[Note: this post is part of the course materials for my upcoming online class, Hormones: from molecules to behavior, with APDT.]
There your dog is, minding his own business, when suddenly another dog attacks him. His brain now has a bunch of physical changes to coordinate very quickly to deal with the emergency: routing energy away from the non-essentials (digestion, reproduction, certain parts of the immune system) and to what his body needs right now (muscle speed and strength). How to get out this message of impending danger to all the body's organs quickly and efficiently?
Human societies sometimes solve this kind of problem with public announcement systems: a public broadcast in an airport to announce a flight change, a Facebook post to announce a change in relationship status, posters around a neighborhood about a lost dog. It’s not the most elegant of solutions. Having a direct connection to everyone you wanted to pass the message to would be better — the passengers on the flight with the changed departure time, your Facebook friends whom you think are particularly cute, the people who actually saw your lost dog running by. But in the absence of being able to call all these people directly, we just get the message out there and hope that the people who didn’t need it won’t be too annoyed, and the ones who do need it will respond appropriately.
Hormones are a similar low-elegance, high-efficiency answer to the same problem. In the case of your dog who is being attacked by another dog, his brain orders the release of stress hormones. Hormones are tiny molecules which can be carried by the bloodstream throughout the body. The message to each of the organs which see the hormones floating by is the same — get ready to deal with danger — but the response of each organ is different. In the case of stress hormones, the body alters its metabolism to prepare to use a lot of energy in fighting or running, the digestion slows, and the immune system is suppressed, among many other consequences.
Note that the brain is quite capable of sending direct messages without using hormones. The peripheral nervous system is a whole complicated network of nerves connecting the brain to individual parts of the body, so if a message needs to be sent directly and privately, it can be. But just as sending a hundred individual hand-addressed wedding invitations is annoying and time-consuming, sometimes the public broadcast approach is just easier.
I’ll go into more detail in future posts about how the brain causes hormones to be released, because it’s different for different systems. In short, the brain sends an executive order, and a hormone is released into the bloodstream. Just like pouring gallons of dye into a river on St. Patrick’s Day, there’s plenty to go around, even miles downstream, or, in this case, all the way to the most distant parts of the body.
The hormone message is carried through the bloodstream throughout the body, washing up against cells from every organ. This is where the story moves from macroscopic — things large enough to see with human eyes, like blood moving through vessels — to microscopic: molecules of hormone and individual cells. You’d be able to see a dog’s cell through a microscope, but not a molecule of hormone, so we’re entirely in the realm of our imagination here.
There is all kinds of stuff in a dog's (or a human's) blood. Not just molecules of cortisol. Molecules of other hormones — I’m personally particularly interested in the ones that are associated with behavior, like cortisol and oxytocin and vasopressin, but there are hormones that have nothing to do with behavior: insulin and glucagon for managing metabolism, lutenizing hormone (LH) and follicle-stimulating hormone (FSH) for reproduction, insulin-like growth factor for growth, and so on. And there are other things besides hormones — cells for the immune system (white blood cells), cells for carrying oxygen (red blood cells), antibodies, little proteins called cytokines released by individual cells to communicate with each other about the stuff cells care about (inflammation, infection, and so on), things that cells eat like sugar and free fatty acids — the list goes on and on. The bloodstream is a superhighway packed with traffic.
Cells need to be able to process all this stuff appropriately. In the case of hormones, they do it with receptors. A receptor is like a keyhole, tuned to exactly one key; the key is called a “ligand.” In the case of a receptor for cortisol (for which the technical name is glucocorticoid receptor), the ligand or key is cortisol. There is a very short list of molecules which will fit into this receptor like keys into a lock, and cortisol is on that list. Insulin might bump up against it as it is going about its way doing insulin things, but it won’t bind with the receptor: it won’t fit into the keyhole.
When cortisol bumps up against this receptor, on the other hand, it does bind. In technical terminology, it is the ligand for the receptor. The receptor is like a little robot which, when it gets its ligand of cortisol, suddenly activates, as if the key in the lock enables its switch to be flipped to “on.” It turns on and goes and does its preprogrammed job, interacting with many other little robots which are receiving other signals.
Somehow, in the chaos of a zillion little machines each doing a very simple job, some very complex biological processes get performed inside cells. It’s this complex interaction that explains why different kinds cells react differently to the same hormonal message. Remember that the muscles need to do one thing when they see cortisol and the intestines need to do something different: this is because their receptors are working in very different cell types, with different environments, and different cells may have more or fewer receptors. Of course there are some cells which don't much care about this particular message, and these cells don't have receptors for cortisol, allowing them to ignore it.
I’ll talk more about what glucocorticoid receptors do in a later post, but it's not all that important to understand this kind of minutia. The story at a high level is that the brain identifies a situation that requires action; it orders the release of a hormone to send a public broadcast message to the rest of the body; cells in the body which have specific receptors for this hormone get the message, and their receptors activate in response to binding to molecules of the hormone and perform the necessary work to respond to the message. The system is simple, but somehow allows for the bewildering complexity of the animal body.
Thursday, January 8, 2015
Monday, December 29, 2014
Upcoming classes: Dogs! Brains! Hormones!
I have two new courses being offered online with the APDT that I’m really looking forward to teaching:
Most of my audience is usually dog trainers who are looking for continuing education credits, but I love getting interested dog lovers in these classes as well, and there’s a lower cost audit option for you guys.
These classes tend to be quite discussion-heavy — the best part for me is getting to talk directly with you guys and answer the questions you have about this stuff that I hadn’t thought of talking about. It is your chance to have a dog behavior researcher at your beck and call, answering your questions!
For those who just want to read stuff on this blog, note that I’ll be writing and posting most of the course materials here over the next few weeks, so keep an eye out for that.
Hope to see you there!
- Canine Hormones: from molecules to behavior, February 3 - March 11, 2015 (12 CEUs). Hormones — those chemicals that float around the body to pass messages between different organs — have a lot to do with behavior. What exactly is a hormone? How do hormones pass messages around? What is the stress response, how does it work, and what does it tell us about a dog's stress levels? What about reproductive hormones like estrogen and testosterone — how do they affect behavior?
- The Canine Brain: from neurons to behavior, March 4 - 24, 2015 (12 CEUs). The brain is an incredibly complicated organ, but it’s also incredibly interesting. What do we know about the parts of the brain and which ones affect the kinds of behaviors we care about in dogs (like fear and aggression)? What kind of cells make up the brain and how do they work? When a dog is learning, what is actually changing in the brain?
Most of my audience is usually dog trainers who are looking for continuing education credits, but I love getting interested dog lovers in these classes as well, and there’s a lower cost audit option for you guys.
These classes tend to be quite discussion-heavy — the best part for me is getting to talk directly with you guys and answer the questions you have about this stuff that I hadn’t thought of talking about. It is your chance to have a dog behavior researcher at your beck and call, answering your questions!
For those who just want to read stuff on this blog, note that I’ll be writing and posting most of the course materials here over the next few weeks, so keep an eye out for that.
Hope to see you there!
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| Dog brains! |
Tuesday, December 9, 2014
The history of dog breeds: Victorians, genetics, and the importance of diversity
Note: there is an interview with me at the Huffington Post about this story.
Dog breeds are amazing creations. I can own a series of Golden Retrievers and predict with fair accuracy how each of them will look and act. (Look more than act, but the incredible variety of dog personalities is a story for another day.) Unfortunately, I can also predict with fair accuracy what diseases each of those dogs will have, because with the Golden looks and personality come the Golden genetic disorders. As a new dog owner years ago, I thought of these genetic problems as part of the package I was handed when I got a purebred dog: you choose the looks and personality, and you choose the diseases at the same time. But there’s a lot more to the story of how dog breeds came to be saddled with particular genetic disorders than just happenstance: we made choices when we created breeds and we continue to make choices about their health today.
The beginning of dog breeds
Humans have been breeding dogs for thousands of years, but for most of our history with them, function was more important than appearance. Dogs were bred to work, and beauty was a side effect: long coats were for keeping warm, small size was for chasing tunneling vermin, long legs were for speed.
During the Victorian era, things changed, with the spectacular growth of dog fancy. Suddenly people were breeding and showing dogs for how they looked, not how they worked. Breeds were no longer loose groups of dogs who looked kind of similar and did a particular job; now for the first time purebred dogs had carefully maintained pedigrees. This was the era when the breed books closed, meaning that breeds were suddenly defined as the set of dogs whose ancestors belonged to a select list. If you wanted to make more Golden Retrievers, you could only breed dogs descended from that original list. If you bred in dogs with unknown ancestry, their offspring were considered mutts and could not be competitively shown, even if they looked just like purebreds.
What happens when you take a relatively small set of dogs and use them to breed a much larger number of dogs? It’s like this small set of dogs is marooned on a desert island with no way to bring in new genetic diversity, and their pedigrees are what marooned them. Their descendants will look like them and act like them – and have their genetic diseases. The genetics from those few founders are all that's available to the descendants. When this reduced genetic diversity is severe, it can be a big problem.
Basenjis and Fanconi syndrome
Reduced genetic diversity is severe in the Basenji breed. This breed originated in Africa, but only the Basenjis descended from a small number of dogs imported to Europe in the 1930s are considered purebred. The diversity in this breed was so low in Basenjis in the Western world that in 1990, one in ten Basenjis suffered from exactly the same genetic disorder, a kidney disease called Fanconi syndrome. One or a few of the founding dogs must have had this disease, and it was passed on to their descendants until a large percentage of Basenjis suffered from it.
The solution: bring in new Basenjis from Africa, breed them to the Western Basenjis, and declare that their offspring may be considered purebred, despite a lack of pedigree. This was done in 1990 and again in 2013, and the effects are still spreading through the Western Basenji population over several generations. (You can read about the trip to the Congo to acquire African Basenjis.)
Dalmatians and urinary tract stones
But what if there isn't an ancestral population waiting to be harvested? Dalmatians also suffer from a genetic kidney disease, in their case stones in their urinary tract caused by high levels of uric acid. It's a painful disease and there was no way to breed out of it: at one point, every single Dalmatian in existence had uric acid levels above normal canine values.
The solution? The Dalmatian Backcross Project, which began in 1973 with the breeding of a Dalmatian to a Pointer. The project husbanded along a line of Low Uric Acid (LUA) Dalmatians, also known as Normal Uric Acid Dalmatians, because what's low in a Dalmatian is normal in any other breed. Puppies from this original Dalmatian/Pointer cross were tested for uric acid levels, and those with normal levels were bred to purebred Dalmatians. This continued generation after generation until a line of Dalmatians had been bred which looked like Dalmatians, not Pointers, but had normal uric acid levels. As of 2011, LUA Dalmatians have been registered with the American Kennel Club and are now considered purebred Dalmatians. It remains to be seen how long the problem of high uric acid levels will remain common in this breed, but at least now there’s a solution in sight.
What we're doing about genetic health in dog breeds
With these success stories, you’d think the problem would be solved. But these are the only two breeds so far to open their breed books to bring in new genetic diversity. [ETA: readers note that a few other breeds have opened their books, including Border collies, Chinooks, Salukis, and Azawakh in the US, and several breeds in Europe. Fantastic!] Both the Dalmatian and the Basenji had easy to diagnose, easy to understand health problems that were also easy to identify with genetic testing: problems controlled by a single gene. Such diseases are relatively unusual. Take the case of the Golden Retriever, who is prone to developing cancer at greatly accelerated rates compared to most other breeds. Cancer is controlled by a lot of genes and is very hard to genetically test for – and therefore hard to breed away from.
While introducing new genetics into Golden Retrievers is very likely to improve the health of the breed, it’s hard to convince breeders to take the leap. As was the case with the Dalmatian Backcross Project, such an undertaking would mean producing dogs that didn't look like Goldens for a few generations. They could still make great pets, but they couldn’t be shown and they probably couldn't be sold for as much money as a purebred. And there’s no guarantee that their descendants could ever be registered as purebreds – the fight to get LUA Dalmatians accepted was long and hard. I use Goldens as an example because I live with one, but many of the breeds we love suffer from low genetic diversity and associated genetic health concerns.
I believe we need as a society to get past our obsession with historical breeds. We can breed for appearance, but that has to take a back seat to breeding for health. We have a model with the Dalmatian Backcross Project. All we need is the will to improve the genetic health of more breeds.
Dog breeds are amazing creations. I can own a series of Golden Retrievers and predict with fair accuracy how each of them will look and act. (Look more than act, but the incredible variety of dog personalities is a story for another day.) Unfortunately, I can also predict with fair accuracy what diseases each of those dogs will have, because with the Golden looks and personality come the Golden genetic disorders. As a new dog owner years ago, I thought of these genetic problems as part of the package I was handed when I got a purebred dog: you choose the looks and personality, and you choose the diseases at the same time. But there’s a lot more to the story of how dog breeds came to be saddled with particular genetic disorders than just happenstance: we made choices when we created breeds and we continue to make choices about their health today.
 |
| Figure from: Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication Nature, Vol. 464, No. 7290. (17 March 2010), pp. 898-902, doi:10.1038/nature08837 by Bridgett M. vonHoldt, John P. Pollinger, Kirk E. Lohmueller, et al. |
The beginning of dog breeds
Humans have been breeding dogs for thousands of years, but for most of our history with them, function was more important than appearance. Dogs were bred to work, and beauty was a side effect: long coats were for keeping warm, small size was for chasing tunneling vermin, long legs were for speed.
During the Victorian era, things changed, with the spectacular growth of dog fancy. Suddenly people were breeding and showing dogs for how they looked, not how they worked. Breeds were no longer loose groups of dogs who looked kind of similar and did a particular job; now for the first time purebred dogs had carefully maintained pedigrees. This was the era when the breed books closed, meaning that breeds were suddenly defined as the set of dogs whose ancestors belonged to a select list. If you wanted to make more Golden Retrievers, you could only breed dogs descended from that original list. If you bred in dogs with unknown ancestry, their offspring were considered mutts and could not be competitively shown, even if they looked just like purebreds.
What happens when you take a relatively small set of dogs and use them to breed a much larger number of dogs? It’s like this small set of dogs is marooned on a desert island with no way to bring in new genetic diversity, and their pedigrees are what marooned them. Their descendants will look like them and act like them – and have their genetic diseases. The genetics from those few founders are all that's available to the descendants. When this reduced genetic diversity is severe, it can be a big problem.
Basenjis and Fanconi syndrome
Reduced genetic diversity is severe in the Basenji breed. This breed originated in Africa, but only the Basenjis descended from a small number of dogs imported to Europe in the 1930s are considered purebred. The diversity in this breed was so low in Basenjis in the Western world that in 1990, one in ten Basenjis suffered from exactly the same genetic disorder, a kidney disease called Fanconi syndrome. One or a few of the founding dogs must have had this disease, and it was passed on to their descendants until a large percentage of Basenjis suffered from it.
The solution: bring in new Basenjis from Africa, breed them to the Western Basenjis, and declare that their offspring may be considered purebred, despite a lack of pedigree. This was done in 1990 and again in 2013, and the effects are still spreading through the Western Basenji population over several generations. (You can read about the trip to the Congo to acquire African Basenjis.)
Dalmatians and urinary tract stones
But what if there isn't an ancestral population waiting to be harvested? Dalmatians also suffer from a genetic kidney disease, in their case stones in their urinary tract caused by high levels of uric acid. It's a painful disease and there was no way to breed out of it: at one point, every single Dalmatian in existence had uric acid levels above normal canine values.
The solution? The Dalmatian Backcross Project, which began in 1973 with the breeding of a Dalmatian to a Pointer. The project husbanded along a line of Low Uric Acid (LUA) Dalmatians, also known as Normal Uric Acid Dalmatians, because what's low in a Dalmatian is normal in any other breed. Puppies from this original Dalmatian/Pointer cross were tested for uric acid levels, and those with normal levels were bred to purebred Dalmatians. This continued generation after generation until a line of Dalmatians had been bred which looked like Dalmatians, not Pointers, but had normal uric acid levels. As of 2011, LUA Dalmatians have been registered with the American Kennel Club and are now considered purebred Dalmatians. It remains to be seen how long the problem of high uric acid levels will remain common in this breed, but at least now there’s a solution in sight.
What we're doing about genetic health in dog breeds
With these success stories, you’d think the problem would be solved. But these are the only two breeds so far to open their breed books to bring in new genetic diversity. [ETA: readers note that a few other breeds have opened their books, including Border collies, Chinooks, Salukis, and Azawakh in the US, and several breeds in Europe. Fantastic!] Both the Dalmatian and the Basenji had easy to diagnose, easy to understand health problems that were also easy to identify with genetic testing: problems controlled by a single gene. Such diseases are relatively unusual. Take the case of the Golden Retriever, who is prone to developing cancer at greatly accelerated rates compared to most other breeds. Cancer is controlled by a lot of genes and is very hard to genetically test for – and therefore hard to breed away from.
While introducing new genetics into Golden Retrievers is very likely to improve the health of the breed, it’s hard to convince breeders to take the leap. As was the case with the Dalmatian Backcross Project, such an undertaking would mean producing dogs that didn't look like Goldens for a few generations. They could still make great pets, but they couldn’t be shown and they probably couldn't be sold for as much money as a purebred. And there’s no guarantee that their descendants could ever be registered as purebreds – the fight to get LUA Dalmatians accepted was long and hard. I use Goldens as an example because I live with one, but many of the breeds we love suffer from low genetic diversity and associated genetic health concerns.
I believe we need as a society to get past our obsession with historical breeds. We can breed for appearance, but that has to take a back seat to breeding for health. We have a model with the Dalmatian Backcross Project. All we need is the will to improve the genetic health of more breeds.
 |
| Jack the Pumpkin King, my 14 year old Golden Retriever. He has so far only developed a small tumor, which was easily removed. However, he suffers from skin allergies and epilepsy, both genetic disorders. |
Saturday, November 22, 2014
Testing behavioral assessment
My Bark article, Testing the Tests, is now available on the web for free. I did a lot of background reading for this story and I learned a lot of interesting stuff about shelter behavioral assessments: how they're designed, how to evaluate whether they work, and new work that's going into improving them. Check it out!
Saturday, November 8, 2014
How antidepressants work: the good parts version
[Author’s note: Please consider my last post, How do antidepressants work (in dogs and the rest of us)?, to be the director’s cut of this topic: fairly long and juicy, with some bits in which I indulge my inner geek and perhaps go into more detail than is truly necessary. This, then, is the good parts version: the same material, but presented as an overview from a higher altitude, with fewer details and assuming less scientific knowledge. These posts are both intended as material for my upcoming online class with APDT, and I want to make sure students of all levels of science background are covered. Also, it’s good for me to take a step back from time to time and remember that not everyone wants to know every gory detail about this brain stuff.]
We don’t fully understand what causes depression in humans, and we don’t fully understand how the medications we use to treat depression work. We do know that those medications work well in dogs just as they do in us. In dogs, however, they are more often used to treat fearfulness or aggression. We know that antidepressants generally take effect only after several weeks of constant use, and that they work much better if they are paired with behavior modification training in dogs or therapy in humans. And we actually do know enough about how they work to take a guess at why that's true.
Depression in humans and fearfulness and aggression in dogs are related to stress: something in our lives that we can't control and can’t quite adjust to. In humans, that might be extended unemployment or long term caretaking for a sick family member. In dogs, it can be the inability to control who comes to visit your house (that terrifying mailman) or perhaps a lack of understanding of the big scary world (for undersocialized dogs).
Sometimes training or therapy aren’t enough to help us deal with these problems; some problems are too hard for our brains to cope with on their own. Antidepressants seem to help our brains adapt, however. A part of the brain deeply involved in learning and memory, the hippocampus, tends to be smaller in people who are depressed and tends to get larger again when they take antidepressants. This change may be associated with an improved ability to make new mental connections.
So that’s why antidepressants take weeks to take effect: that part of the brain is growing and changing, which doesn’t happen after just one pill. And that may also be why antidepressants work so much better in the context of training or therapy. It’s nice for your brain to be more able to learn new ways of coping with a difficult world, but the ability to learn is not the same as actual learning. To learn, you have to get out there and do: talk through your problems and find the way to feel differently about them and take new approaches to solutions if you’re a human, or get to practice new ways of interacting with the mailman if you’re a dog.
The take home message for dog owners? Don’t expect your dog to respond to antidepressants immediately; it will take a few weeks. And don’t expect your dog to respond without behavior modification. Antidepressants aren’t magic bullets and they won’t fix the problem on their own. But they will make it easier for all the training you do to take effect.
We don’t fully understand what causes depression in humans, and we don’t fully understand how the medications we use to treat depression work. We do know that those medications work well in dogs just as they do in us. In dogs, however, they are more often used to treat fearfulness or aggression. We know that antidepressants generally take effect only after several weeks of constant use, and that they work much better if they are paired with behavior modification training in dogs or therapy in humans. And we actually do know enough about how they work to take a guess at why that's true.
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| You can buy your very own Prozac bone sticker! |
Depression in humans and fearfulness and aggression in dogs are related to stress: something in our lives that we can't control and can’t quite adjust to. In humans, that might be extended unemployment or long term caretaking for a sick family member. In dogs, it can be the inability to control who comes to visit your house (that terrifying mailman) or perhaps a lack of understanding of the big scary world (for undersocialized dogs).
Sometimes training or therapy aren’t enough to help us deal with these problems; some problems are too hard for our brains to cope with on their own. Antidepressants seem to help our brains adapt, however. A part of the brain deeply involved in learning and memory, the hippocampus, tends to be smaller in people who are depressed and tends to get larger again when they take antidepressants. This change may be associated with an improved ability to make new mental connections.
So that’s why antidepressants take weeks to take effect: that part of the brain is growing and changing, which doesn’t happen after just one pill. And that may also be why antidepressants work so much better in the context of training or therapy. It’s nice for your brain to be more able to learn new ways of coping with a difficult world, but the ability to learn is not the same as actual learning. To learn, you have to get out there and do: talk through your problems and find the way to feel differently about them and take new approaches to solutions if you’re a human, or get to practice new ways of interacting with the mailman if you’re a dog.
The take home message for dog owners? Don’t expect your dog to respond to antidepressants immediately; it will take a few weeks. And don’t expect your dog to respond without behavior modification. Antidepressants aren’t magic bullets and they won’t fix the problem on their own. But they will make it easier for all the training you do to take effect.
Sunday, November 2, 2014
How do antidepressants work (in dogs and the rest of us)?
There are plenty of humans and dogs on antidepressants, and we believe that the mechanisms of these medications are much the same in both human and dog brains. But despite the fact that these are widely used medications, we aren’t completely clear how they work. Yes, this is going to be another post in which I ask a question and then don’t really tell you the answer. But I’ll tell you what we do know.
What is depression?
There are probably many different kinds of depression, so that the disease is slightly different in many (or all) people and dogs. As a result, getting a handle on the mechanisms of depression and its treatments is difficult. So studies about depression and antidepressants have to speak in generalities, such as “this is true for 50% of people with depression.”
In general, then, depression is triggered by chronic stress, which results in increased levels of stress hormones. The major stress hormone in humans and dogs is cortisol, so that’s the term I’ll use in this post. The major stress hormone in mice and rats is the closely-related corticosterone, so if you delve into more of the research in this area, you may find that hormone mentioned as well. It’s basically the same as cortisol. Note that while I’ll talk about depression in this post, in dogs we more commonly perceive stress-related problems as behavior problems, such as shyness or aggression. These problems, in certain cases, can be very successfully treated with antidepressants in combination with training.
Depression and the hippocampus
The area of the brain which is the most sensitive to increased levels of cortisol is the hippocampus, a part of the limbic system which is involved in learning, memory, and emotion. The cells of the hippocampus are armed with little widgets called glucocorticoid receptors, or GR, which grab cortisol molecules as they float by. Once a GR has attached itself to some cortisol, it becomes active, and takes itself over to the cell’s DNA. Here it tells the cell to activate some genes and deactivate other genes. This is how cortisol effects stress-related changes in our body: by telling the massive recipe-book inside our cells which genes to cook up and which ones to leave idle.
So the first generality about depression is that it results in more cortisol than normal. The second generality is that it also results in a smaller hippocampus than normal. We can guess, though we’re not sure, that this is somehow related to all that GR activation. We know that in depression, fewer new neurons are born in the hippocampus, so that is probably part of the answer. However, it’s not the whole answer, because even in healthy people, new neurons are created at a very low rate, not fast enough to explain this decrease in size of the hippocampus. Another possibility is that the shape of individual neurons changes. Neurons branch out like trees to touch lots of other neurons, and the neurons of depressed people have fewer branches. So the problem could be caused by fewer neurons, or by neurons that have fewer branches and therefore less communication with other neurons. We’re not sure which, but either way, the changes are significant.
Antidepressants and the GR
Antidepressants affect many substances in the brain (most famously, the class of antidepressants of which Prozac is a member affect serotonin levels). We have trouble picking out cause and effect here. We assume that antidepressants aren’t affecting all of these substances directly; we assume that some of these affects are indirect, in other words, side effects. We’d like to know which substances antidepressants directly affect in the brain, in other words, what their mechanisms are, but we’re still not sure.
We do know that they affect the GR, though we don’t know if they do so directly or indirectly. So far, we haven’t found any direct effects on the GR. One theory is that antidepressants affect another widget, one which pumps cortisol out of cells so that the GR can’t grab it and become active. The decrease in number of active GR, then, causes the changes in the brain which result in mood improvement.
We do know that depressed people on antidepressants start to have increased birth of new neurons in their hippocampus, which itself increases in size. Why does this affect mood? We don’t know, but we can hypothesize that improved ability to make new mental connections and learn is at the heart of the change. This helps us understand why antidepressants typically take several weeks to work: our brains are changing, growing, and that takes time.
Antidepressants and dogs
As usual, all the research on how this stuff works was done in rats, mice, and humans. But we do think that the mechanisms are similar in dogs, and indeed in most or all mammals. Many dogs are on antidepressants with positive effects, including my shy dog Jenny, who receives both buspirone and lots of counter-conditioning. As research continues to get us more answers about how these medications actually work in the brain, we will do better and better at understanding which kinds of antidepressants are better for which individuals, when to start them, and when to stop them.
Anacker C., Livia A. Carvalho & Carmine M. Pariante (2011). The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?, Psychoneuroendocrinology, 36 (3) 415-425. DOI: http://dx.doi.org/10.1016/j.psyneuen.2010.03.007
For further reading, check out related posts by Scicurious:
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| You can buy your very own Prozac bone sticker! |
What is depression?
There are probably many different kinds of depression, so that the disease is slightly different in many (or all) people and dogs. As a result, getting a handle on the mechanisms of depression and its treatments is difficult. So studies about depression and antidepressants have to speak in generalities, such as “this is true for 50% of people with depression.”
In general, then, depression is triggered by chronic stress, which results in increased levels of stress hormones. The major stress hormone in humans and dogs is cortisol, so that’s the term I’ll use in this post. The major stress hormone in mice and rats is the closely-related corticosterone, so if you delve into more of the research in this area, you may find that hormone mentioned as well. It’s basically the same as cortisol. Note that while I’ll talk about depression in this post, in dogs we more commonly perceive stress-related problems as behavior problems, such as shyness or aggression. These problems, in certain cases, can be very successfully treated with antidepressants in combination with training.
Depression and the hippocampus
The area of the brain which is the most sensitive to increased levels of cortisol is the hippocampus, a part of the limbic system which is involved in learning, memory, and emotion. The cells of the hippocampus are armed with little widgets called glucocorticoid receptors, or GR, which grab cortisol molecules as they float by. Once a GR has attached itself to some cortisol, it becomes active, and takes itself over to the cell’s DNA. Here it tells the cell to activate some genes and deactivate other genes. This is how cortisol effects stress-related changes in our body: by telling the massive recipe-book inside our cells which genes to cook up and which ones to leave idle.
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| Image courtesy of Wikipedia |
So the first generality about depression is that it results in more cortisol than normal. The second generality is that it also results in a smaller hippocampus than normal. We can guess, though we’re not sure, that this is somehow related to all that GR activation. We know that in depression, fewer new neurons are born in the hippocampus, so that is probably part of the answer. However, it’s not the whole answer, because even in healthy people, new neurons are created at a very low rate, not fast enough to explain this decrease in size of the hippocampus. Another possibility is that the shape of individual neurons changes. Neurons branch out like trees to touch lots of other neurons, and the neurons of depressed people have fewer branches. So the problem could be caused by fewer neurons, or by neurons that have fewer branches and therefore less communication with other neurons. We’re not sure which, but either way, the changes are significant.
Antidepressants and the GR
Antidepressants affect many substances in the brain (most famously, the class of antidepressants of which Prozac is a member affect serotonin levels). We have trouble picking out cause and effect here. We assume that antidepressants aren’t affecting all of these substances directly; we assume that some of these affects are indirect, in other words, side effects. We’d like to know which substances antidepressants directly affect in the brain, in other words, what their mechanisms are, but we’re still not sure.
We do know that they affect the GR, though we don’t know if they do so directly or indirectly. So far, we haven’t found any direct effects on the GR. One theory is that antidepressants affect another widget, one which pumps cortisol out of cells so that the GR can’t grab it and become active. The decrease in number of active GR, then, causes the changes in the brain which result in mood improvement.
We do know that depressed people on antidepressants start to have increased birth of new neurons in their hippocampus, which itself increases in size. Why does this affect mood? We don’t know, but we can hypothesize that improved ability to make new mental connections and learn is at the heart of the change. This helps us understand why antidepressants typically take several weeks to work: our brains are changing, growing, and that takes time.
Antidepressants and dogs
As usual, all the research on how this stuff works was done in rats, mice, and humans. But we do think that the mechanisms are similar in dogs, and indeed in most or all mammals. Many dogs are on antidepressants with positive effects, including my shy dog Jenny, who receives both buspirone and lots of counter-conditioning. As research continues to get us more answers about how these medications actually work in the brain, we will do better and better at understanding which kinds of antidepressants are better for which individuals, when to start them, and when to stop them.
Anacker C., Livia A. Carvalho & Carmine M. Pariante (2011). The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?, Psychoneuroendocrinology, 36 (3) 415-425. DOI: http://dx.doi.org/10.1016/j.psyneuen.2010.03.007
For further reading, check out related posts by Scicurious:
Monday, October 27, 2014
Can prenatal stress be reversed?
I was scanning the titles of new journal articles a while back, and came across one that made me think, hey, that may be about rats, but it is totally relevant to dogs. And then I thought, why don’t I teach a class on it? Read and interpret this really interesting journal article with a group of dog trainers and dog lovers?
I will be teaching the class Prenatal Stress and Anti-Depressants for APDT the week of November 18 (and you are invited to take it). This post will be used as reading material for it. In the class, we will talk about this article and what conclusions we can draw from it and apply to dogs. So I may not draw as many the conclusions for you in this post as I usually do; the plan is for the students to do that together in class. But it was a fascinating paper and there’s lots of good material in it, so read on if you want a conclusion-free summary of it!
Pereira-Figueiredo I., Juan Carro, Orlando Castellano & Dolores E. Lopez (2014). The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes, Frontiers in Behavioral Neuroscience, 8 DOI: http://dx.doi.org/10.3389/fnbeh.2014.00260
Why prenatal stress?
So what’s prenatal stress and why is it important to dogs? The authors of the article don’t provide much background on this phenomenon, but it’s an interesting one: when a mammal undergoes unusually high stress during her pregnancy, the personality of her offspring can be affected. We believe that the stress hormones rising in her bloodstream can pass through her placenta to the fetus or fetuses, and can change how their brains develop at this very early stage of life. That’s prenatal stress: stress experienced before birth.
Part of what this paper investigates is exactly how prenatal stress affects the developing personality, because we don’t yet fully understand how this stuff works. In general, though, we expect prenatally stressed animals to be more anxious and less confident than animals who were not prenatally stressed.
Does prenatal stress affect dogs? We don’t know for sure, but we think it is something that can affect most or all mammals. Would it happen commonly? Hard to say, but I imagine a pregnant dog who is stray or in a shelter and highly stressed, and I wonder what effects this might have on her puppies.
What can you do about it?
If you have a puppy that you believe was prenatally stressed and whose personality you thought was adversely affected, what are your options? Careful socialization and good enrichment are always an excellent choice, but in some cases you might consider medication. This study looks at whether a particular anti-depressant, sertraline, might help change the individual’s personality long-term if given in adolescence. Sertraline is an SSRI, in the same class of medications as Prozac. These are widely used medications believed to be fairly safe, but one of the questions these researchers ask is whether it is safe when given throughout an animal’s entire adolescence.
SSRIs such as sertraline affect the levels of serotonin in your brain. Serotonin is a chemical which affects mood; depressed people tend to have less of it, as do aggressive people. As a result, it is the target of a fair number of anti-depressants, which work to increase its levels. Prenatal stress is known to disrupt the serotonin system in the brain, so a medication which affects serotonin is a reasonable choice for prenatally stressed individuals.
So the idea is: give these prenatally stressed animals a medication which increases their serotonin levels while they are adolescents and their brains are still developing. The hope is that they will develop into more normal adults than they would have without the medication. So, exactly how do you investigate such a question?
Methods: how the study worked
First, the researchers stressed some pregnant rats by putting them in clear tubes to restrain them, and shining bright light on them. This was repeated for forty-five minutes at a time, three times a day. They also kept control rats, who were not stressed during their pregnancy. The pups born to these two sets of rats were then in two categories: prenatally stressed pups and non-stressed pups.
The rat pups began their anti-depressant treatment with sertraline when they were one month old. Now there were four groups of rat pups:
Having these four groups allowed the researchers to pick apart the two different effects, the effect of prenatal stress and the effect of anti-depressants during adolescence.
The pups were tested at two months of age, the beginning of rat adolescence, to see if the prenatal stress had affected their personalities. They were assessed for how they dealt with startling noises and being exposed to open space (scary for a rat!). Their blood was also tested to see how their immune systems were developing, because immune systems develop differently in animals who have been subjected to high stress. All these tests were run again one month later, at the end of rat adolescence, to see how the anti-depressant given throughout adolescence had affected treated rats compared to the control groups.
Results: what they found
The study’s main conclusions are that effects of prenatal stress can be seen in rats, and that giving sertraline during adolescence did not harm them.
The rapid weight gain in the pre-natally stressed females is an effect that’s been seen before, and seen in humans. Children born with low birth weights often grow to have issues with their weight and can suffer from diseases related to a poorly regulated metabolism. This loss of control of energy balance has been associated with dysregulation of serotonin in humans, adding additional support to the choice of sertraline, an anti-depressant which interacts with the serotonin system.
It is interesting that no anxiety-like behavioral changes were seen in the prenatally stressed rats. Prenatal stress is known to cause anxious personalities in many cases. However, these rats were as confident (or as anxious!) in the open space test as rats who had not been prenatally stressed. The researchers comment that this particular test has been done on prenatally stressed rats in other studies, and that those rats didn’t show anxiety in the open space test either, so this does seem to be a real result, rather than a statistical error.
They did see some differences, though. Male rats who had been prenatally stressed did show some additional reluctance to explore (i.e. anxiety) on their first day only in the open space test. After that they explored equal amounts compared to other groups.
The researchers also note that while most of the rats that they tested were equally anxious on all days that they were tested in the open space, females who had not been prenatally stressed appeared to begin to explore more on repeated tests, as if they were learning to be less anxious as their surroundings became more familiar. This was not the case in male rats or in rats who had been pre-natally stressed.
Remember also that female rats who were prenatally stressed did not habituate to startling sounds as well as rats from other groups. Is it possible that with this particular model of prenatal stress, the personality effects of prenatal stress appear not as classical anxiety, but as difficulty habituating to new situations or stressors such as loud noises?
Finally, the researchers looked at effects of pre-natal stress on the immune system, and found significant effects (decreased numbers of white blood cells) which were reversed by treatment with the anti-depressant sertraline. Why did they care about the immune system? Because the immune system and the stress system are closely intertwined. Stressed animals show changes in the numbers of their white blood cells just as the prenatally stressed rats did. The researchers were using the changes in the immune system as markers for changes in the stress system.
There are two possibilities for why these prenatally rats showed stress-associated changes in their immune systems: either because they themselves had high stress levels, or because their immune systems were developing prenatally (in utero) in a high stress environment due to their mother’s stress levels. Either way, it is interesting that treatment with sertraline reversed these effects, suggesting that it may have either changed current stress levels in these adolescent rats (even though the only serious stressors they had undergone were before their birth!), or had counteracted other effects from that prenatal stressor.
Conclusions
It can be hard to know exactly what conclusions to draw from a scientific paper. What do you think? What are the most important findings in this paper (maybe just two or three of them)? Do you think those findings are real phenomena, or maybe just statistical mistakes? If they’re real, do you think they can be extrapolated from rats to humans or dogs?
I will be teaching the class Prenatal Stress and Anti-Depressants for APDT the week of November 18 (and you are invited to take it). This post will be used as reading material for it. In the class, we will talk about this article and what conclusions we can draw from it and apply to dogs. So I may not draw as many the conclusions for you in this post as I usually do; the plan is for the students to do that together in class. But it was a fascinating paper and there’s lots of good material in it, so read on if you want a conclusion-free summary of it!
Pereira-Figueiredo I., Juan Carro, Orlando Castellano & Dolores E. Lopez (2014). The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes, Frontiers in Behavioral Neuroscience, 8 DOI: http://dx.doi.org/10.3389/fnbeh.2014.00260
Why prenatal stress?
So what’s prenatal stress and why is it important to dogs? The authors of the article don’t provide much background on this phenomenon, but it’s an interesting one: when a mammal undergoes unusually high stress during her pregnancy, the personality of her offspring can be affected. We believe that the stress hormones rising in her bloodstream can pass through her placenta to the fetus or fetuses, and can change how their brains develop at this very early stage of life. That’s prenatal stress: stress experienced before birth.
Part of what this paper investigates is exactly how prenatal stress affects the developing personality, because we don’t yet fully understand how this stuff works. In general, though, we expect prenatally stressed animals to be more anxious and less confident than animals who were not prenatally stressed.
Does prenatal stress affect dogs? We don’t know for sure, but we think it is something that can affect most or all mammals. Would it happen commonly? Hard to say, but I imagine a pregnant dog who is stray or in a shelter and highly stressed, and I wonder what effects this might have on her puppies.
What can you do about it?
If you have a puppy that you believe was prenatally stressed and whose personality you thought was adversely affected, what are your options? Careful socialization and good enrichment are always an excellent choice, but in some cases you might consider medication. This study looks at whether a particular anti-depressant, sertraline, might help change the individual’s personality long-term if given in adolescence. Sertraline is an SSRI, in the same class of medications as Prozac. These are widely used medications believed to be fairly safe, but one of the questions these researchers ask is whether it is safe when given throughout an animal’s entire adolescence.
SSRIs such as sertraline affect the levels of serotonin in your brain. Serotonin is a chemical which affects mood; depressed people tend to have less of it, as do aggressive people. As a result, it is the target of a fair number of anti-depressants, which work to increase its levels. Prenatal stress is known to disrupt the serotonin system in the brain, so a medication which affects serotonin is a reasonable choice for prenatally stressed individuals.
So the idea is: give these prenatally stressed animals a medication which increases their serotonin levels while they are adolescents and their brains are still developing. The hope is that they will develop into more normal adults than they would have without the medication. So, exactly how do you investigate such a question?
Methods: how the study worked
First, the researchers stressed some pregnant rats by putting them in clear tubes to restrain them, and shining bright light on them. This was repeated for forty-five minutes at a time, three times a day. They also kept control rats, who were not stressed during their pregnancy. The pups born to these two sets of rats were then in two categories: prenatally stressed pups and non-stressed pups.
The rat pups began their anti-depressant treatment with sertraline when they were one month old. Now there were four groups of rat pups:
| prenatal stress anti-depressants |
prenatal stress no anti-depressants |
| no prenatal stress anti-depressants |
no prenatal stress no anti-depressants |
Having these four groups allowed the researchers to pick apart the two different effects, the effect of prenatal stress and the effect of anti-depressants during adolescence.
The pups were tested at two months of age, the beginning of rat adolescence, to see if the prenatal stress had affected their personalities. They were assessed for how they dealt with startling noises and being exposed to open space (scary for a rat!). Their blood was also tested to see how their immune systems were developing, because immune systems develop differently in animals who have been subjected to high stress. All these tests were run again one month later, at the end of rat adolescence, to see how the anti-depressant given throughout adolescence had affected treated rats compared to the control groups.
Results: what they found
- Although we may think of prenatal stress as mostly affecting an animal’s behavior, it’s been shown to also affect metabolism, so this study looked at birth weight. Interestingly, prenatal stress only reduced the birth weight of the female rat pups, not the males. The weights of these females had equalized compared to non-stressed pups by weaning age. After weaning, though, the prenatally stressed females continued to gain weight and ended up heavier as adults than the non-stressed females. When prenatally stressed females were given the anti-depressant sertraline, however, this weight difference was reduced.
- The pups were also tested for their startle response when they heard a sudden sound. Prenatally stressed rat pups did seem to have a larger startle amplitude (size) compared to controls, but this wasn’t statistically significant, and was not reversed by sertraline treatment.
- Prenatally stressed females did not habituate to the startling sound after several exposures as well as rats from other groups did; treatment with sertraline reversed this effect.
- The pups’ behavior in an open space was tested. No difference was seen between prenatally stressed and non-stressed pups, except in males on their first time being tested (not on later tests).
- In the open space test, only non-stressed females explored more (became more confident) on repeated testing; males and prenatally stressed females did not become more confident with repeated exposure to the open space.
- The pre-natally stressed rats showed a significant decrease in their number of white blood cells. This change was reversed when they were treated with sertraline.
The study’s main conclusions are that effects of prenatal stress can be seen in rats, and that giving sertraline during adolescence did not harm them.
The rapid weight gain in the pre-natally stressed females is an effect that’s been seen before, and seen in humans. Children born with low birth weights often grow to have issues with their weight and can suffer from diseases related to a poorly regulated metabolism. This loss of control of energy balance has been associated with dysregulation of serotonin in humans, adding additional support to the choice of sertraline, an anti-depressant which interacts with the serotonin system.
It is interesting that no anxiety-like behavioral changes were seen in the prenatally stressed rats. Prenatal stress is known to cause anxious personalities in many cases. However, these rats were as confident (or as anxious!) in the open space test as rats who had not been prenatally stressed. The researchers comment that this particular test has been done on prenatally stressed rats in other studies, and that those rats didn’t show anxiety in the open space test either, so this does seem to be a real result, rather than a statistical error.
They did see some differences, though. Male rats who had been prenatally stressed did show some additional reluctance to explore (i.e. anxiety) on their first day only in the open space test. After that they explored equal amounts compared to other groups.
The researchers also note that while most of the rats that they tested were equally anxious on all days that they were tested in the open space, females who had not been prenatally stressed appeared to begin to explore more on repeated tests, as if they were learning to be less anxious as their surroundings became more familiar. This was not the case in male rats or in rats who had been pre-natally stressed.
Remember also that female rats who were prenatally stressed did not habituate to startling sounds as well as rats from other groups. Is it possible that with this particular model of prenatal stress, the personality effects of prenatal stress appear not as classical anxiety, but as difficulty habituating to new situations or stressors such as loud noises?
Finally, the researchers looked at effects of pre-natal stress on the immune system, and found significant effects (decreased numbers of white blood cells) which were reversed by treatment with the anti-depressant sertraline. Why did they care about the immune system? Because the immune system and the stress system are closely intertwined. Stressed animals show changes in the numbers of their white blood cells just as the prenatally stressed rats did. The researchers were using the changes in the immune system as markers for changes in the stress system.
There are two possibilities for why these prenatally rats showed stress-associated changes in their immune systems: either because they themselves had high stress levels, or because their immune systems were developing prenatally (in utero) in a high stress environment due to their mother’s stress levels. Either way, it is interesting that treatment with sertraline reversed these effects, suggesting that it may have either changed current stress levels in these adolescent rats (even though the only serious stressors they had undergone were before their birth!), or had counteracted other effects from that prenatal stressor.
Conclusions
It can be hard to know exactly what conclusions to draw from a scientific paper. What do you think? What are the most important findings in this paper (maybe just two or three of them)? Do you think those findings are real phenomena, or maybe just statistical mistakes? If they’re real, do you think they can be extrapolated from rats to humans or dogs?
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