Stress response in key brain region may explain depression

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New research explains how a key brain region is implicated in depression. Westend61/Getty Images
  • Stress over a sustained period can lead to depression, but how chronic stress leads to depression is unclear.
  • A recent study shows that individuals without depression, unlike those with the condition, adapt to elevated everyday stress by changes in the response of the medial prefrontal cortex, a brain region involved in regulating the stress response.
  • An inability to produce an adaptive response to elevated everyday stress may lead to depression.
  • The extent of this inability to produce an adaptive response to stress may predict deficits in daily functioning.

Major depressive disorder (MDD), also known as clinical depression, is one of the most common mental health conditions in the United States. According to the National Institute of Mental Health (NIMH), approximately 7.1% of adults had a depressive episode in 2017.

Furthermore, recent research carried out by the Centers for Disease Control and Prevention (CDC) suggests the stress of the current COVID-19 pandemic may be associated with an increase in self-reported depression and anxiety symptoms, particularly in adults under 30 years old.

Experiencing stress over a prolonged period, such as during the pandemic, is associated with the development of depression. One of the major symptoms of depression includes anhedonia, or the inability to anticipate or feel pleasure.

However, researchers do not have a comprehensive understanding of how chronic stress leads to depression or the accompanying symptoms of anhedonia.

Evidence suggests that the medial prefrontal cortex (mPFC), a brain region involved in processing reward and regulating the stress response, may be involved in mediating these effects of chronic stress.

While the mPFC is involved in regulating the stress response, acute and chronic stress also elicit changes in the mPFC.

Studies in rodents have shown that glutamate, an excitatory neurotransmitter, is released by neurons in the mPFC during acute stress.

However, rodents exposed to chronic stress exhibit lower levels of glutamate release in the mPFC when faced with a new acute stressful event.

Scientists think that such a reduction in the mPFC glutamate response due to chronic stress could be a protective adaptation to stress.

Studies had already shown that mPFC glutamate activity is altered in depression.

Now, a study led by a team of researchers at Emory University in the United States shows that people with depression, unlike individuals without the condition, are unable to produce an adaptive decrease in mPFC glutamate levels in response to experiencing a recent increase in everyday stress.

Furthermore, the extent to which an individual with depression lacked such an adaptive response predicted their levels of anhedonia in daily life.

“We were able to show how a neural response to stress is meaningfully related to what people experience in their daily lives,” says Dr. Jessica Cooper, the study’s first author. “We now have a large, rich data set that gives us a tangible lead to build upon as we further investigate how stress contributes to depression.”

The study appears in the journal Nature.

To investigate the role of the mPFC in depression, the researchers recruited 65 individuals without depression and 23 people with MDD who were not taking medication.

Around 11–12 days before the experiment, the researchers used the Perceived Stress Scale (PSS) to measure each participant’s subjective or perceived stress levels over the past month.

On the test day, the participants completed a task that induced acute stress. The researchers used magnetic resonance spectroscopy (MRS), a noninvasive imaging technique, to measure changes in glutamate levels in the mPFC before and after the acute stress test.

The team found that the magnitude of change in mPFC glutamate levels due to the acute stress test was associated with perceived stress levels in people without depression.

People without depression and with lower levels of recent perceived stress, as measured by the PSS, showed an increase in mPFC glutamate levels after the test. In contrast, those without depression but with higher perceived stress showed no change or a decrease in mPFC levels.

While there were changes in mPFC glutamate levels in people with depression during the acute stress test, these changes were not correlated with their PSS score.

The authors suggest that the absence of an adaptive change in mPFC glutamate levels may play a role in the development of stress-related mental health conditions, such as depression.

To establish whether the mPFC glutamate response during the acute stress test was associated with daily functioning, the researchers surveyed the participants with depression every other day after the stress test for 4 weeks.

The surveys assessed the participant’s optimism or pessimism regarding their life activities and the actual outcomes of these activities. Using this data, the researchers determined the accuracy of the participants’ optimistic or pessimistic expectations.

Participants with MDD were likely to have more inaccurate pessimistic expectations than those without depression.

The researchers then created a model using the mPFC glutamate response data obtained from the participants without depression. Based on this, they quantified the extent to which the mPFC glutamate response in participants with MDD deviated from those without depression.

The researchers called this score the maladaptive glutamate response (MGR). The MGR score in participants with MDD was positively correlated with inaccurate pessimistic expectations.

Thus, the extent to which participants with MDD did not exhibit an adaptive decrease in mPFC glutamate levels during acute stress was associated with an inability to anticipate pleasure or anticipatory anhedonia.

The authors acknowledge that the study had a few limitations. For example, the authors note that, despite their efforts, the range of PSS scores used to estimate perceived stress levels did not overlap among people with MDD and people without depression.

They note, “This was not entirely unexpected, as PSS scores are known to be much higher in MDD samples; however, it does limit our ability to determine whether the maladaptive glutamate response we observed was driven primarily by the high severity of perceived stress in MDD, the presence of their current depression, or both.”

“These results advance our understanding of the neurobiological adaptation to stress and may play a valuable role in identifying new treatment targets and markers of treatment response in human stress-related illness,” the authors conclude.

Janelle B. Smith

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