Well, although we don't know why we sleep, one thing that's quite clear is that we should sleep every day. And sleep is one example of many rhythms in our body and brain that operate on roughly a daily cycle. These are called circadian rhythms. So there are really a diverse set of physiological and homeostatic functions that follow these kinds of daily rhythms. And the period of these rhythms is approximately 24 hours. So, here's some examples. on the top we see a record of body temperature. In the middle, a measurement of the production and the circulation of growth hormone in the serum. And on the bottom, the hormone, Cortisol. And we see that they each show their own kind of daily rhythm. In case of body temperature, body temperature begins to fall just about the time that we began to approach our usual bedtime. And body temperature is basically bottoming out during our sleeping time and then it begins to rise close to the time that we normally awake. So, this is pretty good evidence that perhaps sleep has something to do with thermal regulation. Looking at various hormones, we see that some hormones seem to rise and peak as we are preparing for sleep. And then fall and remain low for the duration of the night's sleep. Other hormones begin to elevate, perhaps in preparation for the onset of activity once we awake. That might be the case for Cortisol. Now, these daily or circadian cycles are actually quite closely aligned to our environmental cycle of 24 hours. but there's quite a bit of interesting neurobiology that explains how that happens. As it turns out, we have within our brain a circadian clock, a daily clock. However, the period over which that clock operates, as it turns out, is a little bit longer than 24 hours. So here's some experimental data from human volunteers, who were willing to sequester themselves. In a room that could be deprived of cues about day and night. And so when the cues were present, we see that the subjects were active and sleeping for a 24-hour period. And the period tended to start and stop at about same time each day. being trained by the presence of cues in the form of perhaps a radio signal or television, something of that sort. But when these cues were now deprived from this environment, we see that there is a gradual shift forward in time of these daily cycles, suggesting that. At least for this cohort of subjects, the average period was longer than 24 hours, actually by quite a bit of time. we actually think that the period is, is not 26 hours but much much more closer to 24 hours. But nevertheless it's longer than our environmental circadian cycle. That's tied to the solar day. And in this experiment, when the cues are once again restored, now the subjects are more or less, entrained to the environment going forward. So where does this kind of circadian rhythmicity come from within the brain? And how is it tied to environmental signals? [SOUND] Well the answer is that there is a set of cells in a nucleus of the hypothalamus called the Suprachiasmatic nucleus that contain a molecular clock. And this molecular clock is responsible for generating our circadian rhythm. Now this molecular clock is then entrained to the environment via projections from the retina. So here we have a familiar figure for you now I'm sure. It's a depiction of our central visual pathways. And while when we studied vision, our focus was on the projections from the retinas back to this visual thalamus, which then relays signals into the Striate cortex, right? Well, we also mentioned very briefly, that there is a projection from the retina to the hypothalamus which is focused on this small nucleus. The suprachiasmatic nucleus which is in the hypothalamus, and it's the regulator of circadian rhythms. It's where these rhythms are actually generated. Before I tell you more about the suprachiasmatic nucleus, I just want to say a word about the retinal cells that send their projections into the anterior hypothalamus here. this projection actually comes from a population of ganglion cells that contain a photo pigment. So you'll recall that when we talked about the retina, of course we emphasized the fact that our photo pigments reside in photo receptors, which are a distinct type of cell. exemplified by rods and cones that are in the most distal part of the retina. And, as you may remember, one of the surprises about photo transduction for cones and rods in the retina. Is that when a light turns on, these cones hyperpolarize. Remember there's a dark current where these cells are somewhat depolarized relative to all of the neurons, when they are present in the dark. And when light strikes the photo pigment, a transduction cascade unfolds. And the result is hyperpolarization. Well it turns out that's not the case for the photosensitive cells that send their signal into the hypothalamus. These are a unique class of ganglion cells. We can call them photosensitive ganglion cells. And they contain a pigment called melanopsin. And you see what happens relative to the cones. When light is turned on, there's a bit of a sluggish response, where the cells are very slow to depolarize and then once they hit threshold for firing action potentials, they're dangling cells after all, so they can fire action potentials. There is now a, a long barrage of action potentials and even after the light shuts off, the action potentials and the depolarization envelope continues for some period of time. So, these are cells that are not going to be very good at all. for contributing to image formation in the brain but on the other hand they be quite adequate for sensing the overall level of illumination in the environment. And then communicating robust signals into the brain regarding slow gradual changes in illumination. So the projections of these cells then go to the superchiasmatic nucleus. And some really wonderful experiments were done that really helped to establish neurons in this nucleus as being the master clock for the body. for example, we know that if we can isolate these cells from the hypothalamus, basically take them out of the brain, and grow them up in a culture situation. That these cells will continue to generate a rhythm, that is roughly a day's length in, in period. Also we know that if we take away these cells, if we oblate them from the brain of any animal then the Circadian rhythms break down and we will know that if we put the super cosmotic nucleus neurons of on e animal into an animal whose super cosmotic nucleus has been destroyed. Then circadian rhythms can be restored and the recipient animal from this donor. So, taken together, this is very good evidence suggesting that the suprachiasmatic nucleus harbors the cells that generate the circadian rhythm. And fairly recently, molecular biologists were able to tease apart The genes and the gene products that are responsible for creating these circadian rhythms. And it turns out there's really a beautiful set of genes and proteins that are turned on and that then feed back upon. The transcription of the very genes that produce the proteins in question. And there are essentially two sets of complimentary pathways that feed back upon each other. And as they do so, they generate a rhythm. So here's roughly how this goes. So as light is striking the retina, and activating those photosensitive ganglion cells. Action potentials arrive at the suprachiasmatic nucleus and active these cells, and with light activation. Being conveyed to these cells, they turn on a set of genes. And among the gene products that are turned on with light activation are genes that produce these proteins called CLOCK and BMAL1. So these genes turn on these proteins, these proteins are produced in the cytoplasm. And these proteins then associate with one another as dimers. And then they enter the nucleus of the cell. And they form this complex that combine to regulatory elements of target genes. And those Regulatory elements are called E-boxes. And these basically form transcription factors that can then turn on a set of target genes. Well those genes produce their products, and these include a variety of proteins. The ones we understand best are these Proteins CCG and proteins from the Per family, Per 3, Per 2. Several of these proteins will aggregate and form their own dimers that then translocate to the nucleus. And as they do so, they inhibit or they prevent The binding of this b mal one and clock protein dimer to these e boxes. So this is a form of negative feedback. and it takes some time for this to unfold. So obviously when you Transcribe a gene, and produce messenger RNA. And then translate that to protein. There's a certain half life to the viability of the message, and then the protein product itself. So as the protein and the transcript begin to degrade. there's a self-limiting period to the duration of this cycle. So, that fact together with this negative feedback ensures that this period is going to run for just a little bit more than, 24 hours, maybe about 24 and a half hours. So it will take about that length of time. For this cell to be reset and ready to again receive a signal about environmental illumination from this retinal hypothalamic pathway. Well, I think there's a, a much more cogent presentation of these molecular mechanisms for those of you that are interested in it. And you can find it on the website that supports our textbook. And I provided for you a hyperlink in your tutorial notes, so hopefully if that link's working just click on that and that will take you right to this tutorial. All right. So, so far, what I've told you is that, these circadian rhythms can be entrained from the retina. And they generate the cycles of activity that, with retinal input, are tied to about a 24 hour solar day. So what then are the down stream consequences of these indigenous rhythms that are entrained to the environment? Well, one such consequence is the regulation of hormones that then can affect wide spread systems throughout the brain and the rest of the body. And one important hormonal system that's activated in this way is the melatonin system, which is produced by the pineal gland. So here's a bit of an illustration showing you the pathway by which this happens. So here's our retinal ganglion cell, providing input to the hypothalamus, the superchaosmotic nucleus. Here and the suprachiasmatic nucleus has projections really to a number of other hypothalamic nuclei. One of them is this paraventricular nucleus. You may remember from our consideration of the visceral motor system that the paraventricular nucleus has some large cells that grow axons all the way down. To the intermedial lateral cell column of the spinal cord, where the cells then can activate our pre-ganglionic sympathetic neurons. And some of those pre-ganglionic sympathetic neurons will synapse on the superior cervical ganglion, and activate our ganglionic sympathetic neuron that innervates the pineal gland. So in this way turning on the Suprachiasmatic nucleus and the Hypothalami circuit at just the appropriate time during out circadian cycle can lead to the production of melatonin by the Pineal gland. And melatonin is a very important hormone. It begins to prompt a transition. from wakefulness towards drowsiness and eventually sleep. So melatonin is one of the more proximal signals, not the only one, but one of the important signals that helps to promote a change in the state of body and brain in the direction towards sleep. So here's the data showing the production of melatonin throughout our circadian rhythm. And as you can see here, the production of melatonin rises in the early evening typically. And continues to rise after we've fallen asleep. And then somewhere during the night's sleep The levels of melatonin fall precipitously as we approach daybreak. And as we awake and begin our day they remain low through much of the day, until they begin to start building up again in the later afternoon. So this daily cycle of melatonin is an important consideration and modulating Our daily rhythms of sleepiness and wakefulness. Some of you may have tried taking a commercial version of melatonin as a way of dealing with jet lag or perhaps other kinds of disorders of sleep. And, unfortunately, it doesn't seem to work that well for everyone, taken exogenously. We don't really know why that is. But at least some individuals will certainly report a great benefit of melatonin as therapy for dealing with, insomnia. either because of jet lag or other environmental or behavioral causes, or because of some underlying disorder of sleep.
