Our second poster from Tuesday is a seemingly odd combination, the combination of a heart attack…and anxiety and depressive disorders.
Tronson et al. “Role of a systemic inflammatory event in central cytokine signaling, depression, and fear” Northwestern University, 682.04, FF6.
I mentioned before that you can walk around SfN and hear the rumblings of the up and coming things in neuroscience. One of those things is sex differences, the differences between males and females in their responses. And the other one that I’ve been hearing is the word “cytokines”. Cytokines are cell signaling proteins which modulate the immune system, sometimes decreasing or increasing immune responses. While previously, scientists have focused on their role in wound healing, the idea of “inflammation” as something, both in the brain and in the rest of the body, that can change behavior is one that has been gaining a lot of traction.
So what does one do if you want to study how injury to the body can affect behavior? Well, you start with a heart attack. Heart attacks, aside from being one of the most common cardiac injuries in the world (12.6% of all deaths worldwide), have some interesting chronic effects. Many people who suffer from a heart attack will suffer episodes of depression or even PTSD afterward which are related to the heart attack itself. And heart attacks, or myocardial infarction, are a good way to study the effects of inflammation on behavior. Because they are so common, cardiologists have studies the effects of heart attacks in detail, and we have a really good idea of how they impact inflammatory processes in the body.
So for this study, the scientists wanted to look at the effect of myocardial infarction not on the processes in the body, but on behavior. So they took a bunch of mice, gave them nothing, fake little surgeries, or a small heart attack (which you can do by using a tool to freeze a small portion of the left ventricle). After recovery and testing to make sure the mice were ok, they started looking at behavior.
They found that male mice showed increases in contextual fear conditioning two weeks after undergoing a heart attack. Fear conditioning is a behavioral test used to test learning and memory, as well as anxiety behaviors in mice. A mouse is put in an environment, and is given a mild shock. The next day, it’s put back in, and you look to see how many times the animal freezes, remembering and worrying that it will be shocked again. When this happened to male mice, the ones that had had a heart attack showed increases in freezing two weeks after compared to mice which had not had a heart attack. And the scientists found that this was reversed 6 weeks later, with a new set of mice. These mice with heart attacks were LESS fearful on average, which may indicate a inability to learn the context.
In females though, it was a different story. They showed no differences at two weeks, but showed a lack of fear 6 weeks later, and this was not only in female mice getting heart attacks, but in shams as well, meaning that in this case it may be the surgery itself that is causing the difference. But the LACK of fear itself is also something unusual, and it might be a sign that learning and memory aren’t so great in these animals, something that the authors will be testing soon.
Next up were measures of anxiety and depressive-like behavior. The authors first used the Novelty Suppressed Feeding test (NSF), which involves taking a hungry mouse and putting it in a brand new cage with bright lights and a little bit of food. It’s a novel environment that normally suppresses an animal’s urge to feed, but desperate times call for desperate measures, and a hungry mouse will eventually approach the food. If you give chronic antidepressants or drugs to decrease anxiety, they will approach the food sooner, and if you give drugs that increase anxiety, they will sometimes avoid the food altogether. In this test, the females didn’t show any differences, but the males showed an increase anxiety like behavior 8 weeks after surgery. And this was confirmed when the scientists looked with sucrose preference, checking to see how much animals prefer sugar water. And they DO love sugar water, but if you’ve got an animal showing depressive-like symptoms, they prefer it less, which is used as a measure of anhedonia. Following the experimentally induced heart attack, the males in this study showed reduced sucrose preference, which suggests a depressive like state, while females again showed no change. It’s clear that the response to a heart attack in a male vs a female is just not the same.
But what is modulating these effects? This is where the cytokines come in. The authors looked at a chemical called SOCS3, a suppressor of cytokine signaling. They found that SOCS3 signaling was increased in the hippocampus and hypothalamus, areas associated with anxiety and depression. And this effect is much stronger in females. SOCS3 has two different ways to become activated, areas called phosphorylation sites. While males with heart attacks show phosphorylation at one of the sites, females show activation at two of them. This means that not only do females have a stronger response, they also have a DIFFERENT way of doing it, showing males and female responses to a heart attack are different not only in behavior, but in mechanism. If these findings translate to humans, it could mean that treating the after effects of heart attacks may have to differ between men and women, and it helps us understand how physical injury can impact behavior.