There's a couple of other key players that I want to localize for you. If we look into the medial part of the hypothalamus, we can identify some of these clusters of cells. Here's our Suprachismatic nucleus sitting right about the Optic chiasm, of course. And back in the posterior part of the hypothalamus is where we find that tubero-mammillary nucleus, just dorsal to the mammillary body. Now, our orexin neurons are those that are producing this peptide that are involved in promoting the wakeful state. And the orexin neurons are found in the lateral part of the hypothalamus. So just a little bit deep to the wall there of the third ventricle. Now, I want to also talk about this nucleus here, the ventrolateral preoptic nucleus. So, this is a nucleus that's found In the anterior part of the hypothalamus. And it's very important because it seems to interact with structures in the posterior part of the hypothalamus, specifically this tubero-mammillary nucleus. And the ventral lateral preoptic area, or preoptic nucleus. Has an antagonistic effect with respect to these orexin neurons. So this preoptic area is going to try to suppress the activity of these histaminergic neurons among some of our other activating neurons. So there's a bit of a push and a pull that's happening here. With the orexin neurons providing the push signal promoting wakefulness, and this preoptic region providing the pull signal. Which is trying to pull the brain into a state consistent with drowsiness and eventually falling asleep. So schematically then, here's what this might look like. So, here's our orexin neurons that are sending excitatory signals, activating our brain stem reticular formation neurons that are supporting wakefulness. As well as sending projections to the posterior hypothalamus, where they're activating those histaminergic projections. From the tuberomammillary nucleus supporting the wakeful state. Now, these circuits are being antagonized by this anterior part of the hypothalamus. This ventral lateral pre-optic nucleus, which is suppressing the activity of this tubero-mammillary nucleus. And likewise sending signals that have a suppressive influence over our cholinergic neurons and our adrenergic neurons and our serotonergic neurons of the brain stem. So this transition, then, between being vigilant, being awake, being attentive, and being a bit sleepy and being a bit drowsy. Is likely playing out in the posterior hypothalamus, depending upon the balance of these influences. Whether the sleep promoting system Is winning or is the vigilance promoting system. Now before I say a little bit more about this, I do want to share with you an image that was taken by a student of mine just a few months ago in the brain anatomy lab. And it's a very unusual look at this beautiful. Structure right here, the locus coeruleus. So thanks to Jonathan Wineholt who took this picture, what I had a student do, actually not Jonathan but another student. We were dissecting some human brains as a way of learning human neuroanatomy. And I asked the student to make a midsagittal cut with a large knife through this brain. And the student was just a bit off the mid line. But that turned out to be really fortuitous. Because look at what we found when we looked into the brain stem, following this parasagittal section. We found this beautiful band of dark substance in the dorsal lateral tegmentum of the pons. And what we're looking at here is a trail of pigment that is present in the cells that produce norepinephrine. So this is, in fact Are Locus Serillius which is a Latin term meaning blue spots. So, this is the, the blue spot in the brain, or this is the dark substance. We also have some dark substance here on the medial edge of the ventral tegmental layer and substantia nigra compacted com-, complex in the midbrain. So we're actually seeing the dark substance in two places here, in this Parasagittal preparation. So thank you to Jonathan for sharing this picture with us and perhaps you'll have opportunity one day to see the blue spot for yourself in the human brain. So let's get back to talking about this balance between the sleep-promoting systems and the wakefulness-promoting systems. So one of the key factors in promoting a transition from being awake to being asleep is the activation of this ventral lateral preoptic area of the hypothalamus. It turns out that one substance that is activating this region is the substance, Adenosine. And sleep researchers tend to be really excited these days about finally beginning to understand how Adenosine seems to be operating in promoting a transition toward sleep. Of course, as you know, Adenosine is the a in ATP, Adenosine Triphosphate, which is the main molecule that carries energy in our brain cells. So as that phospate group is cleaved energy is released, and that energy can be used to support a whole host of metabolic function within brain cells. Well, as it turns out, we think, as our brain cells are active during the day, and energy is being consumed at a higher rate. Then ATP is being broken down into Adenosine diphosphate, and eventually Adenosine monophosphate, and then finally free Adenosine is available and is released from cells, and begins to accumulate in the extracellular spaces. Well in the region just in front of the hypothalamus called the basal forebrain, there are nuclei there that seem to be sensitive to these rising levels of Adenosine. So as Adenisone rises in this region of the basal forebrain, it drives activity That is exciting these cells of the ventral lateral preoptic area. So the basal forebrain then seems to play an important role in driving this sleep promoting system that's coming out of the anterior hypothalamus. Leading to a suppression of the posterior hypothalamus as well as these brainstem nuclei that are otherwise responsible for maintaining. alertness in the conscious state. And Adenosine has been conceptualized as being a thermostat, of sorts, that is sensitive to the energy that's being consumed by neurons. So as energy is being depleted by these brain cells Adenosine is accumulating, signalling the body to drift off into a state of quiescence, that is to falling asleep. And as we progress through a typical night's sleep, adenosine levels fall again. So this has led to the hypothesis that adenosine is a kind of energy thermostat. In the basal forebrain region that is indicating the expenditure of energy over a very long time scale, the time scale of the daily rhythm. And this accumulating extracellular Adenosine then, might be one of the proximal factors in promoting a transition from wakefulness towards sleep. Now, it's quite interesting that of course human cultures for thousands of years have discovered that Xanthines like caffeine and Theophylline can block the activity of Adenosine on the basal forebrain region. Adenosine binds to Adenosine receptors, and caffeine and theophylline block these receptors. So while Adenosine is accumulating the impact of that accumulating Adenosine on the basal forebrain is mitigated by the consumption of these caffeinated substances. So those of us that find ourselves quite addicted to caffeine are trying to fight our energy thermostat and I suspect in the long run that's probably not a, a very wise lifestyle choice. So perhaps a little moderation is in order here probably is in my lifestyle for certain. [SOUND] Okay. Well, let's now turn to a bit of a closer look at the rhythms that are generated at the neuronal level that are reflected at the macroscopic level in our electroencephelographic depiction of brain waves. So these rhythms reflect a bi-stable condition of our thalamocortical projection neurons. So these thalamocortical projection neurons basically exist in, in one of two physiological States. they may be at times in an oscillatory state, or they may be tonically active. And as it turns out, this oscillatory state is the state that we find these cells in as we transition to deeper and deeper levels of non-REM sleep. The active state of body and brain is when these cells are then depolarized out of this oscillatory mode and are in a more tonic, active state. Where they can faithfully transmit information from their input sources through their thalamic relays to the cortical regions that they innervate. Here's a look at these neurons in, these two states. So, when an animal is asleep. And we look at the recordings of membrane potential from a thalamocortical cell. We see that these cells are oscillating. In a fairly slow rhythm there is a slow depolarization envelope that hits threshold and then fires a series of action potentials. And then that leads to a deep hyper-polarization. So this is the oscillatory state. The membrane potential is hyper-polarized. And that hyper-polarization triggers a slow depolarizing envelope that is attributable to the activation of a calcium ion channel. And so this depolarizing envelope is actually a calcium spike, although it's not particularly spiky. Because it has such a slow time course. But as this depolarizing envelope proceeds, eventually a threshold is reached for the activation of our much faster voltage gated Sodium and Potassium channels. So when that threshold is reached, Hodgkin Huxley style action potentials fire. And that leads to a barrage of activity, a little burst of activity, that rides on the top of that depolarizing envelope. And after that brief barrage of action potentials, then the membrane potential hyper polarizes again beginning yet another cycle. So this oscillatory mode is what explains this slow wave hyper-synchronous behavior that can be observed in thalamocortical systems while we fall into deeper levels of sleep. Now, this hyperpolarized state is induced [SOUND] by withdrawal of these brain stem inputs that are otherwise promoting depolarization. So a withdrawal of cholinergic and adrenergic inputs to these thalamic neurons causes them to slip into this hyperpolarized state. Where this burst generating mode begins to take hold of the membrane potential of these cells. And when these cells are oscillating, they are not responding to the inputs that they might otherwise convey onto the cerebral cortex. So this oscillatory mode is a means of physiologically disconnecting the thalamus from the outside world. And we think this is quite important because it helps us to not be distracted, not be awakened, not be aroused by stimuli that's failed to reach some kind of threshold of activation. So, obviously, that would be consistent with, maintaining a sleeping condition even with some, lower level degree of stimulus in the environment. Now, suppose there is a very strong stimulus in the environment. That may be enough to sufficiently drive afferent activity in the thalamic neurons. To depolarize them out of this oscillatory mode. Or, it might be sufficient to activate the brain stem systems that promote the waking state. Through one means or another, depolarizing these thalamocortical neurons will shift them out of their oscillatory mode into a tonic firing mode. And we see that here with this gradual depolarization of the membrane potential, and in this instance, it was induced by activating brain stem inputs from the cholinergic nuclei and from the locus coeruleus, and after these neurons have been depolarized. Now, they can respond to sensory stimuli. So this now is a barrage of action potentials. That is driven by the presentation of a sensory stimulus to this sensory thalamocortical neuron. So, the brain stem activating systems associated with the cholinergic and the adrenergic populations are those that are really critical. For inducing this state change in thalamocortical neurons from this oscillatory mode to this tonic firing mode. The oscilltory mode is a mode where the thalamus is disconnected from the outisde world, and the tonic firing mode is when the thalamus is now engaged and ready to faithfully transmit signals that it receives. Through the ascending sensory pathways that are running through the thalamus.
