CSB346 Lecture 4 Notes

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Cell and Systems Biology
John Peever

CSB346 Lecture 4 – Respiratory Rhythm Generation (January 22, 2013) Slide 1 – Neural signals to breath - Breathing is controlled by the brainstem. - We are going to focus on the neurons in the brainstem, how do they function and how do we understand how breathing is generated by those neurons. We will go back to the idea that the neurons are there. The neurons in the pre-BötC give you the regular rhythm, so just simple respiration. All the other neurons in the VRG, DRG, and PRG are talking to each other and creating the shape of breathing, not so much when we breathe, but how we breathe. Slide 2 – Respiratory muscle activities - The main controller of breathing is in the brainstem. This is called the RRG. All the neurons that create breathing (the rhythm and the shape) are the components of the RRG. The neurons become active at different parts of the respiratory cycle. They activate respiratory MNs and respiratory muscles. The muscles contract and you get thoracic expansion so air can come in. Slide 3 – Respiratory muscle activities - There are different respiratory muscles. The main respiratory muscle is the diaphragm, which is controlled by the phrenic nerve. There are two phrenic nerves on both sides. You have two nerves that control the diaphragm. - You have other nerves that control the upper airway muscles, which are the muscles that make sure that the airway is open and air can come in. - Most of the nerves are active during inspiration. The pharyngeal branch of the vagus nerve is active during expiration. They all have different shapes. How do the neurons talk to each other to generate different types of muscle activity and different types of activities. Slide 4 – How is respiratory rhythm generated? - The neurons are located in the brainstem. - This is a human brainstem. This contains the neurons that generate the respiratory rhythm. Slide 5 – What is a rhythm generator? - All the neurons are referred to as the RRG. - A RG generates a rhythm, which is something that is repetitive, always constant, and generated by a network of interneurons. The interneurons talk to each other and create the oscillation of breathing in and breathing out. - There are other types of rhythm generator, such as locomotion. o When you want to run, you start running, your leg is going to be moving, but you don’t think about it. Your body just knows that you have to move the left leg then the right leg. The RG in the spinal cord helps you with movements like running and helps control the activity of the right leg and the left leg. o The RRG have some neurons that control inspiration and some that control expiration. This is something that you don’t really think about. You don’t think of your breathing. You just breathe in and breathe out. The only time you think about breathing is when you are talking or singing. - There are a lot of different types of RGs (e.g., locomotion, breathing, chewing). You don’t think about it. You start it and then it is done. The initiation of a movement (e.g., running, breathing, chewing) creates a repetitiveness of the movement that is always constant. Slide 6 – What is a RRG? - In the RRG, the initiation is that you start breathing in. After breathing in, you are going to expire. Breathing is a repetitive thing that you don’t think about. - The output of the RG is motoneurons, which control the muscles that are allowing you to breathe in and out. Slide 7 – An example RRG - This is a simple way to think about how we generate this oscillation. - All the neurons located in the VRG, DRG, and PRG can be categorized as two groups: inspiratory neurons and expiratory neurons. The two talk to each other. Since they are interneurons, they are going to inhibit each other. When the inspiratory neurons are active, they inhibit the expiratory cells. When they slowly die down, the expiratory neurons will be less inhibited. The expiratory cells are going to inhibit inspiratory cells. You get a balance between inspiration and expiration. - This is a simple model of how breathing can be generated as a balance between inspiration and expiration, and the activity of these two groups of cells. Slide 8 – Where is thethRG? - Until the 19 century, we had no idea that the control of breathing was in the brain. In the early 19 century, people started to record neurons in the brainstem. This is what they show here. - This is the activity of the hypoglossal nerve, which controls the activity of the tongue muscle. They went to the brainstem and recorded MNs in this area. They showed that the activity of the MNs was matching the activity of the muscles. - They were able record neurons in the brainstem, which correlate to the activity of the muscles. - The neurons match breathing, but are they just active because the diaphragm is contracting or is it because they are telling the diaphragm to contract? Slide 9 – Where is the RRG? In vitro evidence - They took parts of the brainstem, put it in a dish, and they were able to record from the neurons and record from all the nerve endings that are supposedly going to respiratory muscles. - You can see a respiratory rhythm. The neurons were active. The nerves were active at the same time. You don’t need the lung. You just need this part of the brain to generate the rhythm. Slide 10 – The RRG in vitro responds to pH - In the same study, they wanted to show that the neurons will respond to the normal stimulus of the respiratory system. If they increase CO2, then what happens to the activity of the neurons? Can they respond to a change in metabolism? o They increased the amount of H+ ions (e.g., decrease pH; more acidic). What does the cell do? If you lower the pH, then you increase the frequency of the firing of the neurons. If you remove the H+ ions from the bath solution, you decrease the frequency of the activity of the neurons. o The neurons can generate a rhythm that is like breathing and that leads to the activity of respiratory nerves, but also responds to the normal stimulus that the respiratory system is supposed to respond to. - The respiratory neurons control the rhythm. How we breathe is located in the brainstem. The neurons can respond to the change in metabolism. Slide 12 – Examples of respiratory cells - All the inspiratory and expiratory cells create a network that shape how we breathe. - This is a schematic of the activity of different neurons throughout the inspiratory and expiratory cycle. When you record these different neurons in the brainstem, there are different ways for the neuron to be active. o I-Aug is inspiratory and augmenting neurons (e.g., the frequency of the firing is slowly increasing towards the end of inspiration; they become more active) o I-Dec is inspiratory and decrementing (e.g., slowly decrease the frequency of the firing; they become less active) o Late-I is making the transition between inspiration and expiration o E-Dec is expiratory and decrementing (e.g., firing a lot at the beginning and slowly dying down) - There is an association between the activity of the inspiratory neurons and the activity of the expiratory neurons. Since they inhibit each other and they have different ways of firing, then that shapes the overall way we breathe. - The bottom trace is how the phrenic nerve is active. When we breathe in, we slowly increase the amount of air that we get into the lungs. We slowly increase the activity or contraction of the muscle until the lung is fully expanded, and then it is relaxed. o The neurons are defining the rate of increasing the contraction of the diaphragm and then relaxing of the diaphragm. This is by the interaction of the different firing patterns between the inspiratory cells and the expiratory cells that you get a slow increase in inspiration and expiration. Slide 13 – Types of respiratory cells - These are real neurons. For each panel, the bottom trace is the phrenic nerve, which corresponds to the activity of the diaphragm. The top trace is the activity of a single neuron. - He looked at how the cells are firing in relation to the activity of the phrenic nerve. o (A) It is slow in the beginning. There is more activity in the end. o (D) It is active during expiration. It is slowly increasing its activity. There are a lot of action potentials in the end. - This is how cells have different shapes and can shape our breathing. Slide 14 – Functional organization of the RRG - The RRG are on both sides of the brainstem. Can one generate the rhythm independent of the other? What if you cut the communication between the left and the right side? What happens? - He cut the brainstem in half. He recorded the left and right phrenic nerves. Before the cut, the phrenic nerves are generally active at the same time. After the cut, they are not in synchrony anymore. The right phrenic is active during the inspiration phase of the left phrenic. The rhythm is not as regular as before. The two sides don’t communicate with each other anymore. You get a weird pattern of respiration that is not in phase. - You need to think about the RRG as a whole (e.g., the left and the right side). - How is the RRG organized? Is there a functional RG on the left and right side of the brain? - I removed all of the brain that makes them be able to recognize what pain is and be effectively conscious, but allows them to continue breathing. I removed everything rostal to the midbrain. I cut the brainstem into two halves, starting where we assumed the RRG is located on each side then down to the beginning of the spinal cord. - The hypothesis was that if this side of the brain can generate rhythm and send it to the phrenic MNs that cause inspiration in the diaphragm, then we should see two completely separate rhythms on each side of the brain. - This is the phrenic nerve on the left side and the right side. There are two phrenic nerves. This is what rhythm looks like before we cut the brain in half. - After we cut it in half, the rhythm being generated on the right side of the brain is entirely different from the left side of the brain. You still have inspiration. The left nerve is faster and wider. The right phrenic nerve is slower and narrower. o The amplitude is irrelevant because you can’t determine amplitude because we are recording the nerve. The nerve is sitting on an electrode. If the nerve moves, then it screws up the amplitude reading. Do not worry about the amplitude. - It is the frequency and the fact that they are firing out of phase. o This means that the left RRG generated one rhythm and the right RRG generated another rhythm, and they were independent of each other. This means that this side of the brain doesn’t have to talk to that side of the brain to generate rhythm. o We now know that one half of the brain can generate breathing by itself, even if one side of the brain is damaged. - This is fundamental to the whole organization of the system. - How reduced can we get this network? This experiment was in an intact animal where a small part of the brain was present. Could we slice a tiny area of the brain and look at the pre-BötC? Slide 15 – Smith et al. - They were able to locate a small group of cells in the medulla called the pre-BötC. When you cut a slice of the brainstem, put it in a dish, put an electrode there, and then you are able to record rhythm that is like breathing. This is a central group of cells that can generate breathing. The pre-BötC is generating the rhythm. - You can slice the brainstem into a thin slice. You still get the rhythm that looks like what respiration would be in an intact animal. You know that the system can be isolated in a reduced way. Slide 16 – Visualizing the respiratory network - How does that work? How do the cells respond? What are the characteristics of those cells? - They cut the brainstem, took a slice, put it in a dish, and recorded the hypoglossal nerve to see if you could still generate breathing. They were able to look at the activity of the pre-BötC by looking at the movement of Ca2+ in the cells. They were using fluorescent dyes that were sensitive to Ca2+. They were able to show that the neurons were just active right before the phrenic nerve. o You would see an increase in fluorescence in the pre-BötC. o They were showing how to visualize the neurons in vivo. - They were able to record the hypoglossal nerve that controls the tongue muscle. They were able to see the increase of activity of those neurons because of the fluorescence of Ca2+. - They took the slice of tissue. Can we visualize the cells in the slice and look at their behaviour in relationship to this inspiration and expiration? They filled all the cells in the slice with a dye that allowed them to see changes in Ca2+. o Ca2+ movements into and out of cells are an index of whether they are excited or not. If Ca2+ is increasing inside of a cell, then the cell is firing action potentials or the cell is being active. - The hypothesis was that if the pre-BötC was really causing the inspirations in the slice of tissue, then they would see cells in that area light up every time there was an inspiration in the hypoglossal nerve rootlets that go to the tongue. o If the group of cells of the pre-BötC drives inspiration and sends information to the MNs, and then the MNs, through their axons, which make up the hypoglossal rootlets, are then causing the inspiration. o They found that every time there was an inspira
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