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Neurobiology of stress


| RESEARCHED AND WRITTEN BY Zofia Hochtaubel

| EDITED BY Yushu


Nowadays, almost everyone experiences stressful situations during the week. Whether it's work-related pressures, personal challenges, or the demands of a fast-paced lifestyle, stress has become an inevitable part of modern life. In 2019, the World Health Organization (WHO) classified stress as the health epidemic of the 21st century. Although stress is the natural response of an organism to a difficult situation, excessive or chronic stress can have detrimental effects on both physical and mental health.



But how does it work?


First, let's look at the "history of stress research". In the early 1900s physiologist Walter Bradfort Cannon proposed the "fighting-or-flight" response, which intensified or interrupted functions to mobilize energy in response to stress. Later he coined the term "homeostasis" which is any self-regulating process by which an organism tends to maintain stability while adjusting to conditions that are best for its survival. This concept, along with the "fight-or-flight" response, has been instrumental in stress research. However it was Hans Selye who first defined stress from a biological perspective. He discovered that patients with various diseases often exhibited similar symptoms, leading to the development of the General Adaptation Syndrome. This syndrome is characterized by non-specific responses that develop in three stages: alarm( this phase involves acute symptoms), resistance (a phase where these symptoms disappear), and exhaustion (a phase where the first-stage reaction may reappear or the organism collapses). In this context, in 1936 Selye defined stress as “a nonspecific response of the body to any demand made upon it” .

Later, scientists discovered that the response to stressful stimuli is triggered by the stress system, which integrates a wide variety of brain structures capable of detecting events and interpreting them as either a real or potential threat (stressor). The perception of threats leads to the release of mediating molecules, which interact with receptors in the periphery and brain, resulting in the stress response. This response restores body homeostasis and promotes adaptation. The concepts of stress, stressor, and stress response are widely accepted by the scientific community.



Stressors


Stressors activate the hypothalamic pituitary adrenal axis and sympathetic nervous system, leading to physiological changes. Long-term exposure can cause depression, post-traumatic stress disorder, and anxiety disorders. Behavioral control over stressors determines their consequences and plays a role in pathological behaviors.

The brain processes physical and psychological stressors differently, with physical stressors causing actual disturbances of physiological status (e.g., infection) and psychological stressors threatening the current state (e.g., predator-related cues). These stressors are processed by different circuitries in the brain, which may overlap at times.

Physical stressors mainly activate vital functions and control structures on the brainstem and hypothalamus, such as the nucleus of the solitary tract (NTS) and locus coeruleus (LC). Prosencephalic regions, such as the prelimbic area (PL) in the prefrontal cortex (PFC), also participate in physical stress processing. The central nucleus of the amygdala (CeA) participates in autonomic response integration.

Psychological stressors are perceived in anticipatory conditions, which may heavily rely on limbic structures and can be modulated by the reward system. The prefrontal cortex is critical for developing appropriate responses to environmental changes and is densely innervated by dopaminergic projections from the Ventral Tegmental Area (VTA) and Nucleus Accumbens (NAc). Disruption of the prefrontal cortex is associated with anhedonia (lack of feeling pleasure) and aberrant reward-seeking behavior.

The Hippocampus (HIPPO) is activated in response to both physical and psychological stressors, with the CA1[1] region having important connections with limbic structures. The paraventricular nucleus of the hypothalamus (PVN) and locus coeruleus (LC) represent the main relay of the stress response, enabling cognitive processing and complex behavioral responses.



A schematic illustration of the primary neuroanatomical substrates involved in the processing of physical (pink) and psychological (blue) stressors.



Stress response


When an organism faces a threatening stimulus, the brain activates various brain areas to recruit the hypothalamus, a complex structure composed of sub-nuclei. The PVN, among these nuclei, is responsible for activating the HPA axis, a key component of the stress response. The PVN synthesizes three neurochemical compounds: oxytocin, vasopressin, and CRH, which act as neurotransmitters or hormones. CRH stimulates the pituitary gland to synthesize and release the adrenocorticotropic hormone (ACTH), which is secreted through the hypophyseal portal system and acts on the cortex of the adrenal gland, responsible for glucocorticoid synthesis and secretion. The main glucocorticoid in humans is cortisol, and these glucocorticoids are in turn considered to be key players in an organism's response to stress. They have specific effects on cognitive functions, resulting in short-term and reversible deficits in episodic and spatial memory. Glucocorticoids are steroids that can penetrate cell membranes and affect the brain by binding cortisol to two receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). These receptors mediate the effects of glucocorticoids, determining their distribution, affinity, and mechanism of action, which can regulate homeostasis or promote adaptation through the stress response.

Other molecules connected to the stress are epinephrine and norepinephrine, also known as adrenaline or noradrenaline. They are hormones and neurotransmitters that are regulated and secreted by the adrenal medulla (the inner portion of the adrenal gland) in response to stress and body imbalances. When the brain perceives danger, the amygdala triggers the hypothalamus to activate the autonomic nervous system (ANS), which stimulates the adrenal gland to pump epinephrine into the bloodstream, resulting in physiological changes such as increased heart rate, blood flow, faster breathing, raised blood sugar levels, and improved physical performance. Noradrenaline release during acute stress induces a state anxiety response, allowing the organism to maintain high attention, facilitate sensory processing, and enhance executive functions, ultimately increasing memory consolidation during stressful experiences.


Short-term and long-term stress


There are two types of stress: short-term and long-term. Short-term stress is often motivating. After the stressor has subsided, the human body returns to its previous state of functioning. Long-term stress, on the other hand, is damaging to the body. In this case, the stress reaction is not blocked, and high levels of cortisol in the blood remain for an extended period of time. This chronic cortisol excess may cause damage to the gastric mucosa due to stimulation of hydrochloric acid secretion, decreased absorption of calcium ions in the intestines, leading to osteoporosis and hypertension, stopping the menstrual cycle in women and erection problems in men, and decreased immunity.

Stress is the body's normal reaction to daily difficulties and changes. We can't get rid of it, but we can learn to live with it. Physical activity is the most effective method because it releases endorphins, which are hormones that make you feel good. The second method for dealing with stress is to reconnect with others. Studies have shown that a 30-second hug reduces stress more than any other type of physical contact. Rest, regular sleep, and a good diet all help in the fight against stress. If you are unable to cope with stress on your own, do not be afraid to ask a therapist for help. Take care of yourself and free yourself from this 21st-century disease of chronic stress.




[1] - CA1 is the first area in the hippocampus circuit from which a main output channel leads to the entorhinal cortex layer V.









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