If we want to be happy, we need to make a lot of mice really sad

Disclaimer: This article references forms of animal experimentation that may be disturbing to some readers. This article rests on the belief that all research should minimize the suffering of living things, but in order to answer certain questions, science must employ methods that some find gruesome and unethical. This article aims to discuss some of these methods, not through a lens of saying this is the correct way to study a topic, but that it is a few ways in which Duke and numerous other research institutions create the very human experience of mental illness in non-human systems.

39% of students will experience a significant mental health issue during their college career. This year alone, the World Health Organization reported that depression and anxiety rates rose by a whopping 25%, and the gradual end to the pandemic doesn’t seem to be helping. And suicide is still the second leading cause of death among young adults. 

But we already know all that. And we don’t want to hear more college mental health statistics because, well, they’re depressing. What we want to know is how these conditions work, and how best to treat them. However, mental illnesses are frustratingly complicated, which makes studying them in humans, with our big complicated brains, even more complicated! And we haven’t even begun to consider the high costs of human psychiatric neuroimaging equipment, not to mention the long, tedious legal processes that are required for ethical research in human subjects.

As a result, about 7-8% of psychology research uses animals, with around 90% of them being rodents and birds like mice, rats, or pigeons. Animal studies have been imperative to our understanding of the brain, from the genetics of emotions, to the biology of learning and memory, to the sociology of complex communal behaviors. Animals are necessary for the testing of new psychiatric drugs, as well as other psychoactive (or even psychedelic) substances. At Duke, dozens of labs departments rely on this experimental design for the bulk of their work, and we even have our own Mouse Behavioral and Neuroendocrine Core Facility to streamline the process.

But how do you actually simulate psychopathology in an animal to better study the disease? Or to put it another way, how do you intentionally make a mouse depressed? 

The first step in creating this model is to implant the disease. Let’s focus on depression, for the sake of brevity, and because it’s one of the more prevalent mental illnesses. There are three main ways to experimentally induce depression, which can be broadly categorized as either genetic, pharmacological, or environmental. In the first one, scientists can breed animal strains with mutations in genes implicated in certain aspects of depression, like serotonin production or hormonal regulation. Arguably, the most popular genetic rat model is called the Wistar-Kyoto (WKY strain). Rats affected by this strain demonstrate a hyper-reactivity to stress, altered levels of neurotransmitters, and a resistance to fluoxetine, a popular SSRI.

The second method involves a more intrusive fiddling with animal brain anatomy and physiology. Either someone can perform a short surgery to selectively injure certain parts of an animal brain, or they can pump large amounts of corticosterone—literally liquid stress— into the animal’s bloodstream. A popular lesion site in rats is the olfactory bulb, which processes smell, and the resulting anosmia (or loss of smell) is associated with agitated and depressive symptoms. Alternatively, many researchers create the experience of depression through reserpine, a drug to treat high blood pressure, in accordance with the WKY vs. SHR rats. 

The last method is the behavioral approach. Essentially, a researcher just shoves their animal into the face of adversity and watches what happens. They can expose these animals to a variety of “acute” and/or “chronic” stressors, “severe” or “mild,” in the prenatal to late-adult stage. “Stress” can look like a lot of things, from crowded cages during pregnancy, to sleep deprivation, to light disturbances and a whole host of other triggers. In the behavioral neuroscience world, you’ll start become familiar with terms like “learned helplessness,” in which an animal undergoes an inescapable traumatic event (i.e. an electric shock in a locked cage), and is subsequently unable to navigate a similar situation in the future, even when resources are present (i.e. an electric shock in an unlocked cage, in which the rats with learned helplessness don’t try to escape). Or there’s the “chronic social defeat” stress model, in which “naive” rats are repeated sent to interact with proven “aggressive” rats, subjected these “daily sessions of psychological stress,” not unlike the time I was a hitter on my middle school volleyball team (just kidding, I was the benchwarmer).

Now that the animals have depression, scientists need to find some way of testing their depressive behaviors (and no, I’m not talking about sending them to a four-year private institution). Some of the most popular methods include the Forced Swim Test (FST) and Tail Suspension Test (TST), in which a rodent is either submerged in a water tank or is held up by their tail, respectively, and they’re timed until they stop showing signs of restraint. Anhedonia, the loss of interest in pleasurable activities common in depression, is often tested by measuring a rodent’s preference for a sucrose solution of frequency in intercourse (as in, choosing sweets, sex, or sadness). And there are a variety of maze-based assessments in which the time for completion can correlate to aspects of cognitive function and/or anxiety symptoms.

Reading about these strange, almost twisted experimental designs, these creative forms of controlled suffering, is discomforting to say the least. But the reality is, if we want to study mental illness, we have to make something mentally ill. If we want to understand how our brains respond to stress, we have to create stress in the way that’s most feasible and ethical at this time. If we want to be happy, we need to make a lot of mice really sad, over and over again, until we get the answers we need.

It places us in a conundrum, because unlike other diseases, we can’t simulate mental illness in computer simulations or cells in a Petri dish. To make matters worse, given the vast biochemical differences between human and rodent brains, many animal models have been criticized for lacking translatability or even validity for real treatments or therapies. After all, for many of us, the unique, pervasive triggers known to cause mental illness can’t be replicated in a lab, like institutional racism or relationship abuse. In trying to replicate “trauma” through these rather primitive stimuli, and reducing the concept of mental illness to a purely bio-mechanistic sense, do we lose sight of what it truly means to suffer from these illnesses? And on the flip-side, with the commonness of things like maternal separation, food/light deprivation, and social isolation for animals in experiments outside of psychology, could depression or anxiety be introducing an insidious source of bias in other areas of science?

Mental trauma in animal studies is often an overlooked component of research ethics. On the one hand, it’s a necessary part of neuropsychiatry, but if done incorrectly, it can lead to a whole lot of unnecessary suffering with psychological effects that can far exceed the duration of any experiment. So for those interested in careers in psychiatry, whether that’s studying how illnesses like depression affect the brain, or prescribing drugs or therapies to patients, it’s important that we appreciate the animals that have have their tails suspended, genomes hacked, or memories reshaped just so that we can keep our own heads above water. They do more than we could humanly imagine for us to be mentally healthy. 

Monika Narain is a Trinity sophomore. Her columns typically run on alternate Fridays.


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