CSB346 Lecture 9 Notes

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Cell and Systems Biology
John Peever

CSB346 Lecture 9 – Respiratory Control during Sleep (April 2, 2013) Slide 3 – Sleep affects ventilatory control - Breathing disorders during sleep are one of the primary disorders of the neural control of breathing. Slide 4 – Sleep directly affects the respiratory network - The respiratory network is the group of neurons in the brainstem that are hypothesized to generate the breathing rhythm. Slide 5 – Sleep states - The two broad states of sleep are REM sleep (also called dreaming sleep, active sleep, or paradoxical sleep), which is the most fundamentally remarkable, and NREM sleep. - REM sleep o The brain waves are somewhat similar to awake state. The brain waves in a sleeping brain and a waking brain look the same, except you are unconscious and unaware of your environment in REM sleep. o There is loss of muscle tone (e.g., muscle paralysis) but the brain looks like it is largely awake. Why do you have a waking brain with no motor activity? This is an odd phenomenon. The loss of muscle tone in REM sleep is designed to keep the sleeping brain quiet, so you can’t act out your dreams. o You have muscle twitches. There is no overall muscle tone but there are muscle twitches. This is odd. They seem to largely coincide with rapid eye movements. o Penile erections and vaginal moistening are common in healthy males and healthy females respectively. o You are easily awoken in REM sleep than in NREM sleep. Even though you are largely disconnected from your environment, it is easy to poke people and wake them up. o It is a time of vivid dreams. There is also dreaming in NREM sleep, but the contents of what is being dreamed about are not vivid (e.g., general, no real storyline). - NREM sleep o All of the physiological variables are constant (e.g., blood pressure, breathing, heart rate, brain activity). It is the disconnected deep sleep. This is considered the restorative type of sleep. Slide 6 – Breathing patterns in sleep and wake - You can tell when someone is in NREM sleep (or deep sleep) just by looking at their breathing. Their breathing is slow, deep, and quiet breaths. You are largely disconnected from the external world, and breathing is slow and methodical. - In REM sleep, they have a schizophrenic breathing pattern. The breathing pattern is fractionated. REM sleep is a time of very chaotic breathing. - Quiet wakefulness is a mixture of the two. It is a shallower breathing. It is faster on average. Ventilation is more variable due to the fact that you are paying attention to something. Slide 7 – Breathing patterns in NREM sleep - NREM sleep is the easiest stage to tell that you are in NREM sleep just by looking at breathing. o V = tidal volume = volume of respiration o Thor mvt = how much the rib cage is moving in and out o Abd mvt = how much the abdomen is moving in and out o CECO2 = overall fluctuations in CO2 levels o SaO2 = overall levels of how much O2 is in the arterial blood - You can see that nothing is changing and everything is constant. This is what defines NREM sleep. It is the consistency. Slide 8 – Breathing patterns in REM sleep - When you sleep, you enter into the four stages of NREM sleep (but not always in that order) and then you enter into REM sleep. You transition between REM and NREM sleep within seconds. Within seconds, your breathing goes from being unchanging to looking completely chaotic. o V  The volume of respiration almost falls to zero. o SaO2  The arterial saturation dips down. It doesn’t stay the same. This is an important observation, but often under-emphasized. The variability is not pathology. - During REM sleep, breathing is chaotic. Those breaths physically impact how much CO2 and O2 is in your blood. The chaotic breathing pattern is having an effect on basic physiology of how much O2 and CO2 is in the blood. This is OK in us when we are healthy, but it is not good if you are someone with heart issues. Slide 9 – NREM sleep  Respiratory neurons - He recorded respiratory neurons from the VRG. Since breathing changes when you go to sleep, the respiratory cells that generate breathing must be sensitive to the changes in sleep. - It is an inspiratory cell from the VRG. The VRG is in and around the NA. He shows that there are respiratory cells sitting in the X areas, which are the region of the VRG. He watches what the cells do as the animals goes from awake to sleep. - Even though the cat gets drowsy, the cell starts to change its firing. It starts missing a lot of activity. The cat falls asleep and the cell stops working. - This is to point out that sleep directly impacts the respiratory network that generates breathing. It impacts the cells within it. o NREM sleep can impact the respiratory neurons that make up the respiratory network. o Sleep impacts the control of the respiratory neurons that are presumably generating normal breathing. The neurons in the VRG are being affected by the state of sleep. o This is showing that the brain is changing the way it works when you fall asleep. Slide 10 – REM sleep  Respiratory neurons - The firing of respiratory neurons is being recorded. He recorded one cell. This is how many action potentials that cell fires when it is in NREM sleep. At the line, the animal transitions from being in NREM sleep into REM sleep. Look at how the firing of the cell changes. It goes from being a constant state to a diverse number of action potentials that is being fired per second. It is all over the place. The action potentials are higher than in NREM sleep, but it goes up and down. In NREM sleep, it is largely quite similar overall. - In REM sleep, the activity of a respiratory cell is very variable. This is fitting with what you see in overall levels of ventilation. - This slide does not necessarily support the previous slide. o Previous slide  In NREM sleep, the cell is firing during wake but it stops firing during sleep.  This shows you that respiratory neurons are affected by sleep. They are active when you are awake, but they stop when you are asleep. Cells o This slide  The cell is firing at a very constant pattern because it is above zero.  This shows you that cells behave differently in REM sleep than they do in NREM sleep. The signature of most cells in REM sleep is that they are chaotic. They don’t have a monotonous routine pattern. This may be reflecting the overall instability or chaotic nature of REM sleep. Slide 11 – Sleep affects the chemical control of breathing - The cells in the respiratory network are sensitive to sleep. - Sleep impacts the way that the brain and the respiratory network listens to chemical signals. Slide 12 – Sleep affects chemosensitivity - They looked how much O2 saturation in your arterial blood supply you have. They looked at how ventilation changes as a function of how much O2 you have. - As you become hypoxic, you breathe more in the awake. On average, when O2 levels drop, breathing goes up, although it is a highly variable response, but it is the general phenomena. - During REM sleep, the slope is less steep. This means that you are not particularly responsive to hypoxia when you are in REM sleep. This is not good, especially if you have a heart problem. o Chemosensitivity (and also the respiratory system) suffers from the lack of sensitivity when you are asleep. - The 2, 3, and 4 are representing the different stages of NREM sleep. Even in NREM sleep, the sensitivity to O2 (e.g., how ventilation is responding) is blunted or reduced. Slide 13 – Sleep affects chemosensitivity - The response to CO2 is also blunted in humans. In dogs, CO2 responsiveness is almost absent. - We are looking at the amplitude of every contraction of the tongue muscle. Every time you breathe, your tongue contracts a bit. The Y axis is a neural index of ventilation. - We are looking at how the height of those changes in REM, NREM, or wakefulness as a function of how much CO2 is being inspired. This was done in a rat. o During wakefulness, as you increase CO2 levels, the height of the breath is getting bigger overall. You can infer that ventilation is increasing. o When the rat enters into NREM sleep, you can that the overall level of GG activity are reduced, even at baseline levels (e.g., no CO2). The response to CO2 is somewhat reduced, but not massively. o In REM sleep, the rat doesn’t respond to CO2. It is not statistically significant. - The respiratory system is not sensitive to chemosensation, especially CO2. Remember that CO2 is a powerful stimulus to breathe, yet during REM sleep, it seems like the brain doesn’t realize that it is being stimulated by CO2. Slide 14 – Sleep affects the mechanical reflex control of breathing. - Not only does sleep impact the respiratory network and the cells that control breathing, but it also impacts how the respiratory network responds to fundamental changes in chemosensitivity. The response to CO2 is ignored in REM sleep, and reduced or blunted in NREM sleep, compared to wakefulness. Hypoxic ventilatory response is also reduced. - When there is negative pressure in the upper airway, you have an increase in the GG activity. This is called the negative airway pressure reflex (or upper airway negative pressure reflex). What happens to those reflexes during sleep? Are they altered or affected? Slide 15 – Sleep reduces airway muscle activity - Air enters in through the upper airway. The upper airway is a collapsible tube. The openness of the upper airway is dependent on muscle contraction goes on in the upper airway. - When you are awake, you have high levels of overall muscle tone. When you go to sleep, there is a loss in overall muscle tone. There is lots of airway muscle tone in wakefulness. There is a reduction in tone in NREM sleep. In REM sleep, there is almost no muscle tone. REM sleep is almost a state of paralysis. - The respiratory systems are a remarkable part of the body because the skeletal muscles are one of the only ones that don’t switch off entirely. The diaphragm, the airway, the thoracic rib cage are skeletal muscles that still largely maintain activity in REM sleep. The muscles in your hands, arms, legs, neck, eyelids are almost shut off. o There aren’t negative or no pluses in REM sleep because of the airway muscles. - What is the consequence of the reduction in muscle activity? o The muscles of the airway are contracting and dilating the airspace in wakefulness. o In NREM sleep, they get a little narrower. When the muscles relax, it narrows the airspace and it limits the airflow into the lung. o In REM sleep, it narrows a little bit more. The airway is getting narrow because the muscle tone of the muscles in the throat area is relaxing. The relaxation is causing them to decrease their rigidity and the airspace gets smaller. As the airspace gets smaller, it limits how much air can flow into the lung. - All of the muscles in the airway, intercostals of the thorax, and diaphragm reduce their activity during NREM and REM sleep. The diaphragm doesn’t shut off in REM sleep. - Sleep reduces airway muscle activity, and reduces intercostal and diaphragm activity. Overall, sleep has a negative impact on muscle activity function. The consequence of this is that it can limit how much O2 or air is flowing into the lungs. - The consequences during sleep is that you are going to have increased airway resistance, decreased muscle activity, which leads to decreased ventilation during sleep. - The clinical relevance is that the narrowing of the airway during sleep can potentiate hypopneas (e.g., almost apneas but not quite) or airway obstructions. Slide 16 – Upper airway is suppressed in sleep - This is what happens to the upper airway muscles in an animal that is going to sleep. He focuses on the GG muscle. He surgically implants an electrode into the tongue muscle. - When the rat is awake, the GG (and the DIA) contracts and relaxes. The overall level of activity is high when the rat is awake. The large blips are duet o movement. - When the rat falls into NREM sleep, the level of activity goes down. There is low GG muscle activity when the rat goes into NREM sleep. There is not a huge change in the DIA activity. There is a slight reduction, but it is not as prominent as it is in the tongue. - When the rat falls into REM sleep, the GG muscle activity is almost absent. The respiratory signal completely falls off. o In REM sleep, breathing is disorganized compared to NREM sleep. - This shows you that there are high levels of muscle tone when the rat is awake. It falls off in NREM and is almost absent in REM. This is experimental evidence that shows you that muscle tone is high in waking, goes down in NREM, and falls absent in REM. o This does not tell you anything about ventilation. This tells you the overall levels of
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