A Little Bit of Unpredictable Stress Everyday

That is the recipe for depression. Chronic Mild Stress (CMS). Or at least it is the recipe I used to depress rats. As I mentioned earlier I worked with rats to research the mood-effects of Salvia. One important piece of this research was the idea that a depressed brain is different than a healthy brain and may respond differently to drug exposure. So in order to apply that in rats, I needed a way to create depressed rats. For me, that meant using CMS.

In the CMS model, developed first by Richard Katz, rats exposed to mild stressors everyday showed a decrease in sucrose consumption that was later reversed by administration of an anti-depressant (Katz, 82). Let me explain.

Chronic (happening regularly over time) Mild (not severely traumatic) Stress (a feeling of strain to adapt to changing environmental (or psychological) conditions). Practically this means doing things to rats to make them a little bit uncomfortable everyday. In my research, inspired by work that came out of Paul Willner's lab, this involved the following: overnight strobe-light (2Hz),  cage tilting at 45 degrees, forced paired housing (a strange rat was put in the subject rats cage separated by a wire mesh), continuous illumination (there is no night), overnight food deprivation, overnight water deprivation, and empty water bottle exposure. These were all done briefly enough not to cause excessive stress, remember I was going for uncomfortable not traumatic.

A Long-Evans Lab Rat

There is a hallmark feature of human depression called anhedonia. Anhedonia is the inability to experience pleasure from pleasurable stimuli. Or joylessness. Anhedonia is the reason that depressed people don't laugh at jokes, or smile when a baby giggles, or enjoy doing any of the things they used to enjoy doing. Pleasure doesn't feel good anymore. If you or someone you know has ever been depressed it is likely you witnessed anhedonia.

Happy rats love to drink sugar water. Even when dissolving a very small amount of sugar in water (less than 1% sucrose solution), rats show a strong preference for sweet-water over regular water. We can measure that by giving the rats two water bottles, one with plain drinking water and one with sweet-water. Come back 24-hours later and measure how much of each the rat drank. Happy rats drink around 90% sweet-water. We might say that sweet-water has a greater hedonic value; it is more pleasurable for the rat.

After three weeks of CMS my rats exhibited anhedonia. After three weeks of exposure to the mild stressors listed about the rats no longer show a preference for sweet-water. Again we present the rats with two water bottles, one with plain drinking water and one with sweet-water. 24-hours later we see that they drank about 50% sweet-water. This shows no preference for the sweet-water. Even though the sweet-water might taste better (have a higher hedonic value), the rats don't care. Because they are joyless. They have developed anhedonia. They are depressed (or at least they are now a robust animal model of human depression).

Katz, R. (1982). Animal model of depression: Pharmacological sensitivity of a hedonic deficit Pharmacology Biochemistry and Behavior, 16 (6), 965-968 DOI: 10.1016/0091-3057(82)90053-3

Willner, P. (2005). Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS Neuropsychobiology, 52 (2), 90-110 DOI: 10.1159/000087097