Written by: Caleb Greer, Clinical Intern – Cerebrum Health Centers
Reviewed by: Dr. Brandon Brock, MSN, BSN, RN, NP-C, DCN, DCM, DAAIM, BCIM, DACNB, FICC
Structural content edited by: Tara Brock
Post 4: Sleep – What’s the big deal?
Many people know about sleep and its different cycles, but not many know what defines each in terms of the areas involved and the chemicals that mediate each. This review will mainly cover these structures, their basic physiology, and consequential concepts. Sleep is a multifaceted expression of survival that still puzzles researchers to date due to its massive consumption of lifespan, human and nonhuman alike; consequently, it is because of this life-vacuum that people decided to seek out the reason for its necessity, and, over the years, researchers have discovered that sleep is vital for many functions, such as learning, memory consolidation, and neuropathway reinforcement. Sleep is divided into stages, and some of those stages have stages. We’re just going to stick with the main two – Rapid Eye Movement (REM), and Non-REM. As you move through this paper be sure to follow along with the mind map, especially if you’re a visual/procedural learner – a lot of times there will be extra information in them that weren’t entirely necessary to include in this written portion but important nonetheless.
It’s crazy to think that our bodies perform almost all of our functions without us even knowing about it or having any say on how it happens. You don’t have to think to breath, and you don’t have to think in order for your guts to digest food, and luckily you don’t have to volitionally govern the processes by which you wake up or stay aroused either. Let’s begin with the ascending reticular activating system (ARAS); this bad boy is, as you probably guessed, in that mess of nuclei and white matter called the brainstem reticular formation. I’m not going to go through everything that makes the ARAS tick, but rather I will stick to the main components, which are the raphe nuclei (produce serotonin) and the locus coeruleus (produces norepinephrine). These guys release their neurotransmitters and travel to affect areas that govern attention and arousal, like the thalamus, tuberomammillary nucleus, basal forebrain, and the hypothalamus. When those areas are stimulated, their respective action is to increase arousal and decrease sleep-promoting transmission. In response to ARAS stimulation, more arousal-promoting transmitters are released that perpetuate the wake state. Other factors outside the ARAS influence arousal also, like the suprachiasmatic nucleus (SCN), which regulates the circadian rhythm, and peripheral cues like cortisol and ascending sensory information from daily activity. Something else that I found particularly interesting is the role that inhibitory GABA plays in promoting a wake state: Inhibition is still a means of excitation – just indirectly. In the brainstem and hypothalamus, GABAergic projections not only maintain inhibition of sleep promoting centers, but also the disinhibition of wake promoting centers governed by the inverse state-inducers. This provides possible mechanisms for paradoxical reactions in GABA supplementation for sleep. The next component of maintaining arousal is the lateral hypothalamus, which, oddly enough, also plays an equal and opposite role in REM sleep. The lateral hypothalamus releases a peptide called orexin (or hypocretin), which from research essentially seems like the master controller of arousal. Orexin containing neurons have massive projections across the cortex and brainstem, but more importantly it is significant to note here that they innervate and excite all of the arousal promoting centers we’ve talked about thus far, which means that it is one hell of a modulatory system. So what induces the release of orexin? The answer is homeostasis and survival. Factors such as hunger, temperature, emotion, stress, visceral changes, and anything else that requires arousal mediates the susceptibility of the orexin system. As a student of functional neurology and medicine this is so cool to me – with the amount of people I’ve seen that have had trouble sleeping, do you know how many have also had significant stress? Dysglycemia? Emotional unsteadiness? Poor gut function? I mean the list goes on to possible reasons for the inability to fall asleep, but it boils down to their body telling them no! To try and drive home the importance of orexin, loss of orexigenic neurons has recently been found to be the cause of narcolepsy in a majority of cases (90%), where pathogenesis is hypothesized to be autoimmune. Always remember that everything correlates, and assessing hypothalamic function is critical!
With all these mechanisms to stay awake, you may wonder how you manage to fall asleep at all. Well, interestingly enough there are just as many mechanisms to make you fall asleep as there are to stay awake, and much of it has to do with exogenous lighting, activity level, and self-inhibiting feedback in the arousal system. Decreased lighting leads to less photic stimulation of the retinal cells that talk to the SCN. This difference in stimulation is what entrains circadian rhythm via genetic regulatory factors that I won’t get into. Okay I lied – when neurons in the SCN are excited they start messaging cascades that result in the phosphorylation of a certain genetic transcription factor called cAMP regulatory element binding protein (CREBp) bound to a cAMP regulatory element (CRE), which further results in the transcription of so-called “clock-genes” that are responsible for cellular time keeping (Ex. per1 and per2). So, physiologically, we should be getting ready for sleep when the sun goes down – imagine that. The SCN projects to an area of the hypothalamus that is highly implicated in the generation of non-REM sleep – the ventrolateral preoptic area (VLPO) – which contains GABAergic and galalinergic neurons that project to the arousal centers in the brainstem, leading to a depression of arousal and subsequent sleep. This area also receives input from surrounding hypothalamic areas, like the median preoptic nucleus, that begin firing before sleep onset (whereas the VLPO fires primarily at onset of and during sleep), suggesting that they begin the transition out of wake that allows the VLPO to exert its effects on the arousal centers. Aside from circadian control, our day-to-day activity and metabolic workload influences the transition out of wakefulness and into sleep via a chemical called adenosine. Adenosine appears to be one of the main homeostatic regulators of sleep; it is a byproduct of energy production that accumulates in extracellular fluid as the day goes on and, as you can imagine, the amount present increases with a greater metabolic demand. The mechanism of action here is through inhibitory Gprotein cell signaling in wake-promoting centers and excitatory G-protein cell signaling in sleeppromoting centers. This flip-flop of excitation and inhibition is due to receptor subtypes for adenosine; this mechanism is also the reason for caffeine’s (and any other methylxanthine) arousal promoting effects because it antagonizes adenosine receptors. On that note, studies show that methylxanthine injections into mice reverse the effects of sleep deprivation on memory consolidation and learning retention, suggesting that the build up of too much adenosine results in too much inhibition of hippocampal neurons implicated in these processes. Now that we are on the topic of learning and memory consolidation, it is important to discuss the role that non-REM sleep has in it. During non-REM sleep, ensembles of neuronal networks that were previously activated from conscious experience are replayed and re-fired. This time is also when there is the trafficking of hippocampal-dependent memory into long-term memory mediated by the neocortex, which is what gives non-REM sleep the characteristic of general memory consolidation. No sleep = less retention of previous conscious experience. No more all-nighters (unless there’s lots of coffee)!
Ah, the dream-state. This stage of sleep is also called paradoxical sleep due to its similarity in EEG recording to the wakefulness state. This is also the characteristic that is theorized to give REM sleep its domain over dreaming. While dreaming is still observed in non-REM sleep, sleep studies generally find that 80% of dream recollection occurs after being woken up from REM sleep which implies its important role in the generation of dreams. There has been much mystery as to how REM sleep is switched on and much speculation on what neuroanatomical structures are responsible for it. Due to the high concentration of acetylcholine in the cortex and brainstem during REM sleep the initial culprits were assumed to be the cholinergic nuclei in the brainstem and basal forebrain. As more studies were undertaken, two main nuclei were given the role of the ultimate REM modulators: the laterodorsal tegmental nucleus (LDT) and the pedunculopontine nucleus (PPT). The hypothesized responsibility for these groups is twofold, one being to activate the cortex and the other to depolarize and activate the pontine reticular formation. This activation is presumably accomplished by antagonizing the inhibiting effects of GABAergic projections from REM-off neurons, which is supported by experiments where acetylcholine and GABA are injected (separately) into REM-on regions and the effects are excitation and inhibition, respectively. Again, this phenomenon outlines a possible explanation for paradoxical effects of pharmacological GABA intervention. Further studies demonstrated that a couple small groups of cells around the locus coeruleus and LDT were heavily responsible for Initiating REM sleep. These nuclei rely on non-REM sleep promoters that gradually inhibit the REM-off centers, thus allowing the transition into REM sleep. Another key player in REM sleep is the lateral hypothalamus (here’s that opposing role), which contains melanin-concentrating hormone (MCH). MCH containing neurons project to the exact same areas that orexinergic neurons do but have the opposite effects, which results in an inhibition of REM-off populations. REM sleep has been implicated in the consolidation of memories that have reward/punishment circuitry involved as well as amygdala-dependent memory. Another phenomenon that occurs during REM sleep is muscular atonia, or sleep paralysis. This process arises from glutaminergic projections to descending interneurons from the same nucleus that is proposed to be the REM-on switch. Problems here happen when there are issues with the integrity of sleep cycle, narcolepsy being one of them, where loss of the ability to maintain arousal leads to spontaneous switching of arousal state. Other disorders are associated with REM-specific malfunction and loss of atonia, which results in the acting out of dreams and random muscle twitching. Research is now finding that these REM sleep behavioral disorders have an 80% correlation with developing synucleinopathies (Lewy body dementia, Parkinson’s, multiple systems atrophy) on an average of 10 years down the road. Talk about a nice window of time for reversal and prevention.
I really hope that this paper sheds some light and allows you to better understand some of the mechanisms behind sleep and why it’s important. Some cool clinical things that you can draw from this are that stimulation to these parts of the brainstem or supplementation (based on brain evaluation forms, nutritional assessment, etc.) can effectively help combat common complaints regarding sleep. Asking the right questions can help get you on the right track when it comes to finding out where the lesion or deficiency is along the sleep cycle. Do you have trouble falling asleep or staying asleep? Do you fall in and out of arousal throughout the day? Does your mind race and keep you up even when you’re tired? Does coffee help you stay awake or does it not do anything at all? Sleep is an extremely vital function, so when it is dysfunctional there needs to be an endeavor to figure out why.
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