So I just introduced this idea that certain things have to happen to maintain lactation, and milk removal being one of those components. So let's look a little bit more closely. So what I want to look at now is what's happening in the gland between when, let's say a calf, for example, nurses a mammary gland here, and then some period of time later, nurses it again. So it empties a gland out, and we can, although they don't really empty the gland out, because there's always some residual milk left in the gland. If we kind of conceptually think for a moment, if it empties the gland out, what's then happening in the mammary gland during this process until it nurses again? So that's what we want to do now, so let's have our next slide. So, introduce you to some ideas, and then try to put this together more dynamically, how these fit together. So we can talk about systemic effectors on the memory gland. Systemic effectors here relate to the, mostly, we're talking about hormones. It's a variety of hormones, and we'll talk about some of those hormones later in some of the other videos in this module. Prolactin, I think that's one of the keys that we, that's probably the easiest one to think about, in terms of how this all fits together. So it's stimulatory, these hormones are stimulatory. When the gland is empty, it's telling the gland, because they're secreted at that point during the process of, or associated with the process of removal of the milk. These hormones, especially prolactin, are secreted. It's telling the mammary gland, okay, refill. You're empty, let's fill back up again. On the other end of this, or the other component of this, are what we call local factors. So they're actually in the mammary gland. Remember, systemic factors are endocrine factors, hormones are endocrine factors. Endocrine meaning they're produced in some glands somewhere in the body, circulate through the blood to somewhere else, their target tissue. So if we're talking about prolactin, we're talking about it coming from the pituitary, secreted into the blood, circulates through the blood, goes to the mammary gland and then to have its effect. Local factors, on the other hand, are occurring only in the tissue. So in the mammary gland, we're going to call them autocrine factors. All that means is they're actually produced by the cell. In this case, let me go ahead and introduce you to this idea of this FIL, stands for feedback inhibitor of lactation. FIL, feedback inhibitor of lactation. It's actually probably several components that are in there, so we're still not 100,000% sure of exactly what these things are. But the idea is that they're produced as part of the normal process of making milk, secreted out in the lumen with the other components of milk, turned right back around, and feedback on those same cells. And they're inhibitory, they shut down further milk secretion. So again, there's still some things we don't fully understand about the feedback inhibitor of lactation. But again, they're local, you're not going to find them in other tissues. And they are part of the normal process of making milk. And so, as milk accumulates in the alveolar lumen, the feedback of lactation components also accumulate in the alveolar lumen and gradually shut this process of milk secretion down. All right, so here is the idea. So, let's say, over here at this time period, this time point, the calf nurses the mammary gland, you milk the cow, whatever the case may be. Empties it out, or comes pretty close to emptying it out. Well, you've also taken away this feedback inhibitor of lactation, and you've fired off a prolactin surge. It's a fairly short prolactin surge, but it is a prolactin surge. And so you get this stimulatory effect. It's a really heavy stimulatory effect, so it's making milk, making milk, making milk, making milk. But that effect wanes over time because these hormones don't necessarily stay up all the time. At the same time, you're accumulating milk in the alveolar lumen with this feedback inhibitor of lactation, which is gradually inhibiting further milk secretion. So we're here from the stimulatory effect to this inhibitory effect. So you can kind of think of this, I usually think of this as kind of a balance, as a teeter-totter or a seesaw. And that is over here, empty the gland, a really heavy stimulatory effect. But over time, that wanes and you get accumulation inhibitory effect. And gradually, gradually, gradually, you get to this point of where milk secretion rate is dropping or decreasing. What happens then? The young suckle again, you milk the cow again, and you remove this. Very quickly, we've fired back over here. So gradual, gradual, gradual balance from the positive or stimulatory. Gradual balance over to this inhibitory as milk accumulates and the effects of the hormones kind of wane a bit. And then, very quickly, milk is removed. because milk removal is only occurring over a fairly short period of time, usually a few minutes. And boom, we're right back to where we started from. So during the course of the day, if you milk a cow three times a day, you're going to go through this process. This process is going to be, say, eight hours long. And then, after a few minutes, boom, restarting this whole process again, another eight hours long, and so on. If you milk her twice a day, it's a 12-hour interval, and so on and so forth. So you can see that interval's going to shift and change. So again, it's this balance between this set of signals to the mammary gland, which are systemic, prolactin being a really good example of that. This set of signals to the mammary gland, which are local. Again, this feedback inhibitor of lactation concept, normal part of the process of producing milk, normal components of the milk that are secreted, autocrine, turned right back around to inhibit further milk secretion. What happens if you don't remove the milk? If you kind of keep going this way, and you don't remove the milk for a period of time, eventually, the cell stops secreting milk. And again, we'll talk about that more in some of the other videos here. Let's go ahead and go to the next slide. So, how often does this happen? So again, if you milk a cow twice a day, roughly 12 hour intervals. If you milk a cow three times a day, it's roughly eight-hour intervals, and so on. You can do the math, certainly, in a 24 hour period. How often do animals nurse? A kangaroo, remember, the kangaroo has a pouch, the joey's down in there. It's actually, they say it's attached to a nipple, and so the nipple actually is way down in here. And so, it's supposedly continuously getting milk out of there. Now, I don't really know whether it's continuous or not, but clearly it's removing milk very, very, very often in very, very short intervals. Compare that to, say, whales and some of these aquatic mammals. Whales and dolphins nursing, again, very, very often, about every half an hour. Piglets, 45 minutes to an hour, something like that, that kind of an interval. So again, we're actually going to go back and use this for one of our models for milk removal as we think about those concepts that we just talked about, in terms of prolactin secretion, milk removal and so on. So we'll go back to the piglet and use that. Four to six hours for a calf, so they're going to nurse several times a day. Rabbits only nurse about once a day. Tree shrews, once every other day, something like that. And then you got some really interesting animals down here. Northern fur seal is one example, they only nurse about once a week. And that raises some really interesting questions about, how does she maintain lactation, because you've got this weeklong period of when no milk is being removed. How come the mammary gland does not really regress? And there are people that are actually actively studying that question. So we don't really have a good answer to that at this moment. But clearly, tremendous range of nursing intervals, and that feeds back into how do we interpret that teeter-totter idea that I was talking about. So clearly, this animal's going to respond differently than these guys up here are going to respond in terms of how the mammary gland works with regard to the systemic versus those local factors. Let's go to the review slide. And again, just to remind ourselves, lactation is the combined process of milk secretion, meaning that milk synthesis and the secretion into the lumen of the alveolus, and removal of the milk. So milk ejection, getting the milk actively out of the gland in order to maintain it. Again, galactopoiesis is the word we use for the maintenance of lactation. Lactogenesis is initiation of lactation. But once you start, you gotta keep the thing going, and the only way you can really do that effectively is to get the milk out of the mammary gland. So the punchline here is, if you don't remove the milk from the mammary gland, it shuts itself down. It doesn't just keep going continuously, the process will shut off further milk secretion eventually. Again, lactation reflects a balance between this idea of systemic factors, prolactin being one of those, and local factors, the feedback inhibitor of lactation being the primary ones that we're thinking about. And the process of removing the milk, the actual process of removing the milk, you're taking the feedback inhibitor of lactation out of the gland. So that's stimulatory in that sense, it's removing inhibitory effect. At the same time, you're firing off that prolactin surge and some of the other hormones are being released in response to that. So again, those things all come together. And then the interval between removal is dependent upon, if you're milking a cow or any other dairy animal, we determine what that interval is. Whereas the young are nursing at a tremendous variability amongst species. All the way from, again, the kangaroo, the concept is they're more or less continuous. The other extreme we saw in our example was the northern fur seal, which was about once a week that they'll actually nurse. And so, that gives you an idea of how we kind of have to think about all these things fitting together.
