Genes, The Brain, and Behavior
Transcript of Part 1: Genes, the Brain and Behavior
00:00:00.00 Hi, I'm Cori Bargmann, 00:00:02.15 I'm a professor at the Rockefeller University in New York, 00:00:05.10 and an Investigator of the Howard Hughes Medical Institute. 00:00:08.12 I'm going to talk to you today about how we can use genes to understand the brain and behavior. 00:00:14.09 I'll discuss that in the context of our magnificent human brain, and also in the context of simpler brains, 00:00:20.05 brains that range from the brains of worms to flies to mice to dogs. 00:00:27.20 So, why should we think that we can understand behavior by studying genes? 00:00:32.20 And why do we think it's important to understand behavior studying genes? 00:00:37.04 To illustrate and answer those points, I'd like to use this first slide to tell you about the familial risk of important psychiatric illnesses. 00:00:45.19 If one member of a pair of identical twins suffers from the neurodevelopmental disorder autism, 00:00:51.29 the identical twin has about a 70% chance of having the same disorder. 00:00:56.23 This is vastly higher than the risk of this disorder in a sibling, 00:01:01.06 or in the general population, where it's less than 1%. 00:01:05.02 Now, the fact that this risk is so high in identical twins but much lower in non-identical twins 00:01:11.02 tells us that there is likely to be a genetic contribution to this important psychiatric disorder. 00:01:17.11 The same is seen when other important neurological or psychiatric disorders, 00:01:22.15 including the disorders of schizophrenia, bipolar disorder, depression, or anxiety disorders. 00:01:28.26 These are disorders that collectively affect millions of people. 00:01:33.05 They can be severely disabling, in fact, severely disabling even to the level of shortening the lifespan of the people who are affected. 00:01:41.04 It's very important to us to try to understand what is occurring to allow genes to go wrong and to interact 00:01:48.10 with environmental risks to generate these kinds of problems. 00:01:53.18 So, how do we understand what genes can do? 00:01:56.28 What can we learn from studying genes about different kinds of disorders? 00:02:01.12 Well, the very first genetically defined brain disorder, called phenylketonuria, or PKU, 00:02:08.12 was identified in 1934, and it already provided for us important information about how understanding brain disorders 00:02:17.02 and the genes behind brain disorders, we can intervene productively to improve the lives of people who suffer from these disorders. 00:02:26.02 So phenylketonuria is a very severe developmental disorder. 00:02:29.24 Children with phenylketonuria are mentally delayed and retarded, they have delayed social skills, 00:02:36.00 they're hyperactive, they have movement disorders, they have severe seizures. 00:02:40.08 And all of these result from a single change in a single gene: 00:02:43.28 The gene for phenylalanine hydroxylase, a metabolic gene that converts the amino acid 00:02:49.17 L-phenylalanine to L-tyrosine. Why does the absence of this enzyme cause this severe disorder? 00:02:58.13 This information, this chemical information, propagates from the level of the gene to the level of the individual. 00:03:06.16 The gene, a mutation in phenylalanine hydroxylase, leads to the production of toxic products. 00:03:14.23 These toxic products accumulate in neurons, and because of those toxic products, neurons, which are supposed to have elaborate structures, 00:03:22.15 instead are smaller and simpler in their structure, and many of the neurons die. 00:03:27.23 As a result, the brain of these children has altered function, 00:03:31.27 and the behavior and their medical disorders result. 00:03:35.23 So, all of this is a form of toxicology, but once we understood what the gene was, 00:03:40.23 it was immediately clear that this was something that could also be treated, 00:03:45.11 because phenylalanine is a chemical that is present in our diet. 00:03:50.11 And simply by limiting the amount of phenylalanine in the diet of children with PKU, 00:03:55.07 it's possible to limit many of the effects of this very severe disorder. 00:04:00.03 So, intervening at an environmental level can lead to great improvements in the health of these individuals. 00:04:08.14 Now, for most brain disorders that I mentioned in the first slide, we don't have anything like this ability to intervene. 00:04:15.10 We don't know the genes as well, we don't know their effects on the brain, 00:04:18.29 and we don't have anything as simple as a dietary fix. 00:04:21.28 But this is our goal: Is to be able to understand brains well enough to intervene in each brain disorder, 00:04:28.28 whether at a genetic level, an environmental level, a cellular or a brain level, 00:04:34.05 to try to improve the disorder and the lives of the people suffering from it. 00:04:40.03 So, what are the tools we can use to understand these disorders? 00:04:44.12 Well, we believe that these many disorders and many processes of the brain have a biological origin. 00:04:51.12 And that therefore, like all biological processes, they are under the control of our genes. 00:04:58.23 When we look at the genes in the human genome, we find, much to our surprise, that while humans are unique, 00:05:04.19 and the human brain is unique, the human genes are not unique. 00:05:08.22 Most human genes, the overwhelming majority, are shared with other animals. 00:05:13.24 Only about 1% of all human genes can be considered unique to the human. 00:05:19.24 Another 20% are present in humans and all other vertebrates, although not in simpler animals. 00:05:26.10 Almost half of all human genes are shared between humans and all animals, including butterflies and snails and worms. 00:05:34.12 An additional large fraction are shared even with unicellular organisms, like yeasts. 00:05:40.00 And finally, there's a large fraction that are shared even by bacteria and humans. 00:05:44.13 So when we look at this big pie chart, we realize that most of the time, we can understand genes by studying them in much simpler organisms, 00:05:52.25 and we can then take our knowledge of these genes from simple organisms, and try to return them to understanding the complex human brain. 00:06:02.18 Now, what about the brain itself? What about this complex structure? 00:06:07.10 Many of you who've seen images of the human brain, as shown here at the top... 00:06:11.03 Now the human brain is very complex, but when we look at the brains of simpler animals, we see that the human brain has 00:06:18.03 evolved from them gradually by changing the size and the placement of common brain regions, 00:06:24.06 and that diverse animals share common brain regions, again suggesting that we can study them in simpler animals, not just in humans. 00:06:32.19 In fact, we can see, when we compare the human and the monkey, how similar they are. 00:06:38.07 We can see in the rat and the mouse that some of the same regions are sort of changed in location and changed in size. 00:06:44.14 If we go all the way down to the shark brain, we see something that looks on the outside very different in structure from the human brain below, 00:06:52.05 but by understanding what the different brain regions are, we can see that in fact the parts of the shark brain and the parts of the human brain are rather similar, 00:07:01.00 that even the higher processing centers are present in the shark, along with regions that control things like movement and learning. 00:07:10.04 So we believe that we can study brain regions across different species and understand fundamental principles about how brains work. 00:07:21.11 What do we want to know about behavior? What are the organizing principles of behavior? 00:07:26.14 The way that this is studied, traditionally, is using another science that goes back to the 1930s, a science called neuroethology. 00:07:35.16 Neuroethology is the study of animal behavior, trying to understand common principles and rules that underlie behavior. 00:07:43.04 And a variety of principles have emerged from studying behaviors of many animals. 00:07:47.08 I'll illustrate them here with a few colorful examples. 00:07:50.09 Here, the work of Niko Tinbergen in stickleback fish, was used to establish the principle 00:07:55.20 that animals have stereotyped behaviors in response to sensory stimuli, 00:08:00.18 that they had innate behaviors that can be reliably observed in all individuals when they encounter certain features of their environments. 00:08:08.27 Now, their examples of innate behaviors might include courtship or aggression behaviors, 00:08:14.04 they would also include things like food search behaviors. 00:08:19.21 A second principle that emerged from neuroethology is the recognition that the brain does not exist just to respond to the outside world. 00:08:27.22 The brain has its own internal drives that organize behaviors. 00:08:31.26 And a lovely example of this, from the work of Konrad Lorenz, is the fact that newborn birds, 00:08:37.03 such as ducks and geese, have an internal drive to attach to the first moving object they see. 00:08:44.09 Now, normally this would be their mother, whom they would follow around throughout their young lives. 00:08:49.14 The mother would then bring them to the right foraging grounds and protect them from danger. 00:08:54.03 Now in this particular case, these geese saw Konrad Lorenz as the first thing when they hatched; 00:08:58.25 they are now following him around his garden. 00:09:01.06 And this process of imprinting, and other kinds of special learning processes, 00:09:05.29 are observed with respect to these internal drives that animals show, to have certain kinds of behaviors. 00:09:14.10 A third principle that emerged from neuroethology is the importance of social behavior 00:09:20.06 and the fact that social behavior is widespread among animals. 00:09:24.03 The most dramatic demonstration of this was the work of Karl von Frisch, who worked on honeybees, 00:09:29.07 simple insects, and showed that they have incredibly elaborate forms of communication and social behaviors. 00:09:36.07 So even insects can show elaborate social structures. 00:09:40.03 For example, the waggle dance that the honeybees use to signal to each other about the presence of food. 00:09:45.16 Or their use of pheromones to interact with each other and with their queen. 00:09:50.25 So I'm going to try to illustrate these classical questions from neuroethology, 00:09:56.19 in the context of modern day genetics and modern day nervous system methods, 00:10:01.17 to think of a framework for behavior that incorporates genes, neurons, and brains. 00:10:09.07 This framework here is cartooned on the left, a cartoon that will appear multiple times. 00:10:14.01 We think of environmental cues as leading to perception, decision, and action. 00:10:20.01 And this left side here relates to the basic processes of how animals generate innate responses to an environmental cue. 00:10:28.28 But, we also have to think that behaviors can be internally generated by internal states and motivation, 00:10:35.00 and that things like memory of course will modify all of these outcomes. 00:10:38.17 And I will illustrate how genes affect this right-hand side of the equation as well. 00:10:45.03 So, I will talk about three different topics today, using examples from animals to illustrate 00:10:50.22 how this framework for behavior can be used to understand how genes affect neurons, which affect brains, which affect behavior. 00:10:58.27 And the three examples will be: 00:11:00.12 One example, on the left side, moving from sensation to action, and the innate responses to environmental cues; 00:11:08.27 the second will be an example of internal motivation, using sleep and circadian rhythm as an example; 00:11:15.04 and the third will address the question of why we don't all behave, where variation comes from that gives rise to different behaviors in different individuals. 00:11:27.01 Now, in each of these three sections, I'm going to talk about one particular class of genes, not because it's the 00:11:33.01 only class of genes that affects behavior, but because it is an important class of genes that affects behaviour. 00:11:39.04 And it serves to illustrate these principles very beautifully. 00:11:42.19 And that class of genes are the genes that encode G protein-coupled receptors. 00:11:47.27 G protein-coupled receptors are molecules that sit on the cell surface of neurons and also of other non-neuronal cells. 00:11:55.21 They detect stimuli outside the cell and then propagate a signal to the inside of a cell that causes biochemical changes in the cell: 00:12:04.05 Classically, the production of signal transduction second messengers, like cyclic AMP or inositol trisphosphate. 00:12:12.18 Now, I'm not going to talk about their signaling in detail. 00:12:15.18 What I'm going to point out is that, by transmitting signals from outside the cell to the inside of the cell, 00:12:21.03 G protein-coupled receptors are able to interface with many of the important kinds of systems that regulate behavior. 00:12:28.28 Let's start on the left here with environmental stimuli. 00:12:32.05 G protein-coupled receptors on your sensory neurons are critical for the detection of odors, tastes, and light. 00:12:40.05 When you smell a barbeque, or you taste a cookie, or you see someone walking across the room, 00:12:45.23 the first event that happens in your nervous system is the activation of the G protein-coupled receptor 00:12:51.00 on an olfactory neuron, a taste cell, or a photoreceptor. 00:12:57.04 In addition to their important role in detecting environmental stimuli, 00:13:01.07 G protein-coupled receptors inside the body detect signals that pass from one cell in the body to another cell in the body. 00:13:08.01 These are internal signals. So for example, adrenaline: 00:13:11.27 the speedy heartbeat and sweating that occurs when you're exciting, 00:13:15.23 occurs because G protein-coupled receptors recognize adrenaline that's been secreted into the bloodstream, 00:13:21.15 and tell different cell types that something has happened and cause them to change their behavior appropriately. 00:13:27.16 Dopamine, a small molecule that's used to signal reward or the anticipation of reward, 00:13:32.29 and is implicated in important processes like drug addiction, 00:13:36.01 also signals through G protein-coupled receptors on neurons that detect this molecule. 00:13:42.23 I'm going to start my talk today with talking about the response to external, environmental stimuli, and particularly about the sense of smell. 00:13:51.00 The sense of smell begins with G protein-coupled receptors in the olfactory neurons of the nose. 00:13:56.23 Large families of these receptors detect different chemicals in the environment. 00:14:01.04 Different neurons express different receptors to detect different chemicals, and my favorite of all the 00:14:06.02 G protein-coupled odorant receptors is a molecule called ODR-10, which detects diacetyl, a buttery smell. 00:14:15.28 ODR-10 is a molecule that is found in the nematode worm, Caenorhabditis elegans. 00:14:21.16 C. elegans, as it is known to its friends, is an organism that's been very valuable for studying the nervous system, 00:14:27.20 as well as other biological processes, because it's easy to grow in the lab and easy to manipulate at a genetic level. 00:14:34.25 C. elegans, which is just a millimeter long, detects many different odors, 00:14:40.00 and it responds to them, showing innate preferences for different odors. 00:14:43.21 So for example, the smell of diacetyl is released by some of C. elegans' natural food sources. 00:14:50.11 And therefore, when C. elegans smells this odor, it approaches it, it's attracted to the odor. 00:14:56.24 Conversely, when C. elegans smells certain kinds of toxic odors, 00:15:00.00 like nonanone, it's repelled by those odors, and it goes away from them. 00:15:04.26 Diacetyl is detected by ODR-10, the G protein-coupled receptor I mentioned before. 00:15:10.29 The G protein-coupled receptor is expressed in a pair of neurons in the tip of the worm's nose, these blue neurons here. 00:15:18.27 They're exposed to the environment, and they detect diacetyl in the environment to initiate the odor preference behavior. 00:15:26.02 Another pair of neurons right next to them, in red, detect repulsive odors. 00:15:31.15 So you could think of ODR-10 as a gene for a behavior. 00:15:35.23 ODR-10 is certainly required for the worm's response to diacetyl. 00:15:40.13 So, that's illustrated by comparing panels 1 and panel 2 here. 00:15:45.20 A wild-type worm, or a wild-type group of worms, when placed in an environment with diacetyl at one location, 00:15:51.24 will quickly approach the diacetyl and accumulate at the source of this delicious odor. 00:15:57.01 If the ODR-10 gene is absent, if there's no receptor, the animals now ignore the odor. 00:16:02.17 They'll scatter at random across the environment, as if nothing was happening. 00:16:06.29 So that tells us that ODR-10 is required for detection of the odor, but there's a more important question, and that is: 00:16:13.25 How do you go from that question of detection, to the process of attraction? 00:16:18.08 How do you generate the behavior of approach? 00:16:21.25 That could be because the receptor itself somehow drove the animal to approach the odor. 00:16:28.10 It could be because the animal had learned about the odor. 00:16:31.02 Or it could be because something about the interaction of the receptor and the neuron in which it was expressed was important. 00:16:38.28 To test these different hypotheses, Emily Troemel did an experiment 00:16:43.11 in which she moved the ODR-10 receptor from its normal location, in the AWA neuron, 00:16:48.28 to an abnormal location, in the red neuron, AWB, which normally detects repellents. 00:16:55.22 So, this was done using a combination of the mutant and transgenic technology, 00:17:00.08 which enables us to manipulate the site of expression of any gene within this animal. 00:17:05.10 She then asked whether these animals responded to diacetyl, 00:17:08.19 and they did, but they responded inappropriately. 00:17:12.11 They were repelled by diacetyl instead of being attracted. 00:17:15.21 Moving the receptor to a cell involved in avoidance transformed the behavior from attraction to avoidance. 00:17:23.26 And what this experiment tells you is that the neurons are what determine whether a response is attractive or repulsive, 00:17:31.05 that the sensory neurons are encoding behavioral responses. 00:17:35.05 They're starting the anatomical process of generating different innate responses. 00:17:40.01 The blue AWA neuron encodes approach responses, 00:17:43.27 and receptors expressed on this neuron will drive attraction. 00:17:47.14 The red AWB neuron encodes avoidance responses, 00:17:51.04 and receptors expressed on this neuron will drive repulsion. 00:17:55.23 This example of an innate behavior comes from a very simple animal, but as we move up the evolutionary ladder, 00:18:02.08 we see that similar principles apply in much more complex nervous systems, including mammalian nervous systems. 00:18:09.26 For example, mammals like sweet foods or foods with amino acids that contain valuable nutrients. 00:18:17.24 Mammals avoid toxins and alkaloids; we perceive them as bitter. 00:18:22.25 And work from Charles Zuker, Nick Ryba, and their colleagues, has demonstrated that these mammalian taste responses 00:18:29.10 are hard-wired using exactly the same principle that hardwires worm attraction and avoidance responses. 00:18:36.16 There are different kinds of taste cells in the tongue: 00:18:40.19 T1R taste cells detect these attractive tastants, T2R taste cells detect bitter compounds. 00:18:48.04 Each expresses certain G protein-coupled receptors that detect these molecules in your diet. 00:18:54.29 Now, to ask whether the cells can drive these innate, hard-wired behaviors, 00:19:00.28 the Zuker and Ryba Labs did the following experiment: 00:19:03.26 They took a receptor called a RASSL receptor. It's a receptor that's not found in nature; 00:19:08.22 it's engineered in the laboratory, and it detects a compound that's not found in nature, that's only found in the laboratory. 00:19:15.28 They put the RASSL receptor either on the T2R cells, that sense bitter compounds, 00:19:22.16 or they put it on the T1R cells that sense sweet compounds, and they asked the mice: 00:19:28.02 What do you think about this RASSL ligand? 00:19:31.13 Naive mice that have never seen a RASSL ligand don't respond to it one way or another, 00:19:36.14 but if they have this receptor on their bitter cells, they reject the RASSL ligand; they perceive it as bitter. 00:19:44.27 And if they have this receptor on their sweet cells, they drink the ligand; they perceive it as sweet. 00:19:51.07 So the conclusion from this is that our basic acceptance of sweet and rejection of bitter substances is encoded by neural pathways, 00:20:00.16 and this idea was intuited hundreds of years ago by the French philosopher and mathematician, René Descartes, 00:20:08.11 who in this illustration here showed that a person putting their foot near a fire 00:20:13.26 would generate a nerve signal up an innate pathway that would cause them to remove their foot from the fire. 00:20:19.20 They didn't have to think about this stimulus, they didn't have to learn about this stimulus, 00:20:24.07 they had an anatomical pathway for an innate preference that told them that this fire was too hot. 00:20:30.22 And so by understanding genes, neurons, and brains, 00:20:34.03 we can see the beginning of a principle for one idea about how behaviors emerge, 00:20:40.04 and particularly how innate behaviors are built into a nervous system 00:20:44.10 to help an animal respond sensibly to its environment, from its moment of birth. 00:20:52.15 So we're turning to our framework of behavior, we can now begin to see what's happening on the left side of this diagram, 00:20:58.13 about how environmental cues and perception can lead to distinct actions by propagating information through different parts of the nervous system. 00:21:07.09 Let's think now about the right-hand side of this diagram, 00:21:10.19 and think about internal states that can motivate behavior. 00:21:14.17 And for that, I will talk about important internal states of sleep and arousal. 00:21:20.22 Sleep is one of the important activities that humans do and that animals do. 00:21:27.03 Humans sleep about eight hours a day, usually at night. 00:21:31.20 Some animals sleep in the night, some animals sleep in the day, but as we examine other animals, 00:21:36.14 we see that even animals as simple as fruit flies can show sleep-like behavior and waking-like behavior. 00:21:43.21 We can see this just by monitoring their activity levels: 00:21:46.23 If we look at a fruit fly at light or in dark, 00:21:50.06 we see that they move around a lot during the the light, and they rest during the dark. 00:21:55.02 Interestingly, if you change a fruit fly from light-dark cycles into constant darkness, 00:22:00.21 you see that it still follows a 24-hour rhythm. 00:22:04.11 It moves for about 12 hours and then it rests for about 12 hours. 00:22:08.18 This indicates that it has an internal biological rhythm, which is called the "circadian clock." 00:22:15.09 Seymour Benzer and Ron Konopka decided to look for genes that affected the circadian clock in fruit flies, 00:22:21.29 and they did this by searching for fruit flies whose 24-hour cycle was abnormal, 00:22:27.12 and they were able to identify many classes of mutant fruit flies with abnormalities. 00:22:32.05 Fruit flies, for example, that had no rhythm at all, 00:22:34.18 that would just sort of fly around or sit still at random during the day and the night. 00:22:38.23 Also, fruit flies that had a short cycle; when placed in constant darkness, 00:22:43.21 instead of cycling over 24 hours, they would cycle over as few as 19 hours. 00:22:49.18 And conversely, fruit flies whose cycle was long, 00:22:53.03 where instead of cycling over 24 hours, they might cycle over 28 hours or more. 00:22:57.27 So you can think of these 19 hours as "early risers," 00:23:01.14 and these 28-hour guys as the flies who like to stay up late. 00:23:05.26 Remarkably, all three of these mutations affected a single gene. 00:23:11.07 There was one gene that, because of different kinds of changes in its activity, 00:23:16.03 could either completely disrupt the rhythm, make it shorter, or make it longer. 00:23:21.18 And that pointed to the fact that this gene must have a key role in determining the running of the circadian clock, 00:23:29.01 and this gene is called "per," for "period." 00:23:32.20 A series of molecular studies from many different labs has led to the elucidation of this circadian clock. 00:23:40.22 Indeed, the per gene is an important element of the circadian clock, 00:23:44.21 but there are other molecules that are involved as well. 00:23:48.03 These molecules function within the cell to regulate patterns of gene expression, 00:23:52.19 and they regulate each other's gene expression through a negative feedback loop. 00:23:58.14 So, how this feedback loop works is that, during the night, 00:24:02.22 a transcription factor named "clock" drives the expression of the per gene identified from that early fly screen. 00:24:11.15 Early in the night, per is unstable, 00:24:13.18 but over time it becomes more and more stable and builds up. 00:24:17.03 Its buildup during the night causes it to eventually accumulate at sufficient levels, 00:24:21.27 that it can enter the nucleus early in the day. 00:24:24.14 And when per enters the nucleus, what it does is to inhibit the clock gene that is turning per on. 00:24:31.14 Well, eventually that means that per is going to run down again 00:24:34.24 because the clock gene is no longer leading to its transcription. 00:24:38.07 And so as the day wears on, per becomes less active, and clock becomes active again, 00:24:43.08 so at night, clock can begin to make per again. 00:24:47.01 This feedback loop between these transcriptional regulators, and other regulators that determine their levels, 00:24:53.27 is similar all the way from flies to humans. 00:24:56.25 Within the nuclei of our cells are the same kinds of transcriptional regulators oscillating in the same patterns 00:25:04.13 between night and day, as are observed in the fruit fly. 00:25:12.11 How do these genes affect our behavior? 00:25:15.13 Why are we active at different times? 00:25:18.15 It turns out that, in humans, although many cells have these clock genes and have their own circadian clocks, 00:25:25.13 there are specific brain regions in which these clock genes are important to dominate behavior. 00:25:31.21 And these brain regions are buried deep within the brain in an area called the hypothamalus, 00:25:38.06 and in particular, in a region of the hypothalamus called the suprachiasmatic nucleus. 00:25:43.07 This is what you might think of as the "master clock." 00:25:46.10 The activity of the clock genes in the suprachiasmatic nucleus regulates the physiology and behavior of animals. 00:25:53.20 And so we have here the per and the clock gene oscillating in one region of the brain, 00:25:59.01 to then affect the outcome at the level of the whole organism. 00:26:03.23 Per and clock were discovered initially in flies and mice, but remarkably, 00:26:10.19 in humans, the exact same genes can lead to changes in human behavior. 00:26:15.19 So there's a sleep disorder called "advanced sleep phase syndrome," 00:26:19.14 in which people have what might think of as an extreme, early morning lark behavior. 00:26:25.13 They get up earlier and earlier every morning, they can't stay up late at night, they keep falling asleep. 00:26:30.21 The reason is that these people have mutations in human per genes that cause their clock to run too fast. 00:26:36.26 They think that the day is only 22 hours long instead of 24 hours long deep within their hypothalamus, 00:26:42.22 and no amount of conscious control can help them to regulate all of their behavior accordingly. 00:26:50.03 So, if the hypothalamus keeps a clock, it must be regulating lots of different behaviors as well. 00:26:56.23 How does it go about transforming this information into different kinds of output behaviors? 00:27:02.02 Well, again, focusing specifically on sleep, I'd like to tell you about 00:27:05.27 a disorder of humans that's a complex and fascinating sleep disorder, called "narcolepsy with cataplexy." 00:27:13.23 In narcolepsy with cataplexy, you can think of the sleep state as "invading" the waking state. 00:27:21.13 So people with this disorder tend to fall asleep very quickly, and at inappropriate times. 00:27:27.12 They have hallucinations when they're awake, sometimes because they're dreaming when they're awake; 00:27:32.22 a sleep-appropriate response is appearing while they're awake. 00:27:36.09 And, they can lose their muscle control very suddenly, 00:27:39.18 so their bodies relax in the same way you relax when you're asleep. 00:27:43.01 This happens sometimes with excitement. 00:27:46.01 Now, very little was understood about the biology of human narcolepsy 00:27:50.10 until certain dog owners noticed that their dogs had a disorder very much like human narcolepsy, 00:27:57.04 that they fell asleep inappropriately and that they would collapse sometimes when they were excited. 00:28:02.03 And Emmanuel Mignot, studying these dogs, 00:28:05.05 was able to trace down the genetic changes that caused these dogs to have abnormal sleep-waking behavior. 00:28:13.15 And what he found is that these dogs had a deficiency in a particular brain chemical called hypocretin, 00:28:22.14 that signals through a G protein-coupled receptor called the hypocretin-2 receptor. 00:28:28.29 Building out from this discovery, and similar discoveries in mouse, 00:28:33.23 we were able to make the discovery in humans that the exact same biological system is involved in human narcolepsy-cataplexy, 00:28:42.10 as is involved in the dog disorder and in the mouse disorder. 00:28:47.12 So, there are neurons in the brain that make hypocretin. 00:28:51.19 In human patients with narcolepsy and cataplexy, these neurons are typically lost through autoimmune destruction, 00:28:58.21 leading to the loss of this peptide. 00:29:01.06 The mouse mutants that I didn't tell you about, that also have narcolepsy, 00:29:05.10 have a defect in the hypocretin gene itself. 00:29:08.26 The dog mutant that I did tell you about, these rare dogs that have narcolepsy, 00:29:13.11 have defects in the hypocretin-2 receptor. 00:29:17.15 So, what is this G protein-coupled receptor, and what is the signal that it detects? 00:29:23.06 The signal it detects is something called a neuropeptide, 00:29:26.14 a peptide made by one neuron to communicate with other neurons. 00:29:31.08 Neuropeptides represent one of the three different ways that neurons communicate with each other. 00:29:37.06 So neurons can communicate with each other at synapses, 00:29:40.08 through the process of fast chemical transmission that causes them to excite or inhibit each other locally and strongly. 00:29:47.17 They can communicate with each other through electrical connections, or gap junctions. 00:29:51.22 And they can communicate with each other through these secreted neuropeptides. 00:29:56.14 Now, neuropeptides, like classical transmitters, are secreted by one neuron 00:30:01.07 and affect another, but they have certain differences. 00:30:04.18 Classical transmitters are very fast, neuropeptides are slower. 00:30:08.29 Classical transmitters act at one synapse, neuropeptides can act at a distance... 00:30:13.18 they can broadcast information from one part of the brain to another. 00:30:18.04 And while there are only a few classical transmitters that are used over and over again, 00:30:23.21 they are many neuropeptides, and so individual neuropeptides, like hypocretin, 00:30:28.10 can have rather specific functions, like regulation of sleep and waking. 00:30:34.10 When we look at sleep behavior and its regulation by hypocretin, we see that, 00:30:40.04 within the human brain with its billions of neurons, there are just 2000 hypocretin-producing neurons. 00:30:46.11 These are the neurons that are required to prevent sleep from invading the waking state. 00:30:51.19 They're found deep in the hypothalamus, and they're closely connected with the neurons that drive the circadian clock, 00:30:58.13 so the circadian clock in the hypothalamus communicates with other neurons in the hypothalamus 00:31:05.09 that drive individual functions associated with the circadian clock, like sleep and waking. 00:31:11.01 And then these neurons broadcast information all throughout the brain to many regions involved in sleep and arousal, 00:31:17.13 in part by sending long processes to different regions, 00:31:20.09 and in part because their neuropeptide products can actually diffuse some distance from the site of production. 00:31:27.25 So sleep is an internally generated behavior that we can understand in the context of molecules for the circadian clock, 00:31:35.05 molecules for hypocretin, circuits that regulate the circadian clock and that interact with the neurons that produce hypocretin, 00:31:43.24 and also, in terms of the brain and the behavior of the whole animal. 00:31:50.10 So this is one example of an internal state and a motivation for behavior. 00:31:55.11 In my final example of a framework for behavior, 00:31:58.09 I'm going to talk about social behavior as a motivation for behavior. 00:32:02.17 Now, social behavior is a characteristic of all animals. 00:32:07.06 All animals must interact with other members of their species at certain key moments, 00:32:11.09 for example, during mating behaviors that are required for reproduction. 00:32:15.20 But social behavior, although it's widespread in animals, is also different in different animals, 00:32:21.22 so that, for example, animals recognize their own species but not other species, 00:32:26.17 and also, so that animals in different species behave differently from one another in their social contexts. 00:32:35.07 Moreover, even within the same species, animals will show different social behaviors 00:32:39.29 depending on things like their age, their sex, their reproductive status, and those of the organisms around them. 00:32:47.24 So this is an example of a behavior that shows variability, not just constancy. 00:32:54.12 Now, a nice example of social behavior's variability is illustrated by the behavior of different rodents, 00:33:01.10 that are sometimes called polygamous and monogamous rodents. 00:33:05.12 These are two different kinds of rodents, they're called voles, 00:33:08.07 and if you encounter them, they would look very similar to you, as shown by these different kinds of photographs. 00:33:14.01 But, if you examine their behaviors, you would see that these animals have really different social strategies. 00:33:19.22 Meadow voles are what are called polygamous voles. 00:33:23.09 These voles are largely solitary in their lifestyle. 00:33:26.28 Single males and females will mate briefly and then scatter. 00:33:31.11 There's very limited maternal care of offspring and no paternal care at all. 00:33:35.11 And they also differ in other social behaviors: 00:33:37.20 They're not territorial, and they're not aggressive. 00:33:40.13 By comparison, prairie voles are voles that will form pair bonds that will last for the entire life of 00:33:47.03 a male and a female after a single mating. 00:33:50.13 They live in large colonies, the mothers take very good care of the pups, and so do the fathers... 00:33:55.28 they show paternal care of their offspring. 00:33:58.04 In addition to their pair-bonding, they also show territorial and aggressive behavior, 00:34:02.13 distinguishing those within their own group from those of other groups. 00:34:07.10 So, these closely related rodents provide a way to think about what kinds of genetic changes 00:34:13.09 might evolve to allow these two different species to have such different social behaviors, 00:34:18.28 and that has been the mission of Tom Insel, Larry Young, and their colleagues at Emory University. 00:34:24.22 What they found is that these differences in social behaviors 00:34:28.01 were related to the functions of other important neuropeptides in the mammalian brain. 00:34:34.06 In mammals, social behavior is regulated by two neuropeptides that are related to each other, 00:34:40.03 called "oxytocin" and "vasopressin." 00:34:43.13 Oxytocin is strongly implicated in maternal behaviors, 00:34:47.11 as well as certain forms of maternal physiology, like nursing. 00:34:51.20 Vasopressin is related to male behaviors. 00:34:55.05 So each of these peptides exists in the brain, 00:34:58.07 each of them has its own specialized receptors that detect them. 00:35:03.21 What is the difference between polygamous voles and monogamous voles in these systems that allows them to behave differently? 00:35:13.01 Well, both polygamous and monogamous voles have oxytocin and vasopressin, 00:35:19.13 and both have receptors for oxytocin and vasopressin. 00:35:22.24 So it's not the existence of these genes that differs. 00:35:25.29 Instead, it's the way these genes are deployed in the brain 00:35:30.11 that's different in species that show different behaviors. 00:35:33.28 The difference between monogamous and polygamous voles comes when you examine the 00:35:39.10 vasopressin and oxytocin receptors in the brains of these animals and look at where in the brains these receptors are deployed. 00:35:48.04 So, this slide here shows sections through the brains of a monogamous vole and a polygamous vole. 00:35:55.27 These are both males, and they're sections of the same location of the brain. 00:35:59.13 The bright colors, the greens and reds and yellows, 00:36:02.10 illustrate locations at which the vasopressin V1 receptor is being expressed. 00:36:08.11 And what's evident from looking at this is that, while both of these species have the vasopressin receptor, 00:36:14.20 they utilize the vasopressin receptor in different brain regions. 00:36:20.01 The monogamous vole, shown at top, expresses the vasopressin receptor in regions that are involved in reward, 00:36:26.24 and the rewarding presence of this receptor helps the vole to generate 00:36:30.24 what you might think of as a positive association with its mate, that promotes the formation of a pair bond. 00:36:37.19 The polygamous vole, shown at bottom, does express a vasopressin receptor, 00:36:41.28 but it expresses it in different brain regions that would not allow this animal to form a rewarding memory. 00:36:47.20 And so the utilization of these receptors in different brain regions 00:36:51.28 causes different kinds of associations to be built and different behaviors to result. 00:36:57.13 So, we're turning to the framework for behavior. 00:37:00.20 I've tried to illustrate with a few examples how we can look at behaviors that are interesting between different animals, 00:37:08.18 and also behaviors that are shared by different animals, and think about them in the context of genes, brains, and behavior. 00:37:16.27 Our challenge now, as neuroscientists, is to ask how all of these processes 00:37:21.02 (environmental perception, decision-making, action, memory, internal states, and motivation) 00:37:28.06 relate to the functions of different genes; 00:37:30.15 how those genes relate to the functions, the development, and the flexibility of different parts of the brain; 00:37:37.07 and how those brain systems work together to generate the behavior of an animal, and ultimately, the human. 00:37:43.00 Thank you.
