Welcome. So today we want to continue our discussion of homeostasis. In particular we want to look at the regulatory mechanisms that allow the body to maintain homeostasis. Learning objectives are going to be first that we will contrast reflex and local homeostatic controls. Secondly, we want to define the components of the reflex loop. Third, we want to explain negative and positive feedbacks which are regulatory loops used to control homeostasis. Four, we'll explain, tonic and antagonistic controls, and then five, we want to explain circadian rhythms. This lecture will give us an overview of all the mechanisms that we're going to deal with one by one, within each individual organ system. Each organ system has a specific method that it uses to maintain homeostasis. All of these control mechanisms are not common to all of the organ systems. Instead each organ system, use a specific type(s) of control mechanisms. As you go through the course, you'll be able to come back to look at this lecture and recognize the specific concept or specific mechanism that's being applied. Okay, so what are these homeostatic controls? First we have some homeostatic controls that are effected at a local level. This local response occurs among neighboring cells. For example, as shown here, we have cell #one and we have cell #two. Cell #one secretes a chemical. This chemical then acts on cell #two. Cell #2 has a protein, called a receptor, which cna bind the chemical and become activated by the chemical. The cell gives a response. This type of control is called a paracrine control. Here a cell governs the actions of a neighboring cells. We can also have a system where cell number two is secreting a chemical. That chemical feeds back on itself and regulates itself, it's own activity. This is called autocrine control. We will see autocrine controls and paracrine controls in particular when we're considering the gastrointestinal tract. We also local controls called gap junctions in which two neighboring cells are physically connected. There is a bridge between the two cells. This bridge is called the gap junction or nexus. This little opening, nexus, which is common to the two cells, allows ions to flow from one cell to another. In particular, we will see that calcium moves from cell one to cell two. Gap junctions are found the heart, the cardiovascular system. It allows all the cardiac muscle cells to act as a single sheet so that they contract in an organized fashion and all relax in unison. Contraction and relaxation depend upon the amount of calcium which is being delivered across the gap junctions and to all of the cells. These are local responses. But for most of the course, we are going to be talking about reflex loops. The reflexes, or the reflex loops, are where the response is made at a distance away from the target cell. The target cell is a cell that can respond to whatever the signal is that's being released. The target cells are all the cells of the body. There are some billions of cells within the body. To enable the cells within an organ and organ system to function, they must communicate with one another. Reflexes enable organized, regulated function within the body. Two major communication systems are the endocrine system and the nervous system. That what is diagrammed here. In the endocrine system, we have a cell, the endocrine cell, which secretes a chemical. This chemical is secreted into the blood stream. That chemical is then delivered by the blood stream to cells which have receptors on them. Receptors are proteins located either on the cell surfaces or internal to the cell. These receptors recognize the chemical. Cells with a specific receptor are called target cells. The endocrine cell regulates the activity of the target cells through the secreted chemical. In the case of the neuron, we have a cell, which actually butts up against the second cell in an area called the synapse. This synapse has a very, very small space. The neuron will secrete its chemical into this small space. This chemical is called a neurotransmitter. The chemical will act on the effector cell that is the second cell in the series. This effector cell could be a neuron, it could be a cell from a gland, or it could be a muscle cell. Whatever the cell, the effector cell, or target cell is, it has a receptor which can recognize the chemical that's being released by the neuron. The chemical binds to its receptor and causes the effector cell to change its activity. Both the endocrine cell and the nervous system, governs target cells at a distance from the originating signal. They part of reflex loops. If you recall, the last time we met we said that the reflex loops had specifically three components. The first was a sensor that recognizes the stimulus. This is some kind of an input, coming into the body. This is called an afferent path. It's an inward path to the body. A sensor detects that specific signal and then sends that information to the integration center, the second component in the loop. Typically this is the brain. The integration center has the set point. The brain already has a set point within it that then examines the inputting signal and evaluates whether or not it is higher, the same as the set point, or lower than the set point. If it is different from the set point, then the integration center sends out an efferent signal. This is an efferent path, or a path that's going outward from the integration center. It goes to the effector(s). The effectors generate a response. This response will take care of the stimulus. In most cases the response eliminates the stimulus. This is under those conditions this would is called a negative reflex loop. We'll talk about those in just a few minutes. First let's just consider, two cases that exemplify these reflex loops. The first case, there is an external change to the body. You are leaving your room and you go outside. It is snowing and it is very very cold. As you're standing outside without a coat, your body starts to lose heat. As it does so, the body temperature drops from 37 degrees, (normal body temperature) to let's say, 34 degrees Celsius. As the body is cooling, it temperautre is being sensed (detected) by peripheral thermal sensors which are present along the skin, and also within the body along the core, where they detect the temperature of the blood. These are peripheral thermal sensors. WE also have central thermal sensors. The body's thermal information is sent to the brain, to our integrating center, in an area called the hypothalamus. This area has a set point for body temperature, which says that the body temperature should be 37 degrees centigrade, and obviously the input signal is 34. That is the body is cold. The Integration Center (brain), recognizes that the body is cold, and sends out a signal along an efferent path, an efferent signal, to the Effectors. In this condition we have multiple Effectors. The first are the skeletal muscles. Skeletal muscle will start shivering, it contracts and relaxes and contracts and relaxes. In doing so, shivering, you start to generate heat. The second is that the blood vessels which are perfusing the skin. Those that are directly underneath the skin, constrict. THis diverts blood and heat from the body's surface away from the skin to a deeper portion of the body, or to a deeper portion of the skin. This conserves heat. Not as much heat is lost from radiation. With vasoconstriction, vaso meaning blood vessels, the blood vessels are constricted. Blood moves away from the surface right underneath the surface of the skin into a deeper layer of the body. So we don't lose as much heat, then, from the body through the skin. In addition to that, we can curl up, to decrease the amount of surface that's radiating heat. And then obviously, we can turn around and go back in the house, put on a coat, put on a sweater and then go back outside. Or stay in the house, where it's nice and warm, and the body then will warm up. The effectors then can generate and conserve heat to retrun the body temperature to normal. These actions eliminate the stimulus which was that the body temperature was low, and bring the body temperature back up to normal, which is 37 degrees. Exactly analogous to the thermostat which is within your house. What about internal changes? Our second case is an Internal Change. For instance you get an infection. This infection will activate a cell called the macrophage. The macrophage secretes a chemical which is called a pyrogen. The pyrogen acts on the Hypothalamus, that same area of the brain that was active when we were having an input from the thermoreceptors on the skin when we were outside in the cold. This area of the hypothalamus, has an normal set point of 37 degrees. However, in the presence of the pyrogens, the set point is changed to 40 degrees centigrade. The body now, has a set point of 40 degrees centigrade. The input stimulus, coming to the Hypothalamus from the skin, and from the core temperature of the blood relates a body temperature of 37. The brain then interprets the body as being cold. It sends out an Effector signal to the Effectors which are, again, our skeletal muscles. The skeletal muscle starts to shiver. We have contraction and relaxation of the muscle to generate heat, and we will have Vasoconstriction to move blood, away from the skin surface, to deeper areas to reduce the loss of heat. The consequence is that we generate heat. The body starts to warm, and as the body starts to warm, it moves from 37 to 40 degrees. It's exactly the same reaction that we had when we were going outside in the cold. The body is responding in exactly the same way. The difference here, is that the set point has been reset. This is an important point to remember, because often when the body has a pathological condition, it is trying to do something which it normally would do to rectify a situation. It may be, in fact, responding to a set point that has been set to a higher level. In doing so, this causes a malfunction within the system itself. All right. MOst of the reflex loops that we're gonna be talking about throughout this course are going to be these negative feedback loops. THese are feedback loops which remove the initiating stimulus. The negative feedback loops can be simple, and that’s what’s diagrammed here. Where the Stimulus is received by, for instance, an Endocrine cell, that Endocrine cell secretes a Hormone or a chemical which works on a Target cell, and then it removes the Stimulus, the initiating stimulus. So well, do we have an example of this? You just finished lunch. In that lunch, you ate a lot of rice. The rice has now been digested by the gastrointestinal tract resulting in a rise in the amount of glucose within the blood plasma. An increase in plasma glucose levels activates the beta cells of the pancreas causing a release of insulin into the blood. Insulin is a hormone which acts on skeletal muscle. Insulin causes the skeletal muscle to take up glucose into, removing it from the blood. The glucose is stored in the skeletal muscle. And as insulin is moved into the muscle cells, plasma glucose levels fall. Like I said, this simple reflex loop removed the initiating signal. The negative feedback loops can be also very complicated. An example is the hypothalamus, pituitary, endocrine feedback loops. That's what is shown here. Again, we start with a Stimulus. It acts on the first cell. This cell secretes a chemical, "A". Chemical A works on the second Cell B, which stimulates the secretion of the chemical "B". B acts on the third cell C. The chemical C eventually works on Cell D, the fina effector. There are negative feedbacks to each of these levels in the sequence. So that each level then, is turned off by the stimulated chemical D. Do we have an example of this? Well, temperature. Again, we have a system where we the temperature of the body is falling. This fall in body temperature is detected by the hypothalamus, the brain. The brain releases of a hormone, called a thyroid releasing hormone. This hormone work on the pituitary, another region of the brain which releases thyroid stimulating hormone. This hormone in turn acts on thyroid hormone gland. The thyroid gland secretes thyroid hormone. The thyroid hormone acts on all the cells of the body to increase their metabolism. In doing so, then it revs up the generation of heat. This is a complex reflex loop. It is a negative reflex loop. By generating heat, our initiating signal which was low temperature is removed. In some instances, we'll see positive feedbacks. Positive feedbacks don't occur in very many locations. It is present in the female reproductive tract. For instance, in the ovary of the female, growth and development of the egg is reglated. In reproductive system the pituitary endocrine cell secretes follicle stimulating hormone, FSH, which acts on the target cell in the ovary to increase the receptors for follicle stimulating hormone (FSH) on that target cell. Consequently, all of these follicle stimulating hormone (FSH) receptors increase in number, making the target cell very, very sensitive to the FSH. That's one way to have a positive feedback. You increase the sensitivity of the target cell by increasing its receptors. Another way to do increase response is simply have the first target cell secrete something which causes more of the initiating signal to increase. This latter example is characteristic of the clotting system in your blood. When we start the blood clotting cascade, a cascade of proteases which ends with the fibrin clot. These proteases feed back and activate themselves, so that you have an accelerating system. You get more, and more, and more, and more, of the fibrin clot. Obviously, you don't want the entire bloodstream to clot. So there has to be a way to turn off the positive feedbacks. The way to do so, is through a negative feedback loop. Now there are a couple more things that we want to consider just very briefly, and then when we will come to the organ systems themselves, in more detail. The feed back systems that we've been talking about up to date, have been pathways where we turn something on and we turn something off. But under the condition of tonic control, now, we're just modulating the activity of a specific cell. We're never really turning it off, and we're never really turning it on. Tonic control is exemplified by the smooth muscle cells, which are lining the lumen of a blood vessels, such as your arteries and your arterioles. Under normal conditions in the body, those smooth muscle cells, have a basal state of contraction. This means the lumen of the blood vessel, may not be completely open or completely closed. And that's what's shown here. That's our basal state. If the sympathetic nervous system input to these smooth muscle cells increases then the cells contract. When they do so, they will make this lumen of the blood vessel much smaller. Contracted they decrease the size of the lumen. This is by increased input from the sympathetic nervous system. This is call vaso-constriction. Vaso for the blood vessel constriction. We are causing contraction of the smooth muscle, which is around that lumen and making the lumen smaller. If instead input from the sympathetic nervous system is decreased then, smooth muscle cells will relax. The lumen of the blood vessel will open. This is called vaso-dilation. Vaso again, meaning blood vessel, and we are dilating, opening the lumen of the vessel. Notice a couple of things. One is that we're not turning on or off this system at any one time. We're simply modulating how much activity we have from the sympathetic nervous system. And the second thing is that we have a situation where the smooth muscle can hold a specific state of contraction for very long periods of time. This is tonic long, long held contraction, which is unique to smooth muscle. We couldn't do this with skeletal muscle, and you can't do this with cardiac muscle. But with smooth muscle you can hold the contraction state for very long periods. This is called tonic control. For tonic control, remember the radio dial, where you can dial up the volume, and you can dial down the volume of the sound, but that you never actually turn it off. Now in the body we also have antagonistic control. THis is mediated by the nervous system. There are essentially two types of peripheral nervous systems to deal with. One is called the Parasympathetic and the other is the Sympathetic. On the heart, there is input from both the parasympathetic and the sympathetic. The two nervous systems work in opposite directions, or in an antagonistic manner. They are not binding to the same receptors, but they are working as opposite controlers. The parasympathetics slow heart rate. If a normal heart rate is 100 beats per minute, that's our intrinsic heart beat, then the parasympathetics will slow it to less than 100 beats per minute. High parasympathetic tone is characteristic of a highly trained athlete like Lance Armstrong. They could have a heart rate that is 35 beats per minute. I have a heart rate that is 80 beats per minute. 35 beats per minute is a very, very low heart rate. To do so these athleties have a very high parasympathetic tone due to training. There are situations in which we need to increase our heart rate. For example we start to run, or we are swimming. To do so, we need a higher output of blood from the heart. To increase our cardiac output. the sympathetic nervous system is activated. And under these exercise conditions we can increase our heart rates to above 100 beats per minute. We stimulate the heart to increase its rate of beating. When we discuss the cardiovascular system, we'll describe exactly the mechanisms by which these two nervous systems are able to control heart rate. The last thing that I want to talk about are circadian rhythms. Circadian rhythms are instances where biological systems in your body are changing on a 24 hour cycle, or 24 hour basis, without any input from you. This is an automatic rhythmic kind of a situation. When you go to sleep at night, for instance, your body temperature will drop. When you awaken in the morning, it will rise again. The drop is only a couple of degrees, but while your sleeping, you have a lower basal metabolic rate. so body temperature falls. Many things are regulated by biorhythms, or by circadian rhythms, such as hormones. The levels of two hormones are diagrammed here. One is growth hormone. Growth hormone is released during early sleep, and then it falls to more basal levels when we're waking up. The second hormone, cortisol, increases just before you wake up. Cortisol and growth hormone both raise plasma glucose levels. As you’re sleeping, you are fasting. Blood glucose levels fall. These two hormones raise blood glucose levels. The growth hormone raises the blood glucose level by having a signal coming from the empty stomach, which is another hormone called ghrelin. Ghrelin turns on the secretion of growth hormone. The growth hormone raises blood glucose, and then cortisol rises to further raise blood glucose. Note that high blood glucose levels turn off the growth hormone signal. So growth hormone is regulated by gluocse. Low levels turn on growth hormone secretion. High blood glucose levels turn off growth hormone secretion. These circadian rhythms occur without us thinking about it, and you're all very familiar with them. For instance, when you are traveling. Let's say, you're going from New York to London. You go through a time zone, so that when you arrive in London, you're six hours off from your normal time zone. For about two days, a day of 24 hours to 48 hours, you feel a little odd. You feel a little off. You are hungry when other people are not hungry, you want to sleep when other people don’t want to sleep. Then eventually your body gets accustomed to the time zone that you’re now functioning in. What has happened is that your body has reset the set points. It reset the set points for the circadian rhythms. When the set points are reset, then the set points not only for temperature. but also for cortisol, and for the growth hormone are changed. In fact all of the other factors which are being governed by the circadian rhythm have. a the new set points. It takes a little while for the body to reset the circadian set point. What resets the set point is sleep wake. These are cycles which are dictated by sleep wake and not by light dark inputs. So what about people who are known to be night owls? And what about people who are early birds? What do I mean when I'm talking about night owls and early birds? Are you a night owl or are you an early bird? Night owls are those who can stay up all night long. They've got plenty of energy, and at 4:00 in the morning they're about ready to go to bed. But they certainly have a hard time to wake up at 8 o'clock in the morning. Because when they wake up at 8 o'clock in the morning, then they feel cold. They can't think very clearly. They're looking for their coffee. They can't find their shoes. So they're "off". They're not happy. The early bird is the converse. The early bird wakes up at five o'clock in the morning. They're ready to go. They're full of energy. Their body is warm. They want to find their coffee. They can find their shoes. They are set, up and running. What the difference between these two? These are both normal people. But the difference between them is that their circadian rhythms are different. Circadian rhythms can vary depending upon an individual. They're not necessarily pathological if you are night owl or if you're an early bird. I have a good friend who lived for many, many years in Seattle. He has now lived for something like 20 or 30 years in Durham, North Carolina. Which of course is a different time zone, and he has yet to change his circadian rhythm. His circadian rhythm is still based on Seattle time. All right, so what of our general concepts? The first is that stability of our internal variables are achieved by balancing our inputs and outputs to the body and among the organ systems. Second, we have, in a negative feedback system the change in the variable is corrected by bringing the body back to the initial set point. However, the set points can be reset, and this is an important point. We can reset them, when we're resetting out circadian rhythms. But we can also reset them to tolerate higher sodium within the body, or to tolerate lower temperatures, or to tolerate lower blood pressures or higher blood pressures. So these set points, then, are modified. And then thirdly, it's important to remember that it's not always possible to maintain everything relatively constant. There's gonna be a hierarchy in the maintenance of life. And again, the brain is going to win. Brain wants blood, the brain gets blood. And it will shut down the circulatory system to profusion of all the other organs. The brain and the heart always win. All right so the next time we come in here We're gonna talk about some more about the balances of these fluid compartments. And how we move materials from one compartment to another. All right see you then.