Mood normally fluctuates. Everyone experiences highs and lows in their lives. Sometimes changes in mood can become long-lasting, debilitating and impair one’s ability to hold down a job or meaningful relationships. Around 10% of people at some point suffer from depression, a mood disorder characterized by: feeling sad, distressed, unmotivated, excessively tired, and losing interest in once pleasurable activities (known as anhedonia). Many with depression also have anxiety.

Neuroimaging studies reveal that many brain circuits that normally regulate mood are dysregulated in depression. Deep in the brain, the amygdala processes stimuli such as rewards and potential threats. In depression, the amygdala is overactive and responds excessively to negative events. In turn, the amygdala connects to a set of brain regions that hone the physiological and behavioral response to emotional stimuli. These areas include the medial prefrontal cortex, the nucleus accumbens, the hippocampus and the insula. The hippocampus is involved in memory formation and with the prefrontal cortex, is vulnerable to stress. Depressed people are more susceptible to stress, which can cause physical changes in the brain including atrophy of the hippocampus. This and other changes in depressed people may cause inappropriate responses to emotional events. The medial prefrontal cortex is involved in regulating how strong we react to emotional stimuli. Treatments such as antidepressants, cognitive behavioral therapy and electroconvulsive therapy affect the structure and function of these and other brain regions.

Animal models such as mice help us understand the molecular changes in depression and develop better treatments. It’s impossible to know if a mouse is depressed, subjection to chronic stress show some symptoms similar to depressed humans such as anxiety like behavior, less social interaction and a lack of interest in normally pleasurable activities. Not all human depression is caused by stress, but these models may shed light on the biology of depression and they’re the closest scientists can get. As with humans, stress in mice can lead to atrophy of the hippocampus and prefrontal cortex. Mouse studies show altered neuronal plasticity in brain regions including the hippocampus, prefrontal cortex, amygdala, and nucleus accumbens. In a healthy hippocampus, experiences lead to changes in the connections between
neurons resulting in learning. These changes are referred to as plasticity. Chronic stress reduces this plasticity. Healthy brains produce new neurons in one part of the hippocampus. These neurons mature and integrate into the circuitry where they have a strong effect on hippocampal activity and behavior. These new neurons are also affected by stress. They reduce in number in stressed brains. These effects may result from reduced levels of neurotrophins proteins that increase neuronal growth and plasticity. Reduced plasticity may stop the hippocampus from being able to properly regulate the stress response, which may lead to a vicious cycle where stress perpetuates more stress. The hippocampus is particularly affected but there can be reductions in plasticity elsewhere in the brain and together these changes could contribute to other symptoms of depression.

Whether these cellular changes seen in mice are involved in human depression remains unclear. Most antidepressants today rapidly increase the amount of the neurotransmitters serotonin and/or
norepinephrine in the synapse. But improvements in symptoms in patients and mice usually don’t occur until weeks into the treatment. The reasons for this delay aren’t fully understood, prolonged treatment with antidepressants can over time act to reverse some of the changes induced by chronic stress, increasing neurotrophins expression and rebooting hippocampal plasticity. Non-chemical treatments for depression including electroconvulsive shock also promote hippocampal plasticity in mice. Antidepressant treatment can reverse stress induced changes in other areas of the brain including the prefrontal cortex and reward circuitry. Different treatments may target different regions to improve symptoms.

Recently the drug ketamine was found to have rapid antidepressant effects in patients with depression as well as in rodent models with effects lasting for days. The mechanism behind this is an area of active research. Ketamine blocks a type of synaptic transmission leading to activation of a number of signaling pathways and increasing neurotrophins expression. These molecular changes result in increased plasticity in the prefrontal cortex and hippocampus and likely contribute to ketamine’s behavioural effects.

By studying the changes in the brain caused by chronic stress and how antidepressants like ketamine work, researchers may find new targets for treatment or new drugs that could act more quickly more specifically or more effectively than currently available treatments.