Mood naturally fluctuates and everyone experiences highs and lows in their lives
But in some cases changes in mood can become long-lasting
Debilitating and can impair someone's ability to hold down a job, or sustain meaningful relationships
It's estimated that around 10 percent of people will at some point in their lives suffer from depression a mood disorder
characterized by several symptoms
feeling sad
Distressed
Unmotivated
Excessively tired
And losing interest in once pleasurable activities known as anhedonia
Many people with depression also suffer from anxiety
Neuroimaging studies reveal that many brain circuits that normally regulate mood are dysregulated in depression
Located deep within the brain the amygdala processes highly salient 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 along with the prefrontal cortex is particularly vulnerable to the effects of 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 strongly we react to emotional stimuli
Treatments such as antidepressant drugs cognitive behavioral therapy and electroconvulsive therapy
affect the structure and function of these and other brain regions
Animal models such as mice are critical in helping us understand the cellular and molecular
changes underlying depression and develop better treatments
Although it's impossible to know if a mouse is depressed
My subjected 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
While not all human depression is triggered by stress these models may still shed light on the biology of depression
and they're the closest scientists can get while studying mice as
With humans chronic stress in mice can lead to atrophy of the hippocampus and prefrontal cortex
Mouse studies have also shown altered neuronal plasticity in various brain regions including the hippocampus
prefrontal cortex amygdala and nucleus accumbens
In a healthy hippocampus
Experiences can lead to changes in the connections between neurons resulting in learning these changes are referred to as plasticity
chronic stress can reduce this plasticity
Healthy brains also continue to produce new neurons in one part of the hippocampus
These new neurons slowly 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 reduced 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 like an dona
Whether these cellular changes seen in mice are involved in human depression remains unclear
Most antidepressants available today rapidly increase the amount of the neurotransmitters serotonin
and/or norepinephrine in the synapse
However improvements in symptoms in patients and mice usually don't occur until weeks after starting the treatment
While 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 also 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 an 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 to reverse them?
Researchers may find new targets for treatment or new drugs that could act more quickly
More specifically or more effectively than currently available treatments