precisely the processes that go awry in many neurological and psychiatric disorders.  This is a very new field, but I think there are enough small examples to indicate how this will really change or produce a convergence of clinical neuroscience and these basic developmental mechanisms.

One example just comes from looking at many classically defined neurodevelopmental or cognitive disorders.  In the few cases where genes associated with those disorders have been identified, many of those genes affect precisely the processes that we've been talking about this morning, the process of neuronal identity through genes that control cell identity, transcription factors, the nature of signaling factors, the nature of synaptic proteins, so two examples that I won't stress.

Some of the proteins that I've mentioned briefly that are involved in synapse formation, how one neuron communicates to another, it's been shown that mutations in those genes are associated with forms of autism and with the Asperger Syndrome.   Signaling factors that are involved in neuronal communication have been associated, albeit not completely persuasively, with schizophrenia.

      In the case of transcription factors, one has the surprising example that quite highly complex, cognitive disorders relate to genetic defects in genes that are DNA-binding proteins that control patents of gene expression.  So two good examples of that exist.

One is a syndrome known as Rhett Syndrome which again if you like is a variant form of autism.  There is a gene that probably accounts for the vast majority of Rhett Syndrome cases.  These are children who acquire gradually over the first two to three years of post natal life progressive cognitive impairments, stereotypic motor behaviors.  They lack function of a gene involved in methylating many target genes.  Some  of those target genes are now known and one of those are the trophic factors that we talked about in the context of keeping neurons alive.

An even more striking example is in the case of genes that influence human ability for language and integration of spatial information.  So there is a syndrome described by Tony Monaco and by Vaga Cadan associated with facial abnormalities and with dyspraxias.  There is a clear pedigree.  So these people have abnormal impaired language acquisition.  The gene associated with that pedigree turns out to be a transcription factor which is expressed and involved in the determination of neuronal identity.

This raises very profound questions of taking a disease which appears highly specialized in a cognitive manner and finding out that the gene that causes that is a gene expressed at a relatively early stage of development, probably involved in establishing some aspects of circuitry.  One of the challenges that I think is going to face the field is now understanding causally how the mutation in that one gene influences a relatively specialized set of cognitive behaviors.

Another example is Williams Syndrome which is associated in contrast to for example Down's Syndrome and this KE language defect with in fact an over elaborate use of language by children.  They have a very extensive vocabulary.  They are extremely articulate, but they have very poor ability to extract and integrate information from a visual world.  This is a very highly localized cognitive disorder that has been studied by Ursula Belugi in particular.  All of the children who have this cognitive disorder have a small chromosomal deletion that probably eliminates in large part a transcription factor that controls cell differentiation.

So here is another example where very specialized cognitive dysfunctions are mapping to genes that we can now begin to understand in terms of their role in developmental processes.  Yet there is a very large gap between understanding the nature of the gene, the neuron, the circuit and the behavior.  But I think over the next several years as human genetics begins to give us more information on the nature of these behavioral disorders many of which affect this early childhood period, we're going to be faced with trying to link in very relevant clinical context some of the early developmental mechanisms that we've talked about with some of these behavioral events.  Perhaps that's all I want to say.  I'll stop there.

CHAIRMAN KASS:  Thank you very much.  I'd like to run over and as Ms. Janet says we'll have a slightly shorter lunch because we shouldn't waste the opportunity of having some conversation with Dr. Jessell after this very comprehensive and very stimulating presentation.  Thank you.  Dan Foster please would you start and could we get the lights?

DR. FOSTER:  I have just - I don't know whether you can answer this in 30 seconds, but it's always intrigued me.  From the very beginning, you've talked of a necessity of scaffolding and we move here  in the spinal cord and you have some sort of signaling, a way that neurons can grown and so forth.  I understand a little bit about oligodendrocytes and astrocytes and jagged and notched and so forth.

My question is something different in terms of therapy.  At least in rodents, it looks like that if you inject a neurogenic stem cell even in a peripheral vein that it's going to circulate and get to the brain and then somehow will target to a damaged cell - it might be a stroke or a glial blastoma - you put a human tumor in there.  So the more I listen to you it's almost as though they are chemotactically or someway attracted rather than going on scaffolding.  I'm just dying to know what you think about how that process goes in ten words or less.

PROFESSOR JESSELL:  The first slide I showed I think illustrates the nature of the problem a little bit.  At early embryonic stages the brain is small.  The adult brain is extremely large.  So just distance imposes great challenges.  The environment of the adult brain is completely different from the embryonic brain.  Many of those scaffolds that we talked about have disappeared in the adult brain.

So in an example that you describe where cells seem to be smart enough to get to the right place, I think we have very little understanding of how that homing behavior is actually achieved given that the normal developmental cues are now missing.  I would say that the evidence that that happens in a highly efficient way is not so great.

I think it can happen whether it happens as efficiently as it would in a normal developmental context so maybe only one in a million perhaps by some random probabilistic nature ends up in the right place and then those cells proliferate in an appropriate environment.  The shorter answer is no one knows how this process occurs, but whether it occurs in an efficient way is, I think, also a matter of debate.

DR. FOSTER:  But just to follow, I mean I saw a picture in PNAS where you put a green fluorescent protein on and you were tracking infiltrating cells from a glial blastoma and there were a lot of these neurogenic stem cells that got into the lesion.


DR. FOSTER:  Not only in the mass but moving in there and honing in on it.  So maybe you're saying -

PROFESSOR JESSELL:  I'm completely receptive to the idea that perhaps under conditions where in a tumor the blood brain barrier has broken down, one of the things the tumor does is produce attractants that then guide cells.  I think there is likely to be that process.


DR. CARSON:  Yes, early on, you were discussing the periventricular glial cells which divide and then give rise to neurons.  There's always left behind a glial cell.  Now is it possible later on to provoke that residual glial cell to differentiate?

PROFESSOR JESSELL:  Yes, this relates to why most of the adult nervous system doesn't actually produce neurons, only these two little epicenters.  So does that mean that the precursor cells simply don't exist in those other regions or whether they exist and they're quiescent and something needs to happen in order as you say to provoke them?

There's a lot of evidence, for example, in the spinal cord, one of the areas that is not noted for neuronal production.  If you damage the spinal cord, ependymal cells around the central canal will start to proliferate and start to produce glial cells.  So there clearly are environmental stimuli or trauma that can kick these cells into action.

What they can't do still even under those conditions is produce neurons.  They seem to produce glial cells.  So is there a single gene?  As we saw there are single genes that produce neurons.  Is there just one gene missing from those cells that impairs their ability to produce neurons?  These are things that I think will emerge over the next five years as many people are looking at this as now some of the molecular players in the normal developmental process can be applied to the conditions of cell regeneration in an adult context.

CHAIRMAN KASS:  Mike Gazzaniga.

DR. GAZZANIGA:  Dr. Jessell, a wonderful talk.  I wish my mentor, Roger Sperry, could have been alive to hear your first section of it and that beautiful molecular work.  When one hears the sweep that you gave today, sometimes people can misunderstand the extent to which the people come to think of the brain as a set piece to the extent to which it can be infinitely plastic and change.  Plasticity is used in this funny way.  We all still are capable of learning Leon tells me.  So plasticity in that sense is going on all the time.

But plasticity in the infrastructure of the nervous system aspect is probably not as much as we would like to think it is.  So when we hear these beautiful examples of Merznich and of Rusty Gage and so forth, I would be interested in your opinion on a scale of the set piece - I think those were your words - versus the changing at the edges.


DR. GAZZANIGA:  And as you go through maybe by decade, just give us a sense of your feel for that.

PROFESSOR JESSELL:  I think there's no region of the nervous system in which the two extremes of a genetic predeterminism and environment don't contribute.  I think the question is what are the relative contributions of those types of programs according to a particular region.

I tend to agree with you that there is a remarkable degree of molecular genetic programing of connectivity.  The more one understands the more remarkable that observation is.  In regions like the spinal cord where motor commands are essential for processes like locomotion, I think there is very compelling evidence that many basic features of those sensory-motor integration processes can get wired up in the absence of experience, in the absence of activity.

One of the early sets of experiments as Sperry did before he worked on the visual system really demonstrated that that essentially if you misconnect so that the sensory information coming from an extensor muscle is now rerouted to a reflexor motor neuron, an adult animal has a hard job in adapting to that surgically induced misconnectivity.  So what that says which I think was the basic thesis of Sperry is that essentially there are strong molecular cues that drive the specificity of circuitry.  That will occur in the spinal cord.  It will occur in the cortex.

What I think we're seeing in the cortex for example but probably in other regions is that the extreme view that in the adult state all of those connections are fixed at a functional and structural level is beginning to be eroded a bit.  But the real challenge I think is to work out to what extent the environmental influence what are the constraints achieved by these early molecular programs on which environment can work.

Now all of these experiential influences have to have a molecular basis.  This is not some mystery.  So presumably environment and activity is changing connectivity through a molecular program.  If we knew more effectively the nature of that molecular program - what does the firing of an action potential in the neuron really do biochemically to that cell, what molecules change - then we will be able to integrate more effectively the plasticity environment together with these molecular programs.  To me that's one of the great things to emerge from understanding the molecular biology of development.  It allows you to perhaps demystify some of the environmental influences that clearly do exist.

CHAIRMAN KASS:  Janet, please.

DR. ROWLEY:  Well we spoke about this earlier in our general discussion and the release of this report and the one issue that was not touched on directly is the whole issue of cloning for therapeutic uses.  I would be interested in your opinion on how you think embryonic stem cells for example could be used therapeutically either to deal with those problems of the central nervous system or of course for spinal regeneration.  The second part of that is what kind of research is needed, what kind of support for that research is needed to see whether embryonic stem cells do have a potential in dealing with these very serious problems.

PROFESSOR JESSELL:  So this is something that in a slightly different context we in the lab experimentally got very interested in because what we do on a day-to-day basis is work on spinal cord organization and development and an important set of neurons there are motor-neurons which really mediate all the central nervous system control of action and movement.  There is a reasonably good understanding of the normal developmental processes that take a naive progenitor cell and convert that to a motor neuron.

So one of the things we asked is if we really understand that process as it occurs in the normal embryo, can we then apply that information in the context of other precursor cells like embryonic stem  cells and apply the right embryonic signals in the right order and the right time and the right concentration and simply ask the question of whether you can now convert an embryonic totipotent stem cell and can drive that to a motor neuron using normal developmental signals?  Rather surprisingly that turns out to be quite easy to do.  So the same signals that operate in the normal embryo will operate in the context of an ES cell such that you can produce fully differentiated motor neurons from embryonic stem cells.

One of the things that I think development has taught is how to manipulate other classes of progenitor cells along defined pathways.  That raises all of the questions that you mentioned about what use is that going to be in regenerative medicine.  It may be that the motor neuron is not the ideal neuron in which to test this because of the details of circuitry that are necessary.

So we come back to this question of if you put these cells back in, how are they going to find their right targets in a very different adult environment.  But in some diseases, in demyelinating disorders where one is trying to reintroduce oligodendrocytes or in Parkinson's disease where there is almost proof of principle that if you can put back dopaminogic neurons, you can ameliorate their motor deficit.

If you could make infinite numbers of purified dopamine, mid-brain dopamine neurons, with that be an interesting route to self-therapy in that particular neuro-degenerative disorder.  I think all of those issues are soluble now.  What I think we've learned that molecular biology has taught us how to turn embryonic stem cells let alone the issue of adult progenitor cells.

But I think embryonic stem cells I think can be converted to any class of central nervous system cell that one now is interested in on the basis of the normal developmental program.  To what extent that information is useful in a clinical context I think will very much depend on which disease one is thinking about.  Somewhere it won't be useful and there is somewhere where I think it's promising.

But the technology just from the point of view of cell differentiation I would say exists today.  So if one wanted to generate one class of CNS cell, I think there are good ways now of thinking about how to do that.

DR. ROWLEY:  Then I ask a second part.  What's needed to move this field along?

PROFESSOR JESSELL:  Yes.  Much of the work that is at an experimental stage has been done on mouse embryonic stem cells.  Mouse cells, ES cells, are remarkably constant from cell line to cell line.  The first thing that is needed is to ask whether the developmental potential of human embryonic stem cells mimics or reflects that in the mouse.  I think what we know at the moment is that many of the existing human ES cells, until Melton's recent studies, have shown a remarkable variability in their properties in differentiation along neuro-pathways, a much greater diversity of properties than would be predicted simply from the mouse experiments.

One of the virtues of the report from Melton and his collaborators in generating new cell lines is that many of these cell lines now are going to increase the probability that some of them will behave like their mouse counterparts.  We have actually been working together with the Melton group to extend some of the work on mouse embryonic stem cells to ask which of those human lines that Melton has generated behave most closely to their mouse counterparts.  That's a first step.

DR. ROWLEY:  But then this brings the point which some of us have again dealt with tangentially that these are not cell lines that you can study with Federal funding.

PROFESSOR JESSELL:  No, that's right.  There's a separation.

DR. ROWLEY:  So that one of the critical things that's needed is Federal funding for these new cell lines as they become available to see whether or not they are useful.

PROFESSOR JESSELL:  I would absolutely endorse that.  They are technical limitations.

DR. ROWLEY:  And have you tried any adult stem cell lines to see whether they too can produce functional neurons?

PROFESSOR JESSELL:  Yes.  So using the mouse embryonic stem cell as a positive control, that is we can now turn those cells into motor neurons at will with the addition of two chemical factors.  You are now in a position to ask whether adult progenitor cells from the nervous system can recapitulate the properties of the mouse embryonic stem cell as we currently understand how to do that.  If you do then adult neuro-progenitor cells will not generate motor neurons under the conditions that the mouse embryonic stem cells do.

What that tells us is there are some constraints on adult progenitor cells.  It doesn't mean it can't happen in the future.  It just means as of today I think the developmental repertoire of an adult neuro-progenitor cell is very much more limited than its embryonic counterpart.  Just in a practical sense what you can do with embryonic stem cells today in the context of neutral pathways of differentiation far exceeds what can be achieved with adult neuro-progenitor cells.

CHAIRMAN KASS:  Could I ask before?  We're going to have to draw to a close fairly soon, but stepping back from some of the particular phenomena that you've described and looking at their possible human-social-education significance because we'll be talking about this later on, and the question is exciting and wonderful though this is scientific matter.  If one wanted to think about the possible human implications of this over the next decade or so - I know you're not a prophet, you are a scientist - but the question is what are the one or two areas or questions that you would like us to keep our eye on when we think of the significance of this?

One thing I gather has to do with the knowledge of some of these horrible behavioral and mental disorders and the capacity to be able to learn some of their sources and perhaps ultimately to intervene.  The other vaguer thing when Michael Sandel talks about Mozart and the like and there's all kinds of faddishness out there with respect to taking advantage of this alleged early environmental stimulation to enhance the pre natal capacities, could you say again along those lines and have we missed or did I miss something, some other areas of significance?

PROFESSOR JESSELL:  To me the greatest challenge is that the very few, relevant interesting human behaviors, do we have any idea about the principles of circuitry that underlie those behaviors?  We don't yet know.  We have through imaging methodologies, through other methods of intervention, we have a sketchy idea of some regions of the brain that are more involved in learning and memory, mood disorders.  But the nature of the circuitry and the ability to intervene in that circuitry and relate that to important forms of behavior, I think is still at a very, very primitive state.

So one of the things that I haven't emphasized but I think at a practical level is going to have important consequences, both experimentally and in terms of studies of human behavior, is what molecular biology of circuit assembly has given one so far are a large number of genes that show that neurons that behave differently are molecularly distinct.  The advantage of that is that certainly in experimental animals that is going to give you an unprecedented way of manipulating the circuit on the basis of a neuron by neuron change which hasn't been possible with conventional anatomy and conventional physiology.

So for example if we knew in some region of the cortex a gene that defined one very small subset of functionally coherent neurons, how do you get at those neurons and how do you tell what their contribution to circuit and behavior is at the moment?  Through the gene what we can now do as a field is introduce genetically encoded proteins which allow you to manipulate that set of neurons in a coherent way.  For example you can introduce proteins that allow you  selectively and conditionally to take those neurons out of the circuit and look the consequences for behavior.  Or you can introduce sensors that allow you to selectively activate those neurons and leave all of the other neurons intact and look at the consequence of that particular micro circuit for a given behavior.

So what I think will emerge from this is a much clearer understanding of what behavior in any context really means in terms of the details of the circuit.  What are the core elements of the circuit that contribute to that behavior?  If one knew that, then I think the diversity of range of human behaviors that one sees in the normal population together with pathological behaviors one can start now to analyze that from the level of single neuron or dysfunctions.  What is the relevant aspect of circuit that we're trying to look at?

I think, and Michael will have thoughts on this, my feeling is at the moment is that we simply don't know enough about the basic circuitry that underlies many of these interesting behaviors even to know how to approach the problem.  What I would hope is that link between circuit and behavior becomes consolidated over the next ten years.

CHAIRMAN KASS:  Thank you.  Look we are 12:50 p.m.  We have guests coming at 2:00 p.m.  I don't know how quickly people will serve lunch where we're going.  If Dr. Jessell might be willing to simply standby for people who didn't get a chance to ask their questions, I fear that if I don't discharge you now I won't see you back here before 2:30 p.m. and that's not permitted.  So, Dr. Jessell, thank you for an enormously interesting and stimulating presentation.  It's a massive amount of stuff to present in a kind of coherent way.  I learned a great deal and I trust my colleagues did too.  Thank you and we'll reconvene at 2:00 p.m. 

      (Whereupon, at 12:48 p.m., the above-entitled matter recessed to reconvene at 2:03 p.m. the same day.)

  - The President's Council on Bioethics -  
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