Well this inside out patterning, of neurons, that come to populate the cortical plate, is largely a story of the, genesis of our pyramidal cells. That is, the principle projection neuron of the cerebral cortex that produces glutamate, and uses that as an excitatory neurotransmitter in the brain. Well we know that the cortex also has inhibitory inter neurons. And for many years, we just assumed that the inhibitory neurons of the cerebral cortex follow the same kind of inside-out patterning being derived from neuroblasts that migrate from the ventricular side up to the developing cortical plate. Well, I think it was a big surprise to many of us when it was discovered that that's actually not the case. That most of the inhibitory inter neurons that come to reside in the cerebral cortex are actually derived from a developmental region that's deep in the base of the fore brain. we call this region the ganglionic eminence, and it differentiates into a lateral and a medial division. And it's from these ganglionic eminences that inhibitory neurons are born and differentiate. And as they differentiate, they migrate. Not just in the radial dimension but also in the tangential dimension. So it's from the ganglionic eminences that our inhibitory inter neurons are derived. And come to populate the cerebral cortex through this process of tangential migration. There are other examples of tangential migration in the nervous system that effect other kinds of cells. you can read more about that in the textbook if, if you'd like. but for this particular point I would, I just want you to appreciate the fact that our parabotal cells are derived from the ventricular zone. And migrate in a radial dimension to reach the cortical plate, while our inhibitory neurons are derived from these ganglionic eminences deep in the fore brain. And they migrate in some cases quite a long distance in the tangential direction to reach their ultimate destination in the cerebral cortex. And the implication would be that, there must be signals that guide their migration that inform those neuroblasts about what their ultimate destination must be. Well the ganglionic eminences also gives rise to the basal fore brain structures including the basal ganglia and some cells that are part of the amygdala formation. So, in addition to these inhibitory neurons, this part of the developing procencephalon gives rise to those telencephalic structures that we consider the deep gray matter of the fore brain. So, we've talked, now about the proliferation of cells that gives rise to the neuroblast and how they migrate. And come to populate specific grey matter structures like the cortical plate and the basal ganglia. So an important question that I hope you've thought about at this point in the tutorial is, how is it that these precursor cells that are post-mitotic. And migrating to a particular location, come to differentiate into the diverse forms that we recognize among our neurons and our glial cells that we discover in the adult brain. Well there are basically two broad kinds of, of mechanisms that explain differentiation of these precursor cells into their, their final fate. One mechanism is local cell-to-cell interactions that are mediated via surface receptors, and this is where inductive signalling comes in. The interactions of one cell with those that are nearby are very important in influencing the fate of that cell as differentiation progresses. So we, we can think of these local interactions as a neighborhood effect. That the neighborhood of the cell will influence the ultimate fate as inductive signaling takes place and begins to specify the final destiny of an individual precursor cell. So, the second major factor that can shape the ultimate destiny of a neuroblast is cell lineage. that is, what is the transcriptional history of the cell, and what was the parent cell that gave rise to that particular progeny. So together these cell to cell interactions, mediated via surface receptors and inductive signals, together with transcriptional history influence the ultimate destiny of a given neuroblast. And its final location, its final form, and ultimately its functional position within the networks of the developing brain. Well, there's one final factor that I want to speak about that is very important in brain development, and perhaps it's a surprising factor. That, you might not have necessarily thought was important in brain development. And that factor is the death of brain cells. This is a process that we call apoptosis. And this refers to programmed cell death. Indeed, proliferation of neuroblasts produces in many regions of the brain roughly twice as many brain cells that ultimately survive. And it's through a process of programmed cell death that we achieve the final compliment of cells in the brain that we then carry into post-natal life and have with us through the remaining years of our life. So Impatosis becomes an important mechanism for establishing the appropriate complement of cells in the different gray matter structures in the human central nervous system. Well, this process of cell death reflects the expression of what some have called suicide genes. These are genes whose products induce the dissolution of cellular constituents that ultimately lead to the death of the cell. I'm not a particular fan of this Darwinian perspective of brain development. I think it's not so clear in what sense our cells that die less fit. Than those that don't express this programmed cell-death pattern. Rather, I think it's more likely that there are particular factors that are acquired that support the survival of neurons. And a failure to acquire those factors may lead to the induction of the suicide genes. So, the cell itself may not be less fit in any particular way. It just may not be privileged in a means of acquiring a particular trophic factor that's necessary for survival. We'll say more about tropic factors in a later tutorial. but for now I just wanted to impress upon you the importance of cell death. so this implies that there might actually be some optimal size to the human brain with some particular compliment of brain cells. Well, by optimum, I mean that one can have a pathologically small brain, but perhaps one can also have a pathologically large brain. Where there are too many neurons, insufficient program cell death. we think that's likely. but the range in the middle is actually quite, quite enormous, when we consider the variation in brain size among human individuals. And even within particular regions of the brain. There can be as much as a two fold difference. And the size of particular cortical areas, such as the motor cortex or the visual cortex or the pre-frontal cortex, these are regions where this question has been studied. Presumably this variation in size reflects variation in either the proliferation of brain cells or the program cell death of those cells in early brain development. What we still don't know is what is the functional consequence of this variation in brain size. I've thrown this out to you, as bigger better, I think that in terms of overall brain size we certainly don't have any principled way to answer that question affirmatively. there is good reason to argue that perhaps better is better when it comes to human brain size. That is better might reflect more efficient function, not necessarily more processing units. So, some of this variation in size undoubtedly reflects a differential complement of brain cells that have come to populate specific regions of the cerebral cortex. And it may be that on a local level, that the size of the circuit, the complement of brain cells that contribute to a given neural circuit might be important for functional capacity. This remains an open question. And one that's subject to, to much ongoing research and, considerable debate I'm sure. Well what Iv'e tried to convey in this tutorial is a bit of the story as to how do brain cells get to their final destination in the developing central nervous system. And how do they differentiate into their final fate, be they a, a sensory neuron, a motor neuron, a glial cell. A neuron in the upper layers of cortex that are computing new properties as incoming information from the thalamus is relayed up to those upper cortical layers. Or perhaps they're lower cortical neurons that send axons back down to sub cortical structures like the thalamus, the basal ganglia, even the spinal cord in the case of the motor cortex. Well, the next phase of the story of brain development is indeed the formation of neural circuits. So I want to speak to you next about the outgrowth of neuritic processes that form dendrites and axons and ultimately the synaptic connections among neurons. So, the story continues, and I'll see you next time, as we talk about the construction of circuits in the central nervous system.
