By Anjanette Harris, University of Edinburgh, @anjiefitch
Sufferers of Major Depressive Disorder (MDD) are more than just a little ‘down in the dumps’. Persistent low mood and low self-esteem are classic symptoms, but sufferers also experience learned helplessness, increased anxiety, feelings of guilt and worthlessness, and enjoy the pleasures of life less (also called anhedonia).
To investigate potential therapies and the cause of this debilitating disease, it is sometimes necessary turn to animal models, such as rats and mice. Rats and mice offer a powerful tool to investigate the causes and consequences of mood disorders, because unlike in humans, we can control stressors, genetics, and environmental factors more easily in rats and mice. We can give certain drugs, implement exercise regimens, and modify diets to see what happens.
While a rat or mouse cannot communicate its feelings, we can measure some aspects of depressive behaviour. Rodents normally love sugary water, but when they are anhedonic they have a weaker preference for it. A forced swim test involves placing a rodent in a container of water in which they can swim but not escape. Choosing to float rather than tread water during this test is used as a sign of depression.
Measuring preference for sugar and floating behaviour in rodents is similar to a questionnaire in a human study. While a questionnaire identifies depressed subjects, it reveals very little about the cause of depression. To successfully treat or prevent MDD, we need to understand what goes wrong in the brain.
In humans, a specific type of brain scan called functional magnetic resonance imaging (fMRI) helps bridge the gap between identifying and unpicking what is faulty in a depressed brain. This scan measures oxygen levels in the brain’s blood circulation. Since active brain cells use more oxygen, the fMRI signal indicates the parts of the brain that are working hard.
We can use these scans to look at differences between the brain activity of depressed and healthy people. For example, in response to negative stimuli such as pictures of sad faces, the outer layer of the brain (the cortex) exerts weaker control over the emotional centre (the limbic system) in depressed patients. In addition, networks in the brain that respond to reward are increasingly less active as anhedonia becomes more severe. These findings may help explain why those who are vulnerable to MDD are both unable to supress negative mood when it arises and no longer enjoy previously pleasurable experiences.
While manipulating rodent genomes and administering drugs or stressors is straightforward, neuroimaging is more challenging. We have specially built small scanners, but a key to successful imaging is a still and calm subject. One solution is to anaesthetise the rats or mice. However, since anaesthesia is rarely used in human imaging and a sleeping rodent cannot participate in cognitive tasks, this limits our ability to look at cognitive processing in rats and mice in the same way that we do in humans.
In recent years, researchers have developed ways to gradually acclimate rats or mice to being held still in an fMRI scanner. To study cognitive processes, scientists can use tasks that can be completed in the MRI scanner. For example, they train rats to associate visual or olfactory stimuli –such as a flashing light or a vanilla scent- with a foot shock. They then image their brains while presenting the flashing light or scent.
This technique is an improvement on the classical test for fear in rodents, ‘freezing behaviour’. When a mouse or rat is afraid, it freezes like a statue. Using brain scans translates better to humans than studying freezing behaviour. For example, researchers used the visual task set-up to show that rats that experienced early life stress, have enhanced activity in brain networks that process fear. Early life stress is a known risk factor for anxiety and depression in humans.
Reward, emotional regulation, extinction learning (learning to forget an unpleasant memory), and cognitive bias (whether we perceive ambiguous situations to be positive or negative) are aspects of depression that we can currently assess in humans. The next big challenge is to devise behavioural tasks that enable us to examine these in awake rodents while their brains are being scanned.
This way we can validate rodent models of depression, elucidate what’s happening in the brain during negative affective state, and guide the development of successful treatments for Major Depressive Disorder.