Depression is a disease with a difficult set of symptoms. Not only are the symptoms difficult to describe (how do you really describe anhedonia, before you know the word for it?), symptoms of depression manifest in different ways for different people. One person will eat more, sleep all the time, move slowly. Another will eat almost nothing, never sleep, and be irritable and nervous. They are both depressed. The only universal symptom is the feeling of…depression, and the need for successful treatment. Treatments which often take several weeks to work, are often ineffective, and which come with a host of side effects.

So I was particularly intrigued when Nature published two papers this week looking at the role of dopamine in depressive-like behavior. What I particularly like is that these two papers have somewhat opposite results, due to different behavioral methods, something which I think highlights some of the problems associated with studying depression. Ed Yong covered both of the studies together fabulously over at Not Exactly Rocket Science, but I’d like to look at them both separately, to take a deeper look at each one, see what they’ve achieved, and what other questions they raise.

Today we are on the second of the two papers, one which has a similar angle to the first paper, but an entirely different result. Yesterday's paper looked at how changes in dopamine cell firing from the ventral tegmental area (which projects to areas like the prefrontal cortex and the nucleus accumbens) can impact depressive-like behaviors in mice and rats. Today's paper looks at the ventral tegmental area as well, but instead of cutting on or turning "off" cell firing, the authors of this study looked at different types of neuronal activity, and the effects in socially defeated mice.

Chaudhury et al. "Rapid regulation of depressive-related behaviors by control of midbrain dopamine neurons" Nature, 2012.

Yesterday we talked a little about the ventral tegmental area (VTA, because I get very tired of writing it out all the time). The VTA is located deep in the middle of the brain, and contains dopamine neurons. We usually think of dopamine as a chemical messenger that is related to things like reward or drug addiction. But more properly, dopamine signaling has to do with salience, how important something should be to you at any given time. Dopamine spikes are associated with the pleasure of drugs or good food or sex, but they also say "PAY ATTENTION TO THIS".

Dopamine neurons (and many other types of neurons in the brain), don't just fire once and then stop (which is the simplified version that you often learn in biology). Instead, there are several different ways in which a neuron can fire. Tonic firing, for example, is a kind of low level, constant activity, where a neuron is constantly firing at a low rate. Like this.

Phasic activity, on the other hand, is a short, strong burst of firing, resulting in a stronger signal. This is the type of signal that is usually associated with something highly salient, like drugs.

Dopamine neurons are capable of both types of firing, and by using the technique of optogenetics, the authors of this paper were able to look at both types, and their effects on social defeat responses in mice.

Optogenetics, as I explained yesterday, is a technique where you use a viral vector (a very harmless one) to insert a gene into a targeted type of cell. That gene is then expressed by the cell. While the gene expressed could be virtually anything, in the case of optogenetics (and this paper) the gene is for channelrhodopsin, a channel that, when activated by light, "activates" a neuron to fire. When you put a bunch of these into a bunch of dopamine neurons, and shine a light into the brain, you can make the dopamine neurons, and just the dopamine neurons, fire.

And of course, if you vary the light, you can vary the firing rate. Chaudhury et al used this technique to produce phasic and tonic firing of dopamine neurons, running the laser at different frequencies to produce tonic (low frequency) or phasic (high frequency) firing of the dopamine neurons.

The authors wanted to use optogenetics to influence the behavior of mice exposed to social defeat stress. Social defeat is a behavioral method that takes advantage of the natural propensity for mice to develop a social hierarchy and defend their territory. You take a normal mouse, and put him into a cage with a bigger mouse. The bigger mouse "owns" that cage. He's a retired breeder and very aggressive. He will usually launch himself right at the poor intruder mouse, beat him pretty badly, resulting in a "social defeat". The mice are usually separated very quickly so the larger mouse doesn't injure the intruder, but the defeated mouse is partitioned off in the case, where the aggressive resident can still threaten and bully the poor guy. The defeated mouse, as you might imagine, considers this pretty incredibly stressful. Exposure to social defeat for more than 10 days can result in strong depressive-like behaviors, with the defeated mouse avoiding contact with new (presumably friendly) mice, and drinking very little sucrose water when offered, a test for anhedonia.

And the question the authors wanted to ask was how their optogenetics paradigm, and the tonic and phasic firing of VTA neurons, affected the defeated mouse's response.

What you can see here is the social interaction test (left) and the sucrose drinking test (right) in controls (white bars), mice getting tonic, low level stimulation in the VTA (grey bars), and mice getting phasic, high level stimulation in the VTA (blue bars). This was in a test of subthreshold social defeat, only 2 days, so the mouse was getting beaten up daily, but was not yet showing depressive-like behaviors. You can see that the phasic stimulation (given when the mice were in the cage with the "bully" mouse, separated but able to see and smell the mean mouse) actually produced the usual signs seen with 10 day social defeat, in a mouse that had only been defeated for 2 days. The animals getting phasic stimulation showed less social interaction with other mice, and drank less sucrose.

This was a test with light stimulation to the VTA during the defeat stress. But then the authors used the subthreshold defeat again, with no changes from the optogenetic stimulation, and looked during the test. This time, they activated the VTA using phasic or tonic stimulation only during the test. Again, the phasic stimulation resulted in the behaviors associated with social defeat, with phasically stimulated animals avoiding other mice and drinking less sucrose. The effect was instant.

What's particularly nice is that the effects of phasic or tonic stimulation did not have any effect in animals that had NOT been exposed to sub threshold defeat. Instead, phasic stimulation made an animal MORE susceptible to a below threshold stress.

But what about tougher mice? Whenever you do social defeat stress, a certain proportion of the mice that are stressed will show depressive behaviors (susceptible) while another subset will be tougher and more resistant. When the authors took this resilient population and exposed them to phasic stimulation in the VTA, the resilient population became susceptible. Again, the effects were immediate, showing that in previously severely stressed mice, phasic dopamine firing could induce a depressive-like phenotype. So in this paper, increasing dopamine firing phasically is a bad thing, increasing susceptibility to depressive-like states after stress.

But how does this compare to yesterday's paper? In that paper, stimulating the VTA decreased depressive-like behaviors, showing that increasing dopamine signaling made mice struggle more in the tail suspension test and drink more sucrose. In both of these papers, you have dopamine signaling, but you have opposite behavioral effects. What gives?

It appears that the difference is in the type of stressor. In yesterday's paper, the authors used chronic mild stress, or acute depression tests. Chronic mild stress has been associated before with a decrease in VTA dopamine activity. So it makes sense that a decrease in VTA dopamine activity might mimic a chronic mild stress, and an increase might improve the depressive-like effects following chronic mild stress.

But social defeat stress is another kind of stress entirely. While chronic mild stress is more of a mild grind, annoying noises or lights at night, chilly atmosphere, weird cage bedding (for example), social defeat is much worse. If not separated, the aggressor mouse can kill the intruder, and even when separated, they aggressor will do everything in its power to make the intruder's life miserable. Severe stresses like these are associated with increased VTA dopamine activity (it's very unpleasant, but it's definitely important), like the phasic firing used here that increased the animals' responses.

So when you combine these two papers together, you see that not only can dopamine firing play an important role in stress responses and depressive-like behavior in mice, but that the type of stress involved can make a big difference. This has important implications for the types of stress that we use to study depression in animal models: different types of stress produce different mechanisms behind depressive-like behavior. But it could also be very important, eventually, for how we treat depression. 80% of depressive episodes occur during or immediately following periods of significant stress. But what kind of stress? Is it the constant, stressful grind of grad school, a demanding job, or caring for loved ones? Or is it the faster, more severe stress of being horribly bullied, or otherwise violently hurt? If we can find out more about depression from studies like these, we may find different ways to treat the different types of depression, and it may all start with understanding different types of stress.

Chaudhury, D., Walsh, J., Friedman, A., Juarez, B., Ku, S., Koo, J., Ferguson, D., Tsai, H., Pomeranz, L., Christoffel, D., Nectow, A., Ekstrand, M., Domingos, A., Mazei-Robison, M., Mouzon, E., Lobo, M., Neve, R., Friedman, J., Russo, S., Deisseroth, K., Nestler, E., & Han, M. (2012). Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons Nature DOI: 10.1038/nature11713