Stress: Involved Brain Systems and Counteractive Measures

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Written by Brett Weiss

August 2019

Image by Gerd Altmann from Pixabay

The conventional definition of ‘stress’ entails the process of evaluating real or perceived demands from the environment which get appraised as benign or threatening.  The brain constitutes the principle organ involved in the appraisal of stressful situations, which get judged based on resources available to the individual for adaptation to the stressor.  Stress resiliency or vulnerability depend upon coping mechanisms of the brain as the brain regulates physiological and behavioral responses to stressors.  The following passage will present neuroscientific theory of how the brain responds to stress to promote protection of the body or, in maladaptive circumstances, damage to the body.  The following will also discuss steps that people can take to prevent health-related damage from chronic stress and to possibly reverse the damaging effects of chronic stress.

The types of stress that people experience can be divided into three variations: eustress, distress, and toxic stress.  Eustress pertains to an environmental challenge that elicits physiological and behavioral responses that one overcomes.  Eustress associates with positive feelings and euphoria.  Distress entails “tolerable stress” or environmental challenges which may cause difficulties past the duration that they last.  With distress, one may usually cope given that one has healthy brain architecture.  Distress can promote resilience.  Finally, toxic stress refers to bad situations that happen to an individual who may have brain architecture reflecting effects of adversity in early life.  Adversity early in life may have impaired development of impulse control, judgment, and positive self-esteem.  Toxic stress relates to distress; however, with toxic stress, the stressors may be greater and last for longer durations.

The three kinds of stress relate to two other concepts– ‘allostasis’ and ‘allostatic overload.’  Allostasis refers to achieving stability (homeostasis) in a changing environment.  Humans achieve allostasis physiologically via the sympathetic and parasympathetic nervous systems.  The sympathetic nervous system entails the “fight or flight” response and uses the adrenal system.  The parasympathetic nervous system involves “resting and digesting” and entails actions that include slowing the heart rate.  A balance of functions between the sympathetic and parasympathetic nervous systems is crucial to obtain and maintain allostasis.  When balance between allostasis mechanisms ensue, which cause sympathetic and parasympathetic nervous system disruption, pathophysiology may occur, which constitutes allostatic overload.

Different life factors contribute to health-promoting allostasis versus health damaging allostatic overload.  Some examples which contribute to allostatic overload include disrupted sleep patterns, loneliness, noise, pollution, lack of green areas, and crowding (McEwen, 2017).  Having a stressful lifestyle may cause stressors to operate chronically, often at a low level, resulting in changes in behavior.  For example, being “stressed out” can cause anxiety and depression, loss of sleep, consumption of comfort foods and more calories than our bodies need, smoking, and drinking alcohol.  A “stressed out” state of mind can also cause one to neglect seeing friends, take time off of work, and reduce regular physical activity (McEwen, 2017).  Through all of this, the brain plays a special role.

The brain evaluates what is new (novel) from the environment and what may present as a threat.  In turn, the brain orchestrates behavioral and physiological responses.  These responses may be health promoting or health damaging.  The brain changes architecturally and biochemically under acute and chronic stress and directs systems of the body including the metabolic system, cardiovascular system, and immune system.  Experiences remodel the circuits in the brain such that behavioral responses get altered appropriately with what is experienced.  Healthy brains are resilient and neural circuits adapt to new environments along with changes in gene expression that go along with changes in neural circuitry.  Unhealthy brains are not as plastic and are less able to adapt appropriately (McEwen, 2017).  In cases of unhealthy adaptation, external interventions may be required with pharmacological agents and behavioral modifications.  In situations of persistence of these conditions, excessive excitatory amino acids and glucocorticoids release in the brain and central nervous system.  In some cases, these conditions can lead to irreversible damage.  In fact, neuroscientists postulate that this irreversible damage may be a key step in the irreversible activation of a cascade leading to Alzheimer’s disease, which involves inactivation of an adaptive insulin receptor mechanism (McEwen, 2017).  Otherwise, in normal aging brains, such loss of resilience may be reversible.  For example, these effects may be counteracted with regular physical activity (McEwen, 2017).

Three brain areas process stressful experiences through interfacing with lower brain areas: the amygdala, hippocampus, and prefrontal cortex.  These brain areas help interpret whether experiences are threatening or stressful based on current and past experiences.  Located toward the middle of the brain, the amygdala constitutes an essential component for processing of fearful and emotionally-charged memories, whereas the hippocampus processes memories of the context in which events take place.  Also located also toward the middle of the brain, the hippocampus processes episodic memories (memories of experiences) and declarative memories (memories which one may verbalize).  The hippocampus is also involved in regulation of mood.  The amygdala and hippocampus are linked to one another anatomically and functionally (McEwen and Gianaros, 2010).  The prefrontal cortex sits toward the very front of the brain and interacts with the amygdala and hippocampus for interpretation of stressful experiences.  Generally speaking, these three brain regions interact with the hypothalamic-pituitary-adrenal axis, which releases the stress hormone, cortisol.  Activity of the amygdala has an excitatory effect on the hypothalamic-pituitary-adrenal axis resulting in release of cortisol, while hippocampal activity has an inhibitory effect.  Studies have also shown that the prefrontal cortex plays a role in inhibiting activity of the hypothalamic-pituitary-adrenal axis (McEwen and Gianaros, 2010). 

Repeated stress on the hippocampus has resulted in remodeling of hippocampus circuitry in animal models.  Specifically, loss of connections between neurons (synapses) has been observed.  Importantly, chronic stress has been shown to suppress neurogenesis from a structure called the dentate gyrus of the hippocampus.  Neurogenesis entails the generation of new brain cells (neurons), which occurs throughout a lifetime, even in humans!  Chronic stress-induced damage to the hippocampus can result in two outcomes– impairment of episodic, declarative, and spatial memory which may lead to difficulties in dealing with new challenges and impairing the ability of the hippocampus to regulate the hypothalamic-pituitary-adrenal axis and cortisol release.  In fact, according to the “glucocorticoid cascade hypothesis,” with hippocampal aging and chronic stress, the loss of hippocampal ability to regulate stress hormones like cortisol leads to a deterioration in ability to handle stress and results in allostatic overload and possibly pathology such as Alzheimer’s disease (McEwen and Gianaros, 2010).

Animal studies of the effects of chronic stress on the amygdala have pointed to such stress leading to anxious and aggressive behavior.  Furthermore, people raised in lower socioeconomic status situations show higher levels of amygdala activation.  Lower socioeconomic status situations may activate amygdala activity through exposure to dangerous environments or high-stress family situations (McEwen and Gianaros, 2010).

The prefrontal cortex shows stress-induced changes in neuronal connectivity and structure in animal models.  The medial prefrontal cortex (toward middle of the prefrontal cortex) has reduced neuronal complexity and loss of neuronal connections from repeated stress.  The orbitofrontal cortex (prefrontal cortex area near eyes) shows greater complexity of neuron connections resulting from chronic stress.  In human studies, the prefrontal cortex has been found to regulate behavioral and physiological reactivity to stress (McEwen and Gianaros, 2010).

In order to counteract effects of chronic stress and possibly reverse the effects of damage from chronic stress, two non-pharmacological strategies may help: regular exercise and social integration.  Exercise can increase the production of new neurons through neurogenesis in the dentate gyrus of the hippocampus.  One mechanism by which exercise increases new neurons (neurogenesis) comes from increased levels of circulating IGF-1, a hormone, from exercise.  The brain takes up increased levels of IGF-1, which activates receptors in the hippocampus resulting in higher production of new neurons.  Exercise also has mood-elevating effects which can counteract stress as exercise elevates levels of BDNF, a molecule in the brain which elevates mood.  BDNF is involved in increasing hippocampus volume and improving memory.  Social integration may counteract effects of chronic stress if one makes effort to engage in a wide range of social activities and if one identifies with diverse social roles.  Not much is currently known about how social integration and support benefit human brain circuits in people who experience chronic stress.  There is evidence from animal models, though, that social interactions increase neurogenesis and neuroplasticity in the hippocampus and amygdala (McEwen and Gianaros, 2010).

Chronic stress can lead to damage to circuits in the brain.  In order to facilitate neural protection and reverse ill-effects of chronic stress, exercise and social integration are key, non-pharmacological interventions.  Therapy can also help alter thought-patterns and behaviors to facilitate positive mental health as evidence suggests that a positive future outlook has neuroprotective effects from the damages of stress.


McEwen BS (2017).  “Neurobiological and Systemic Effects of Chronic Stress.”  Chronic Stress (Thousand Oaks).  1.

McEwen BS (2007).  “Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain.”  Physiol Rev.  87: 873-904.

McEwen BS & Gianaros PJ (2010).  “Central role of the brain in stress and adaptation: Links to socioeconomic status, health, and disease.”  Ann N Y Acad Sci.  1186: 190-222.

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