Prof. Gil Zalsman didn’t imagine that the short ride from Bar Ilan University to Tel Aviv University would ruin a multi-year research project.
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In his car were cages full of rats, on their way for MRI imaging at a brain research laboratory in Tel Aviv. But the ride stressed the rats so much that the results of the MRI were compromised. “It turned out that we’d ruined the experiment," Zalsman remembers. "Today I can laugh about it, but when it happened I was miserable and almost gave up.”
Zalsman heads the Geha Mental Health Center, affiliated with the Clalit health maintenance organization. He’s an expert in general and child psychiatry who regularly meets children who’ve experienced traumatic events. He wondered whether the timing of those events were significant in the development of depression in the 20 percent of adults who suffer from the disease. In order to explore the question he turned to experiments on rats.
The reason he did so is that rats are very similar to humans in their brain structure and social behavior. The white lab rat on which most experiments are done is called the Wistar rat. For his research, Zalsman used a related rat strain which expresses depression, the Kyoto Wistar rat. This strain was genetically engineered in a Japanese lab in an attempt to find drugs which combat hypertension. To do this, rats with high blood pressure were cross-bred with one another, leading to a strain which is genetically predisposed to developing depression.
Kyoto Wistar rats differ from healthy Wistar rats — they’re thinner and don’t eat or sleep well. When placed in water, they don’t try to save themselves – regular Wistar rats will flail and try to swim, but the Kyoto strain gives up right away and just floats. Kyoto rats also exhibit anhedonia (lack of ability to experience pleasure) – they prefer drinking regular water over sweetened water, in contrast to their sweet-seeking cousins.
Kyoto rats are also prone to stress and anxiety. Even though they are raised in a lab and have never encountered a cat, the smell of cat urine induces high levels of stress. All these symptoms disappear when they’re given the anti-depressant Prozac; they gain weight, sleep well, swim when placed in water and drink sweetened water. Ever since it was discovered, the Kyoto Wistar has served researchers as a model of depression and anxiety – and it did the same for Zalsman.
Why did you choose a depressive rat?
“Depression is a genetic disease. It is transmitted within families and is very common. We also know that it’s linked to the environment. It’s reasonable to assume that harsh life events will induce depression. Over the last decade we’ve learned that a combination of genetics and environmental factors raise the risk of depression.
“The prevailing theory since 2003 is that a mix of genetics and environment leads to depression. In other words, in order to become depressed one needs a specific genetic makeup and harsh life events. This is true for other diseases as well, such as diabetes. There could be a familial tendency to develop diabetes but if one doesn’t eat cream pies all day one doesn’t become ill. Japanese people who move to the United States and start consuming carbohydrates develop more diabetes than is common in Japan, where there is very little diabetes. In the U.S. it is rife.”
The research looked into the importance of the timing of traumatic events?
“Exactly. There are vulnerable periods in which the brain is much more susceptible. If bad things happen then, it raises the risk of severe depression at a later age. This idea began with my work as a child psychiatrist. When I faced a 5 year-old who had been sexually molested by an adult, the effect was different than in a 15 year-old who had gone through the same experience. The cause is the same, but at every age the disease expresses differently. It’s the same for mumps. If you get it as a one-month-old baby you’re hospitalized in danger of your life, but at the age of three it will only express itself as a rash and a sore throat.”
What does depression in children look like?
“In early childhood it doesn’t look like depression at all. Children don’t say they want to die – they look sad, they’re tearful, irascible and appear to lack hope. They’ll say things like ‘I’m worthless’ and complain of stomach or headaches. At puberty, depression looks like adult depression, with anxieties and attempts at suicide.”
Childhood trauma exacerbates severe depression
The rats used in the Bar Ilan University experiments were exposed to trauma at different periods of their lives. Researchers divided them into four groups. One was exposed to stress at the age of 27 days (equivalent to the age of 5 in humans,) a second was exposed to stress at 44 days (15 in human terms,) the third group wasn’t exposed to any stress and the fourth was raised in an environment full of stimuli, such as swings and games.
The induced stress was diverse. For example, researchers placed the rats on a 10 cm cube atop a one-meter post. There were other stressful situations, such as a wet cage or a tiny cell with no room to move. The project included four other groups of normal, non-depressive Wistar rats, which were exposed to the same types of stress and served as control groups.
When the rats reached adulthood, the researchers examined their behavior. They placed them in a vat filled with water and examined their motion with the aid of a special laser beam, measuring how long they flailed and when they gave up. Researchers also investigated whether they preferred sweet or regular water. The next step was meant to be MRI imaging in a special device at Tel Aviv University, to see if any brain changes could be detected. It was at this critical point that Zalsman’s short ride to Tel Aviv led to the collapse of the whole project.
After consulting his fellow researchers – Prof. Aron Weller and Dr Liat Shbiro from the Gonda Multidisciplinary Brain Research Center at Bar Ilan and Avihai Gutman from Tel Aviv University – they realized that the car ride was highly stressful, thus compromising the results of the study. They had to start over.
What were the results?
“We followed the movement of water molecules in the white and grey matter areas of their brains. In rats with a genetic disposition to depression that were exposed to early traumatic events, there was a reduced density of neurons and nerve fibers in areas of the brain that modulate emotions.”
“The study found that a genetic base for depression, along with traumatic life events that occur within a specific vulnerable period of brain development, will produce a high likelihood of adult depression. The depressive rats that were exposed to stress at a young age became extremely depressive. This occurred in tandem with the development of brain areas that are responsible for emotional modulation, hopelessness and lack of pleasure.”
“By contrast, we found that depression-prone rats that were exposed to trauma during their ‘adolescence’ did not fare worse, and that, moreover, the traumas somehow fortified them so that their depression was ameliorated. That really surprised us.”
How could you see that they were stronger?
“This was judged by tests we use to measure their level of depression. When we placed them in water we saw that they swam for longer durations, they ate more and drank sweet water more often.”
What about the healthy rats?
“Healthy rats that were exposed to trauma during their adolescence also became more robust. They swam longer and in some way the exposure to trauma in adolescence strengthened them. Healthy rats which were exposed to trauma in the early stages of their lives became depressive, but not to the same extent as the genetically depression-prone rats.”
So one could say that timing is important for both healthy and depressive rats?
“That’s correct. Timing is important for all groups, but more so for depressive rats. In any case, it’s bad to undergo traumatic events early in life, but the intensity of the resulting depression varies. It’s more intense in rats with a genetic disposition to depression.”
“A further fascinating finding was that it all happens in very specific brain regions, such as the amygdala, the region responsible for regulating emotions. In small children with a genetic disposition to depression who suffer from some traumatic event, the amygdala is affected. Our breakthrough was the finding that genetic disposition or life events are not sufficient in themselves, but that the timing of these events plays a major role. That’s true for rats and is exhibited in humans as well. I must emphasize that rats differ from humans. and a further reservation is that we don’t know the defect that makes these rats depressive to begin with.”
What are the applications of this research?
“The practical significance is that it’s preferable not to wait until someone becomes depressive, and that working with high-risk populations at early stages is much better. We know that in depression, as in cancer, early detection and treatment decrease the pathology. One can die from depression – people commit suicide. “
“In the U.S. there are already clinics for high-risk patients. When a mother comes in and asks for Prozac, the doctor asks her to bring her children to a psychiatric clinic for follow-up. If one of them is genetically predisposed to depression and his pet dog dies he may require psychological treatment before sinking into depression. That’s the ultimate goal. For that I’m willing to sacrifice these rats.”
It really is hard to listen to descriptions of these rat experiments, especially about rats that were made depressive by humans
“In our mind, animal experiments are legitimate only if they lead to practical treatments that will save lives or cure serious diseases. Depression is the only psychiatric disorder that can lead to death, so we felt ethically and morally justified in sacrificing these rats for this breakthrough research. The next stage will include studies on depressive patients at different ages, in order to search for a cure for this disease. A study such as this one, looking at the effects of stressful situations on brain development, cannot be carried out in humans, so it was necessary to conduct it using animals, with all the ethical limitations and with the approval of the Helsinki committee [which regulates animal experimentation].