Welcome to the final tutorial in Unit five, which is all about the changing brain. And today's tutorial is entitled, The Changing Brain Across the Lifespan, Development, Repair, and Regeneration. Today's tutorial relates to two of our core concepts in the field of neuroscience. First, that life experiences change the nervous system. We'll spend some time in this tutorial talking about a variety of life experiences that have an impact on nervous system structure and function, including injuries to the nervous system. And, hopefully, what you'll see is that fundamentals, discoveries promote healthy living in the treatment of disease. And the more we know about the basic mechanisms of nervous system change in plasticity, and the response of nervous tissue to injury and disease. the more we are likely to develop strategic interventions that will do just this. promote healthy living, and the treatment of human disease. Well I have several learning objectives for in this tutorial. first I'd like for you to be able to discuss neurobiological basis for changes in gray matter and white matter volume, that occur in the developing brain, throughout the years of childhood. I'd like for you to be able to discuss the mechanisms of regeneration of peripheral nerves following injury. And I'd like for you to be able to discuss the mechanisms of plasticity in adult sensorimotor maps following peripheral injury. I'd like for you to be able to discuss the mechanisms of plasticity in adult neural circuits following central injury. That is, injury to the brain or the spinal cord itself. And lastly, I would like for you to be able to have a cogent discussion of the evidence regarding neurogenesis in the adult central nervous system. And that will include evidence for neurogenesis, as well as evidence against neurogenesis. Well we will begin this tutorial as we have the last several. just recognizing that there are three principle forces at work to shape brain development. certainly these are powerful forces in embryogenesis and in early life. But they continue to interact with one another throughout the lifespan as genes are expressing their protein product. So, there's the contribution of nature or genetic specification cells continue to interact with one another in a dynamical way through activity based mechanisms, whether that activity is holy endogenous or modulated by experience. So, so there's the potential for self organization to continue to play out. And of course we interact with the environment through our sensory and motor systems, and this allows for these endogenous patterns of activity to be shaped by the stimuli that we encounter. The way that we actually use our body, so this would be sensory motor experience. And what is particularly interesting to consider, and I wish we could do more, but our knowledge is limited and so is our time as you all well know. these three factors, I think become especially intriguing and important to consider when we think about how the brain responds to injury. For example, we might imagine that when the brain is injured then the dynamical system of that network is perturbed in some way. And this very likely is going to alter they way these ongoing patterns of activity are shaped by interactions with the environment. Likely these dynamical systems will fluctuate, and have an impact on the expression of genes, perhaps the expression of genes that have been dormant since the early days of embryogenesis. And likewise the gene products then will interact with our neural systems that will affect the way they transduce electrical impulses and encode information about the conditions of the body and the outside world. So, these three factors continue to shape how the brain responds to injury. So, that's just a thought I'd like for you to keep in your mind, as we consider some of those contexts later in this tutorial. But let's begin by picking up the story of the changing brain across the lifespan. Where we left off last time, which is in neonatal life at a time when the brain is especially sensitive to the impact, and the influence of nurture or environmental interactions, be they for the better or for the worse. So, I'd like to continue the story of development and extend now the context out, throughout childhood. And one very important consideration that we should mention as we consider how the brain changes in childhood, is the creation of new synaptic connections, and we call this synaptogenesis. And there had been a variety of reports about synaptogenesis in the human brain throughout the 70's and the 80's, and I think largely these data were somewhat flawed. simply because the methods, just are extremely difficult to employ successfully, in human tissue. So, no, no fault to the investigators. But just that, we have not yet developed the methods that allow for the generation of reliable data on this, on this front. While there was a heroic series of studies that led by Pasko Rakic at Yale University, and his collaborators and his students over the years that systematically looked at the density of synaptic connections in an animal model. A very excellent model for understanding synaptogenesis in our brain. They've looked at the rhesus monkey, and they examined a variety of cortical regions over a series of studies that spanned the decade of the 90's and into the early 2000's. And the results of these studies are summarized in this slide here, which is taken from our textbook. And what is being plotted here is the density of synapses across early life in the rhesus monkey. And, what is very clear from these data is that in all the cortical areas that we're examining. This includes primary sensory cortex, motor cortex dorsolateral prefrontal cortex, and cortex that's close to the limbic forebrain of the medial temporal lobe. What's very clear is that, at the time of birth there are relatively few synaptic connections that are established and, and fully functional. thereafter, however, there's an explosive increase in the numbers of synaptic connections. So, we see that in all of our cortical areas that have been studied. in the months after birth, and this might correspond to the first couple of years of infancy in humans, there's a tremendous increase in the numbers of synapses that are being proliferated in the cerebral cortex. Now that's not to say that there may not be some loss of some synaptic connections. Indeed there will be loss of some synaptic connections. But rather it's to emphasize that in early infancy, there is a net gain in synaptic connections, by at least two or three fold over the numbers of synapses that we're born with in the cortical mantle. So, it's reasonable to conclude then that, part of critical period plasticity, where the brain is especially sensitive to the influence of the environment, has to do with this phenomenal rate of synaptogenesis. That we see during the onset and near the peak of the critical periods, in each of these areas. Well for a variety of reasons, we know that the critical period does indeed begin to wane after the first few years of life. Here's just an example of an apparent critical period for the acquisition of the English language. Compared to native speakers the development of fluency begins to fall rather steeply after the first few years of life. As it's shown here in this plot. So after about age seven there's now a progressive decline in the relatively fluency for those individuals for whom English is not their native language. And they're trying to acquire English language skills. Now, before I say more about this, decline of the critical period. and what happens as synaptogenesis, wanes. I should point out that in this early constructive phase, when synapses are being added at a phenomenal rate. Is an opportunity for brain development, to go, in a different direction. A direction that may be related to various kinds of learning disabilities, or other kinds of disorders of cognition. let me give you just a few examples of this. what seems to be known about individuals that are somewhere on the autism spectrum disorder is that, there appears to be an acceleration of this capacity for synaptogenesis. Such that, if one simply looks at overall brain size in children that are beginning to be evaluated and diagnosed with autism spectrum disorder. It's very possible that there is actually an acceleration of the rate of synaptogenesis and their cerebral cortex, which results in an overgrowth of the brain. Especially involving the cortex of the frontal and the temporal lobes. As well as the amygdala, that we'll say more about in the next unit of the course, as well as the cerebellum. And these are brain structures that are involved in social cognition communication, and the executive control of motor actions. Now as development proceeds in these children they, the overgrowth tends to normalize. towards where a typically developing child might be. But that's not to say that connections are restored to normal structure and function. It very well may be that aberrate connections that may have been developed during this period of overgrowth may persists, throughout the childhood and adolescent years, and indeed even into adulthood. Now, I'll give you just one other example, and that's the example of attention deficit hyperactivity disorder. And this disorder commonly known as ADHD, rather than there being an acceleration of synaptogenesis there seems to be a decrease in the rate of synaptogenesis. Such that the cerebral cortex again mainly in the frontal lobe and in parts of the temporal lobe, seems to be thinner than typically developing children that don't have this disorder. So, it very well may be that this decrease in cortical thickness is attributable to a relative, delay or perhaps, a relative reduction in the total numbers of synaptic connections that are established. we still don't really understand the full consequences from a functional perspective, but its reasonable to at least, hypothesize. That this reduced rate of synaptogenesis is leading to the construction of dysfunctional circuits that can modulate behavioral control, and perhaps this is part of the phenotype associated with this particular disorder.
