How Chronic Stress Impacts the Brain

How Chronic Stress Impacts the Brain

To understand chronic stress, we have to start with how we’re wired to deal with occasional stress: Enter the HPA (hypothalamic-pituitary-adrenal) axis.

The HPA axis is one of the primary ways that the brain adjusts and adapts to its outside environment – and to the corresponding challenges it presents. This intricate system is used by our brain to prepare our body to respond to danger, a.k.a. stressors. Activation of the HPA axis is an example of a neuroendocrine response, where the nervous system stimulates the adrenal glands to release hormones that then influence our body’s function. 

When humans are chronically exposed to stress, the HPA axis is essentially “always on,” causing the constant production of steroid hormones, which results in chronically elevated cortisol levels.

Fight, Flight, Freeze

To prepare the body for danger, the HPA axis activates to release the hormones that can act as signaling molecules and prepare the body to protect itself. These hormones can increase blood pressure and blood sugar while suppressing energy intensive systems such as the immune system. Ultimately, it prepares the body for a fight, flight, or freeze response.

While the HPA axis is best known for its role in the body’s stress response, it’s also activated in non-stress situations such as circadian rhythm regulation.

Cue Cortisol

The HPA axis is regulated by three main structures in the brain: the hippocampus, the amygdala, and the medial prefrontal cortex.

The amygdala, which senses and processes fear and anger, is partly responsible for activating the HPA axis. Once activated by a stressor, there is a resulting release of corticotropin-releasing hormone (CRH) from the hypothalamus. This hormone reaches the pituitary gland, which secretes adrenocorticotropic hormone (ACTH) in response. Once ACTH reaches the adrenal gland, it tells the adrenals to release cortisol into the bloodstream. 

The Danger of Being Always On

When humans are chronically exposed to stress, the HPA axis is essentially “always on,” causing the constant production and release of steroid hormones into the bloodstream; ultimately, this results in chronically elevated cortisol levels.

Overall, it’s the constant elevation of these steroid hormones that leads to many of the downstream consequences associated with chronic stress, especially because nearly every cell in the human body has receptors for cortisol. 

Scientists have used the term allostatic load to describe the cumulative strain that chronic stress can exert on the different parts of the body; it’s this multi-systemic damage that increases as humans endure stress for long periods of time. 

The Symptoms

Depression & Burnout

The brain appears to be particularly impacted by chronic HPA axis activation; depression and burnout at work are more common in individuals under high degrees of stress. Again, this is likely mediated by the high levels of glucocorticoids that are produced due to the stress response.

Elevated cortisol is known to have detrimental impacts on brain health – it’s common in mood disorders, such as depression, as well as insomnia. 

Memory & Cognition

Not all regions of the brain are impacted equally by stress. Areas associated with decision making, mood, anxiety, and cognition bear the biggest brunt in the presence of chronic stress. This aligns with data showing that high cortisol levels can have negative effects on memory and cognition. Furthermore, chronic stress can promote atrophy of the hippocampus, a region of the brain that plays a particularly important role in learning and memory. 


The hormones released as a result of HPA axis activation also promote production of both inflammatory and anti-inflammatory compounds (cytokines), leading to dysregulation of the carefully regulated inflammatory system. Various conditions associated with HPA axis overstimulation, such as PTSD, are found to chronically elevated levels of inflammation as part of their pathogenesis. In addition, inflammatory imbalance resulting from HPA axis activation is a driver of mood disorders and cognitive decline that occur as a result of chronic stress. 

Beyond the Brain

Excessive cortisol levels may also result in increased susceptibility to infections, since the immune system is chronically suppressed. Other consequences of high cortisol levels include weight gain, headaches, irritability, anxiety, insomnia, increased risk of diabetes, and gastrointestinal issues.

Many environmental factors that activate the HPA axis are out of our control – a global pandemic, a traumatic event, a high-pressure work environment – but we can support the brain in its response to those stressors. Having healthy outlets to complete the stress cycle, such as exercise, a creative practice, or a supportive listener, are all important. Additionally, a diet rich in nutrients that support balanced neurotransmitter levels can support the brain’s ability to effectively manage stress.

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