Thursday, December 24, 2009

Rats, dogs, foxes, and the SHRP

Working on my Master’s degree has made me yen for more letters after my name, so I’ve been doing some spare-time reading on subjects that might yield PhD-type projects. My putative interest is in development of the stress system in young dogs. The idea is that if a dog’s stress system develops poorly, whether through bad genetics or a bad early environment, then that dog is more likely to bite people when it grows up. The more we know about how their stress system develops, the more we can know about how to grow healthy dogs with good bite inhibition.

For several months I thrashed around in the literature, reading about development of the stress system in rodents (about whom we know quite a bit, because we are more willing to do experiments on them than on dogs), and reading about socialization periods in dogs. It was hard to find good direction, and I wasn’t quite sure where to start. Recently I have had a breakthrough, however.

First, some orientation. You are walking through the woods. You see a shape on the ground. Your brain interprets the shape: long, thin. Your amygdala (part of the limbic system of your brain) yells SCARY SHAPE SCARY SHAPE and you get a blast of adrenaline in your system. Half a second later your cortex (the thinking, conscious part of your brain) catches up: hey, that looks like a snake. Your hypothalamus (which deals with a lot of hormone regulation) sends a message to your pituitary (which releases a lot of your hormones), and the pituitary releases a hormone which travels down to your adrenals, near your kidneys. Your adrenals release our old friend cortisol, which gets into your blood and tells your body that you are having a stressful experience. Cortisol, you of course remember, is what I like to extract from the saliva of dogs to tell if they are unhappy about being stuck in a noisy hospital run. This whole system is what I’ve been referring to as the “stress system,” more properly called the HPA (hypothalamic-pituitary-adrenal) axis.

If you were a rat or mouse, instead of releasing cortisol, your adrenals would release corticosterone. It is a very similar hormone with similar effects. Dogs actually release equal parts cortisol and corticosterone, but we just study their cortisol levels. I still haven’t figured out why we chose cortisol to focus on in them; there are a lot of tools available for studying cortisol, since humans make it primarily, but also a lot for studying corticosterone, since we study rodents quite a bit.

Now, to get back to my recent reading, very young animals don’t get as frightened by scary things as slightly more mature animals or adults. This phenomenon has been studied intensively in the rat: rats younger than two weeks of age don’t show this corticosterone spike when exposed to something upsetting. This is called the “stress hyporesponsive period,” or SHRP.[1] There has been work on what part of the HPA system is responsible for this blunted response: the amygdala? The hypothalamus? The pituitary? Or are the adrenals themselves not responsive yet?

A good way to stress out an infant rat is to expose it to the odor of an adult male rat. Left to their own devices, adult males will happily eat infants, so the young rats are quite right to fear them. An infant rat, upon smelling a strange adult male, will become immobile. However, a neonatal rat younger than 14 days (in other words, one still in the SHRP) will not become immobile: it hasn’t yet developed the machinery to feel, or possibly just to express, fear. If you remove the infant’s adrenals, so that it is unable to make corticosterone, then even when it matures to older than 14 days it will still not properly become immobile when exposed to the scary smell. Moreover, if you inject corticosterone into one of these pre-14 day rats, it will be able to develop the immobility behavior at age 14 days, just like a normal rat. [2] This suggests that corticosterone is responsible for the immobility behavior. However, if you remove the adrenals of a rat which has already developed the immobility behavior (one which is older than 14 days), it will continue to become immobile in the presence of the scary smell. [3] And if you inject extra corticosterone into a rat too young to have developed the immobility behavior, it will develop it early. [4] This suggests that corticosterone is responsible just for the development of the behavior, not for allowing it to actually happen at specific times once it has initially appeared.

What’s going on up in the brain while all this is happening? When infant rats are too young to express (or possibly feel) fear, are their amygdalas just failing to activate? When neurons in a particular brain region have been recently active, they contain a protein called c-fos. You can check a brain region for the prescence of extra c-fos to see if it has been doing anything in the recent past. This was done with young rats. Rats too young to have developed the fear response did not have amygdala activity (no extra amygdala c-fos) after exposure to the scary smell; if they were injected with corticosterone to cause them to develop the fear response early, then they did have amygdala activity; rats old enough to have developed the fear response did have amygdala activity; and rats whose adrenals were removed prior to developing the fear response did not have amygdala activity. [4] Unfortunately, this study does not appear to have looked at whether rats which were allowed to normally develop the fear response (intact adrenals), but then had their adrenals removed after initial development of the response, still showed amygdala activation. Perhaps that question has been answered elsewhere.

So what does all this mean for dogs? Do dogs have an SHRP? I found one unreferenced assertion that they do, but I have not yet found a study actually examining the canine SHRP. The SHRP does exist in various species, and it seems likely to me that it exists in the dog. Puppies start out fearless, and develop fear later. I suspect that a canine SHRP will prove to be an important part of socialization: the time that puppies don’t yet feel fear may be an important one for introducing them to lots of different kinds of people, so that they can learn that these people are a normal part of puppy life and are not to be feared later on.

The development of the HPA system has been studied in domesticated silver foxes — foxes selectively bred to not fear humans. (These foxes show surprising physical similarities to other domesticated animals in body shape and color, despite not having been bred for these features, leading to speculation that there is some general mechanism of domestication. That general mechanism of domestication is actually what I’d like to get at in a PhD project.) Researchers took two groups of foxes: domesticated foxes, and foxes bred for increased aggressiveness to humans. They tested them for behavioral reactions to humans and cortisol level increases after exposure to humans, at ages 30 days, 45 days, and 60 days. The aggressive foxes did not show aggressive behavior or cortisol spikes at 30 days, but they did show it at 45 and 60 days. The domesticated foxes, on the other hand, did not show aggressive behavior until 60 days, and their behavior at that time was described more as “defensive” than “aggressive.” They never showed the cortisol spike. [5]

Is this the same thing as a silver fox SHRP? I’m not sure that this study exactly gets at that, but it seems suggestive. Questions I’d like to ask about the SHRP in dogs are: Does the SHRP definitely exist in dogs? Is the SHRP length different in dogs and wolves? Does the length of the SHRP affect the socialization of the dog? Is the SHRP length different in different dog breeds? And, most important but most difficult to get at, does length of SHRP have anything to do with a dog’s fearfulness as an adult?

[1] Walker Claire-Dominique, Perrin Marilyn, Vale Wylie, Rivier Catherine. Ontogeny of the Stress Response in the Rat: Role of the Pituitary and the Hypothalamus. Endocrinology. 1986;118:1445-1451.

[2] Takahashi L. K., Rubin W. W. Corticosteroid induction of threat-induced behavioral inhibition in preweanling rats. Behavioral neuroscience. 1993;107:860-866.

[3] Takahashi L. Organizing action of corticosterone on the development of behavioral inhibition in the preweanling rat. Developmental Brain Research. 1994;81:121-127.

[4] Moriceau S. Corticosterone controls the developmental emergence of fear and amygdala function to predator odors in infant rat pups. International Journal of Developmental Neuroscience. 2004;22:415-422. [Free full text.]

[5] Plyusnina I., Oskina I., Trut L. An analysis of fear and aggression during early development of behaviour in silver foxes. Applied Animal Behaviour Science. 1991;32:253-268.

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