Stress

The Stress Response

The body’s stress response is mediated by the sympathetic nervous system and the hypothalmic-pituitary-adrenal (HPA) axis.

Learning Objectives

Distinguish between the nervous system and endrocrine system responses to stress

Key Takeaways

Key Points

  • A complex interaction of direct influences and indirect feedback mechanisms among the SNS, the hypothalmus, the pituitary gland, and the adrenal glands contributes to the neuroendocrine regulation involved in reactions to stress and other processes.
  • The SNS is known for its role in mediating the fight-or-flight response. This response is also referred to as the sympatho-adrenal response.
  • Glucocorticoids of the HPA axis have many important functions, but in excess they may be damaging. Researchers have hypothesized that the hormonal changes brought on by stress may contribute to the neural atrophies seen in many neurodegenerative disease states.

The body’s stress response is mediated by the interplay between the sympathetic nervous system (SNS) and the hypothalmic-pituitary-adrenal (HPA) axis. A complex interaction of direct influences and indirect feedback mechanisms among the SNS, the hypothalmus, the pituitary gland and the adrenal glands contributes to the neuroendocrine regulation involved in reactions to stress.

This is a diagram of the mechanism of stress and stress response in the HPA axis. The hypothalamus secretes corticotropin releasing hormone and the anterior pituitary responds by releasing adrenocortictotropic hormone, that causes the adrenal cortex to activate a physical response.

Mechanism of stress and stress response: The hypothalmic-pituitary-adrenal (HPA) axis is an endocrine cascade that mediates several aspects of physiological stress, including responses to acute stressors (i.e., fight-or-flight response) but it also causes chronic stress.

Sympathetic Component

The SNS plays a key role in mediating the neural response to stress known as the fight-or-flight response. This response is also referred to as the sympatho-adrenal response of the body owing to the fact that the preganglionic sympathetic fibers that end in the adrenal medulla secrete acetylcholine, which activates the release of adrenaline and noradrenaline from the medulla.

This response acts primarily on the cardiovascular system and is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly via catecholamines, such as the adrenaline secreted from the adrenal medulla.

HPA Axis Component

A feedback loop exists among the components of the HPA axis and the SNS. The paraventricular nucleus of the hypothalmus contains neuroendocrine neurons that synthesize and release vasopressin —a hormone that acts in the HPA axis as a vasoconstrictor—and corticotropin releasing hormone (CRH).

These two hormones regulate the anterior lobe of the pituitary gland and stimulate the release of adrenocorticotropic hormone (ACTH), also known as corticotropin. ACTH acts on the adrenal cortices that produce glucocorticoid hormones, like cortisol, which is a stress hormone that exerts many effects throughout the body. In the brain cortisol acts on both mineral corticoid and glucocorticoid receptors that are expressed by many different types of neurons.

CRH and vasopressin are released from nerve terminals. CRH gets transported to the anterior pituitary through the circulatory system and vasopressin is transported by axonal transport to the anterior pituitary. There, CRH and vasopressin act to stimulate the secretion of ACTH from the cells where it is synthesized. ACTH is then transported through the circulatory system to the adrenal cortex where it promotes the biosynthesis of corticosteroids like cortisol and cholesterol.

Glucocorticoids of the HPA axis have many important functions, including the modulation of stress reactions, but in excess they may be damaging. Researchers have hypothesized that the hormonal changes brought on by stress may contribute to the neural atrophies seen in many neurodegenerative disease states.

The Fight-or-Flight Response

The fight-or-flight response is regulated by the release of adrenaline or noradrenaline.

Learning Objectives

Discuss the endocrine system’s role in the fight-or-flight response to stress

Key Takeaways

Key Points

  • The fight-or-flight response refers to the physiological changes made by the body upon sensing a threat.
  • Major events in the fight-or-flight response include the secretion of cortisol, adrenaline, and noradrenaline from the adrenal gland.
  • Immediate physiological changes are induced, including acceleration of heart and lung activity, inhibition of digestive activity, shaking, tunnel vision, and loss of hearing.
  • Physiological changes return to normal following removal of the threat, however some long-term stress illnesses exist where falsely detected threats can induce long-term or repeated fight-or-flight episodes.

Key Terms

  • noradrenaline: Also known as norepinephrine, it is a key hormone in the fight-or-flight response.
  • adrenaline: Also known as epinephrine it is a key hormone in the fight-or-flight response.
  • catecholamine: Any of a class of hormones produced by the adrenal gland.

The fight-or-flight response (also called the acute stress response ) was first described by Walter Bradford Cannon. His theory states that animals react to threats with a general discharge of the sympathetic nervous system, priming the animal for fighting or fleeing. This response was later recognized as the first stage of a general adaptation syndrome that regulates stress responses among vertebrates and other organisms.

Upon sensing a threat the brain stimulates the hypothalamus to secrete corticotropin-releasing hormone that induces
adrenocorticotropic hormone from the pituitary to stimulate the release of cortisol from the adrenal cortex to increase blood sugar levels in preparation for fight or flight.

Simultaneously, the adrenal gland also releases catecholamine hormones, such as adrenaline or noradrenaline, into the blood stream. Numerous hormone receptors exist around the body that allow for an immediate, systemic physiological response that can include the following:

  • Acceleration of heart and lung action
  • Paling or flushing, or alternating between both
  • Inhibition of stomach and upper-intestinal action to the point where digestion slows down or stops
  • General effect on the sphincters of the body
  • Constriction of the blood vessels in many parts of the body
  • Liberation of nutrients (particularly fat and glucose) for muscular action
  • Dilation of the blood vessels for muscles
  • Inhibition of the lacrimal gland (responsible for tear production) and salivation
  • Dilation of the pupil (mydriasis)
  • Relaxation of the bladder
  • Inhibition of an erection
  • Auditory exclusion (loss of hearing)
  • Tunnel vision (loss of peripheral vision)
  • Disinhibition of spinal reflexes
  • Shaking
A diagrammatic representation of the fight or flight response. Upon sensing a threat the brain stimulates the hypothalamus to secrete corticotropin-releasing hormone that induces adrenocorticotropic hormone from the pituitary to stimulate the release of cortisol from the adrenal cortex to increase blood sugar levels in preparation for fight or flight. The stress response halts or slows down various processes, such as sexual responses and digestive systems, to focus on the stressor situation.

The fight-or-flight response: A diagrammatic representation of the fight-or-flight response.

The stress response halts or slows down various processes, such as sexual responses and digestive systems, to focus on the stressor situation. This typically causes negative effects like constipation, anorexia, erectile dysfunction, difficulty urinating, and difficulty maintaining sexual arousal. These are functions that are controlled by the parasympathetic nervous system and are therefore suppressed by sympathetic arousal.

Prolonged stress responses may result in chronic suppression of the immune system, leaving the body open to infections. However, a short boost to the immune system shortly after the fight-or-flight response is activated has been described. Some think that this may have filled an ancient need to fight the infections in a wound that one may have received during interaction with a predator.

Stress responses are sometimes a result of mental disorders, such as post-traumatic stress disorder (in which the individual shows a stress response when remembering a past trauma) and in panic disorder (in which the stress response is activated by the catastrophic misinterpretations of bodily sensations).

The Resistance Reaction

Resistance is the second stage of the general adaptation syndrome, where the body has an increased capacity to respond to the stressor.

Learning Objectives

Explain how the endocrine system reacts to stress in the resistance stage

Key Takeaways

Key Points

  • Resistance is the second stage of the general adaptation syndrome.
  • During this stage the body has increased capacity to respond to the stressor.
  • Due to high energetic costs, the body cannot maintain high levels of resistance to stress forever, and if the stressor persists the body may advance into exhaustion.

Key Terms

  • general adaptation syndrome: This describes how a body reacts to a stressor, real or imagined, in the short term and long term.

Stress typically describes a negative concept that can have an impact on one’s mental and physical well-being, but it is unclear what exactly defines stress and whether or not stress is a cause, an effect, or the process connecting the two. With organisms as complex as humans, stress can take on entirely concrete or abstract meanings with highly subjective qualities, satisfying definitions of both cause and effect in ways that can be both tangible and intangible.

Physiologists define stress as how the body reacts to a stressor (any stimulus that causes stress), real or imagined. Acute stressors affect an organism in the short term; chronic stressors over the long term.

Alarm Stage

Alarm is the first stage, which is divided into two phases: the shock phase and the anti-shock phase.

Shock Phase

During this phase, the body can endure changes such as hypovolemia, hypoosmolarity, hyponatremia, hypochloremia, and hypoglycemia—the stressor effect. The organism’s resistance to the stressor drops temporarily below the normal range and some level of shock (e.g., circulatory shock) may be experienced.

Anti-Shock Phase

When the threat or stressor is identified or realized, the body starts to respond and is in a state of alarm. During this stage, the locus coeruleus/sympathetic nervous system is activated and catecholamines such as adrenaline are produced to create the fight-or-flight response.

The result is: increased muscular tonus, increased blood pressure due to peripheral vasoconstriction and tachycardia, and increased glucose in blood. There is also some activation of the HPA axis, producing glucocorticoids such as cortisol.

Resistance Stage

Resistance is the second stage and the increased secretion of glucocorticoids plays a major role by intensifying the systemic response. This response has lypolytic, catabolic, and antianabolic effects: increased glucose, fat and amino acid/protein concentration in blood.

Moreover, these effects cause lymphocytopenia, eosinopenia, neutrophilia, and polycythemia. In high doses, cortisol begins to act as a mineralocorticoid (aldosteron) and brings the body to a state similar to hyperaldosteronism.

If the stressor persists, it becomes necessary to attempt some means of coping with the stress. Although the body begins to try to adapt to the strains or demands of the environment, the body cannot keep this up indefinitely, so its resources are gradually depleted.

Exhaustion or Recovery Stage

The third stage is either exhaustion or recovery.

This is a diagram of general adaptation syndrome. It shows resistance to stress over time, with the alarm stage building up resistance until it reaches the resistance stage. Resistance continues to build up and peak in the resistance stage, until it declines into the exhaustion stage.

General adaptation syndrome: Resistance reaction is the second stage of the general adaptation syndrome and is characterized by a heightened resistance to a stressor.

Exhaustion

Exhaustion is the depletion and inability to maintain normal function and often results in physical illness.

Learning Objectives

Assess the effects of the exhaustion stage of chronic stress

Key Takeaways

Key Points

  • During the exhaustion phase the body’s resources are completely depleted and the body is unable to maintain normal function.
  • Initial autonomic nervous system symptoms may reappear.
  • If the exhaustion stage is extended, long-term damage may result.

Key Terms

  • decompensation: The inability of a diseased or weakened organic system or organ to compensate for its deficiency, which then results in functional deterioration.

Physiologists define stress as how the body reacts to a stressor (a stimulus that causes stress), real or imagined. Acute stressors affect an organism in the short term; chronic stressors over the long term.

Alarm

This is a diagram of general adaptation syndrome. It shows resistance to stress over time, with the alarm stage building up resistance until it reaches the resistance stage. Resistance continues to build up and peak in the resistance stage, until it declines into the exhaustion stage.

GAS: A diagram of the general adaptation syndrome model,

Alarm is the first stage. When the threat or stressor is identified or realized, the body’s stress response is in a state of alarm. During this stage, adrenaline will be produced in order to bring about the fight-or-flight response. The organism’s resistance to the stressor drops temporarily below the normal range and some level of shock may be experienced.

Resistance

Resistance is the second stage. If the stressor persists, it becomes necessary to attempt some means of coping with the stress. Although the body begins to try to adapt to the strains or demands of the environment, the body cannot keep this up indefinitely, so its resources are gradually depleted.

Exhaustion

Exhaustion is the third and final stage in the general adaptation syndrome model. At this point, all of the body’s resources are eventually depleted and the body is unable to maintain normal function. The initial autonomic nervous system symptoms may reappear (sweating, raised heart rate, etc.).

If stage three is extended, long-term damage may result, as the body’s immune system becomes exhausted, and bodily functions become impaired and result in decompensation. The result can manifest itself in obvious illnesses such as ulcers, depression, diabetes, trouble with the digestive system, or even cardiovascular problems, along with other mental illnesses.

Stress and Disease

Over-activation of the stress response can result in pathology and disease.

Learning Objectives

Describe the role played by the endocrine system in stress and disease

Key Takeaways

Key Points

  • Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that can develop after exposure to psychological trauma.
  • While cortisol release typically facilitates increased memory, chronic exposure leads to hippocampal damage that can lead to memory loss.
  • Clinical depression is characterized by an increased HPA- axis function, primarily through a decrease in the normal negative feedback of the system.
  • Additionally, clinical depression is associated with lower serotonin and noradrenaline levels.
  • Excessive production of cortisol has been correlated with an increased risk of heart disease.

Key Terms

  • post-traumatic stress disorder: A serious condition that develops following an intensely stressful situation or event.

Exhaustion is the third and final stage in the general adaptation syndrome model. At this point, all of the body’s resources are eventually depleted and the body is unable to maintain normal function. The initial autonomic nervous system symptoms may reappear (sweating, raised heart rate, etc.).

If stage three is extended, long-term damage may result, as the body’s immune system becomes exhausted, and bodily functions become impaired and result in de-compensation. The result can manifest itself in obvious illnesses such as ulcers, depression, diabetes, trouble with the digestive system, or even cardiovascular problems, along with other mental illnesses.

Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. Diagnostic symptoms for PTSD include re-experiencing the original trauma(s) through flashbacks or nightmares, avoidance of stimuli associated with the trauma, and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance.

This is an illustration of the brain with its regions in associated with stress and PTSD highlighted. The regions are the prefontal cortex, the medial prefrontal cortex, the ventromedial prefrontal cortex, and the amygdala.

Regions of the brain associated with stress and PTSD: Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that can develop after exposure to psychological trauma.

Sensory input, memory formation, and stress response mechanisms are affected in patients with post-traumatic stress disorder. The regions of the brain involved in memory processing that are implicated in PTSD include the hippocampus, amygdala, and frontal cortex, while the heightened stress response is likely to involve the thalamus, hypothalamus, and locus coeruleus.

There is consistent evidence from MRI volumetric studies that hippocampal volume is reduced in post-traumatic stress disorder. This atrophy of the hippocampus is thought to represent decreased neuronal density.

However, other studies suggest that hippocampal changes are explained by whole brain atrophy, and generalized white matter atrophy is exhibited by people with PTSD.

Memory

Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for the storage of flash-bulb memories, and may originate as a means to remember what to avoid in the future.

However, long-term exposure to cortisol damages cells in the hippocampus, which results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval for already stored information.

Depression

Many areas of the brain appear to be involved in depression, including the frontal and temporal lobes and parts of the limbic system, including the cingulate gyrus. However, it is not clear if the changes in these areas cause depression or if the disturbance occurs as a result of the etiology of psychiatric disorders.

The Hypothalamic-Pituitary-Adrenal Axis in Depression

In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated by a down-regulation of its negative feedback controls. Corticotropin-releasing factor is over-secreted from the hypothalamus and induces the release of adrenocorticotropin hormone (ACTH) from the pituitary.

ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands. Adrenal hypertrophy can also occur due to this repeated stimulation. The release of cortisol into the circulatory system has a number of effects, including elevation of blood glucose.

The negative feedback of cortisol to the hypothalamus, pituitary, and immune systems is impaired. This leads to a continual activation of the HPA axis and excess cortisol release. The cortisol receptors then become desensitized, which causes an increase in activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

Serotonin Pathways in Depression

Serotonin transmission from both the caudal raphe nuclei and rostral raphe nuclei is reduced in patients with depression compared with non-depressed controls. Increasing the levels of serotonin in these pathways by reducing serotonin re-uptake, hence increasing serotonin function, is one of the therapeutic approaches to treating depression.

The Noradrenaline Pathways in Depression

In depression, the transmission of noradrenaline is reduced from both of the principal noradrenergic centres. An increase in noradrenaline in the frontal/prefrontal cortex modulates the action of selective noradrenaline re-uptake inhibition and improves mood. Increasing noradrenaline transmission to other areas of the frontal cortex modulates attention.

Heart Disease

Excessive cortisol release also has a negative impact on heart health. High levels of cortisol correlate with an increased risk of heart disease. This is due to the increases in blood sugar and blood pressure levels that cortisol imparts along with it’s pro-inflammatory effects.