Chp. 6: Neuroendocrinology of the Stress-Response

• What is stress? How do we define stress, stressors and the stress-response.

• The nervous system plays a critical role in the stress-response:

– perception of events as stressful

– activation of the HPA axis-->secretes glucocorticoids

– activation of the ANS-->secretes catecholamines (epinephrine and norepinephrine)

– activation of pathways within the brain important for other responses (e.g., locomotion)

• Numerous events occur during an acute stress-response:

– changess in energy metabolism, heart rate, breathing, digestive processes, growth,

analgesia, regulation of immune system, and behavior

– these changes are considered adaptive as they occur for short periods of time and they

allow an individual to take appropriate action in a threatening situation

• However, chronic exposure to stress can alter these responses in specific ways that

leads to the development of physical disease, and in humans, psychiatric illness. This

relationship is influenced by genetic and experiential variables--vulnerability!!

Stress-Response

Definitions:

• stressor: anything that disrupts the body’s physiological balance

• stress-response: the body’s adaptations designed to re-establish balance

• stress: general state of stressors provoking a stress-response

Psychological

What is stress?

Physical

exercise

grizzly bear

injury(hemorrhaging)

Negative

Positive meeting adeadline

physicalabuse

no jobpromotion

public speaking

Stress-Response

Nervous System

perceptionof an

event as“stressful”

activation of the HPA axis

activation ofthe ANS

(sympatheticdivision)

activation ofadditionalpathways

in NS

Hormones

glucocorticoids

plasmacatecholamines

motor responses(locomotion)

Fightor

FlightReactions

HPA AxisHypothalamo-Pituitary-Adrenocortical

Axis (HPA axis):

• stress is perceived by limbic system

• neurons in the limbic system activate the HPA axis

– CRH neurons in hypothalamus release CRH at median eminence

– CRH stimulates release of ACTH from cells in the anterior pituitary

– ACTH stimulates both synthesis and release of glucocorticoids from adrenal cortex

– glucocorticoids act, in part, to mobilize energy for the fight or flight response

– glucocorticoids also act to restrain the HPA axis by inhibiting hormone release at the level of the hypothalamus, pituitary, and higher brain regions (limbic system)

CRH Neuron

HYPO

ANTPIT

ADRENALCORTEX

ACTH

glucocorticoids

CRH

CRH: corticotrophin-releasing hormoneACTH: adrenocorticotrophin hormone

glucocorticoidnegativefeedback

LIMBICSYSTEM

mobilizeenergy

Autonomic Nervous System (ANS)

Parasympathetic Division

“vegetative functions”

increased digestion

increased saliva

decreased heart rate

decreased breathing

increased blood flow to gut

restful state

Sympathetic Division

“fight or flight response”

decreased digestion

decreased saliva

increased heart rate

increased breathing

shunting of blood from gut

to other tissues--skeletal muscle,

heart, & brain

heightened arousal & vigilance

sweating

The ANS consists of two main divisions--the parasympathetic and sympathethicdivisions. These divisions have opposite effects on many physiological processes.

Neurons within the hypothalamus control the activity of neurons in the brainstemand lower spinal cord. Neurons within the brainstem and SC project to neurons within ganglia located close to target tissue. Acetylcholine (ACh) is the neurotranmitter that is released at the synapse in the ganglion and at the target tissue.

Parasympathetic Division

hypothalamus

brainstem

lowerspinalcord

gangliontargettissue

targettissue

AChACh

Neurons within the hypothalamus control the activity of neurons in the intermediolateral cell column (IML) of the spinal cord. Neurons within IML project to neurons within ganglia located close to the spinal cord. Neurons within the ganglia project to target tissues. Acetylcholine (ACh) is the neurotransmitter released at synapse in ganglion and norepinephrine (NE) is released at target tissues. In addition, neurons within IML project directly to the adrenal medulla where they release ACh which stimulates release of epinephrine (E) into blood.

Sympathetic Division

hypothalamus

IML of spinal cord

sympatheticchain ofganglia

targettissue

Adrenal Medulla

ACh NE

E(bloodstream)

Autonomic Nervous System (ANS)

During a stress response, the sympathetic division of the ANS will be activated.

• norepinephrine (NE) will be released at target tissues (e.g., heart)

• epinephrine (E) will be released into the bloodstream to act throughout the body

• epinephrine and norepinephrine (plasma catecholamines) carry out the various events

associated with “fight or flight response”

– decreased digestion, decreased saliva production, increased heart rate, increased breathing,

shunting of blood from gut to other tissues, heightened arousal and vigilance, and sweating

(among other responses)

– in addition, these hormones act to increase glucose levels within the bloodstream (energy

metabolism)

Stress-ResponseAcute Stress Response:

• considered adaptive--it allows us to deal with an emergency situation (short-lived)

• different responses will be seen in different situations, but the outcome will be the

same-- survival (life, grades, etc…)

– grizzly bear: may freeze or run or climb a tree--your response will determine your survival

– poster presentation: may start early to make a really cool poster or wait until the absolute

last minute to make it--your response will determine your grade (and potentially survival in

this course!)

Chronic Stress Response:

• considered maladaptive--detrimental affects on the body

• chronic stress can lead to physical disease: gastric ulcers, visceral obesity, decreased

growth, increased risk for coronary heart disease

• chronic stress can also affect behavior: inhibition of reproduction

• in humans, chronic stress has been linked to psychiatric illness (depression)

Stress-ResponseAcute Stress Response:

• metabolic: to increase levels of glucose within the bloodstream

• cardiovascular/respiratory: to increase cardiovascular tone to speed delivery of

mobilized glucose and oxygen to tissues that need it--heart, skeletal muscle and the

nervous system

• analgesia: to decrease the perception of pain

• inhibition of behaviors and processes that might threaten the survival of the

individual:

– inhibition of mating behavior

– inhibition of feeding

– inhibition of gastrointestinal processes

– inhibition of the immune system

Stress-ResponseAcute Stress Response: Metabolic

• Purpose: to increase levels of glucose within the bloodstream

• Background:

– energy substrates are stored in the body in several forms: 1) excess fats are stored in

adipose tissue as triglycerides, 2) amino acids are stored throughout the body as proteins,

and 3) glucose is stored throughout the body as glycogen

– two hormones secreted by the pancreas play an important role in controlling the levels of

blood sugar (glucose): 1) -cells in the pancreas secrete insulin--a key hormone involved

in storage of glucose and the synthesis of proteins and fatty acids, 2) -cells in the pancreas

secrete glucagon--a key hormone for the release of glucose into the bloodstream

– secretion of insulin and glucagon maintain glucose homeostasis under low stress conditions

– Ex. After a meal, glucose levels are high and -cells secrete insulin allowing for the

transport of glucose from blood into cells for storage; several hours after the meal, glucose

levels drop and -cells secrete glucagon which then acts to increase the release of glucose

from stores until the next meal.

Stress-ResponseAcute Stress Response: Metabolic

• Purpose: to increase levels of glucose within the bloodstream

• During stress, glucocorticoids and plasma catecholamines act to increase levels of

glucose within the bloodstream:

– glucose uptake is inhibited and synthesis of proteins, fatty acids and glycogen is halted

– lipolysis: triglycerides (fatty acids) are broken down and flushed into bloodstream

– glycogenolysis: glycogen is degraded and glucose is flushed into the bloodstream

– proteolysis: proteins are degraded into amino acids and flushed into bloodstream

– gluconeogenesis: fatty acids and amino acids are converted into glucose within the liver

– E/NE acts at adrenergic receptors (membrane) to rapidly increase blood glucose levels via

lipolysis, glycogenolysis, proteolysis, gluconeogenesis; in addition, these hormones act to

inhibit secretion of insulin while increasing secretion of glucagon

– glucocorticoids act at intracellular receptors to increase the synthesis of enzymes (via gene

transcription) that subsequently act to increase the process of gluconeogenesis; this effect is

slower but can last for a longer period of time

Stress-ResponseAcute Stress Response: Cardiovascular/Respiratory

• Purpose: to increase cardiovascular tone to speed delivery of mobilized glucose and

oxygen to tissues that need it--heart, skeletal muscle and the nervous system

• Activation of the sympathetic division of the ANS lead to release of norepinephrine in

tissues and epinephrine (and to a lesser degree norepinephrine) within the

bloodstream; these catecholamines mediate increases in cardiovascular tone.

– in crease in breathing rate

– increase in heart rate

– increase in blood pressure

– shunting of blood away from the digestive tract and toward the heart, skeletal muscle and

nervous system

– in addition, vasopressin is released from axon terminals in the posterior pituitary and acts to

stimulate water reabsorption in the kidney; this increase in blood volume also serves to

increase blood pressure

Stress-ResponseAcute Stress Response: Analgesia

• Purpose: to decrease the perception of pain

• Two forms of stress-induced analgesia (SIA):

– opiate-dependent SIA: endogenous opiates (enkephalins and -endorphin) are released

within the brain to inhibit the processing of sensory information associated with pain

– opiate-independent SIA: other neurotransmitters (e.g., glutamate) can also act to inhibit the

processing of painful information; endogenous opiates are not involved in this process

– both forms of SIA would occur during a normal stress encounter

• Adaptive nature of SIA: the zebra and the lion

– a lion attacks but does not kill a zebra; the zebra’s stomach is ripped open (stress response),

yet for the next few hours, it has enough strength to evade the lion; a part of this response

is the occurrence of SIA; if the zebra stopped to attend to it’s wound, it would most likely

be killed by the lion; the decrease in perception of pain allows the zebra to continue to flee

from the lion

Stress-ResponseAcute Stress Response: Alterations in behavior

• CRH released within the brain causes a shift in behavior from nonstressful responses

(e.g., feeding, mating) to responses geared toward dealing with threatening stimuli--

increased attention, caution, and fight or flight responses

CRH release in brainactivates

behaviorsassociated withincreased state

of fear (anxiety)

inhibits behaviors

not associated with stress

inhibition ofmating

inhibition offeeding

increasedfreezing

increasedvigilance

(attention)

increasedbehavioralreactivity

Stress-ResponseAcute Stress Response: Gastrointestinal Tract

• at times of rest or feeding (low stress), see high parasympathetic tone of ANS

associated with digestive processes:

– secretion of saliva in the mouth

– secretion of digestive enzymes, hormones and mucus in the stomach and intestines

– stimulation of stomach churning and gut motility

• under stress conditions, see high sympathetic tone of ANS:

• all of the digestive processes are inhibited

– one obvious sign of stress: our mouths become dry when we are nervous because we stop

secreting saliva

• decreased blood flow to the GI tract

• increased defecation (imbalance between parasympathetic and sympathetic control)

Stress-Response

Acute Stress Response: Nonspecific & Specific Defense Mechanisms

• stress inhibits inflammation associated with injury or infection

– inflammation occurs during an infection or injury; it is a recuperative process--influx of

WBCs and proteins into infected region that destroy the pathogen, remove cellular debris,

and repair damage

– inflammatory response means “setting on fire”; infected or damaged region will appear red

and hot, with an increase in swelling; the infected region will be painful, and if located

near joints, it will also be stiff (limited movement)

– elevations in glucocorticoids inhibit inflammation

– stress-induced inhibition of inflammation is adaptive by limiting a process that is painful

and could limit mobility (important for fight or flight responses)--similar to stress-induced

analgesia

– this recuperative process will take place when the level of stress is reduced (e.g., stressor is

gone)

Stress-ResponseAcute Stress Response: Nonspecific & Specific Defense Mechanisms

• stress hormones also limit activation of the immune system that occurs during an

infection

– an infection which activates the immune system will also activate the HPA axis (secretion

of glucocorticoids)

– glucocorticoids, act in part, to inhibit the synthesis and release of various interleukin

molecules as well as the synthesis of their receptors

– effect: limited proliferation of nonspecific defense mechanisms--NK cells and

macrophages, and limited proliferation of specific defense mechanisms--humoral- and cell-

mediated immunity

• immune system activates the HPA axis which acts to inhibit the immune system

• why?

– adaptive significance: may protect the body from becoming too active and possibly

attacking self (autoimmune disease)

Stress-ResponseBackground--Defense against pathogens

The body has two systems to defend against pathogens, or infectious agents:

• nonspecific defense system

– this system nonspecifically attacks all types of pathogens--viruses, viral-infected cells,

bacteria, and other foreign agents

– this system is also mediates inflammatory response that occurs in response to an infection

or an injury

– this system includes: skin, mucous membranes (pH and enzymes), white blood cells,

complement (serum proteins)

– WBCs: neutrophils and macrophages phagocytose pathogen and dead or dying cells

– WBCs: natural killer cells (NK cells) kill virus-infected cells and tumors (damage to cell

membranes leading to cell lysis)

Stress-ResponseBackground--Defense against pathogens

The body has two systems to defend against pathogens, or infectious agents:

• specific defense system--immune system

– this system attacks substances detected as “foreign” by proliferating cells that either attack

the invader directly or produce specific defensive proteins called antibodies that lead to the

destruction of the pathogen

– B cells and T cells are lymphocytes that originate in bone marrow; B cells also mature in

bone marrow--hence B designation; T cells migrate to, and mature within, the thymus--

hence the T designation; the maturation process involves development of

immunocompetence--specific cells in both groups can detect unique antigenic regions of

bacteria and viruses--capacity for selective destruction of viruses and bacteria

– several types of T cells: helper T cell, cytotoxic T cell, suppressor T cell; one main type of

B cell; however, there are a multitude of T and B cells that respond to different antigenic

sequences of different pathogens

Stress-ResponseThe Basic Immune Response:

• the activation of an immune response involves the activation and proliferation of

numerous cell types, a process that requires the synthesis and release of interleukins

and the synthesis of receptors that can respond to the various interleukins

• (see attached pages illustrating basic concept)

Stress-ResponseAcute Stress Response:

• considered adaptive--it allows us to deal with an emergency situation (short-lived)

• metabolic: to increase levels of glucose within the bloodstream

• cardiovascular/respiratory: to increase cardiovascular tone to speed delivery of

mobilized glucose and oxygen to tissues that need it--heart, skeletal muscle and the

nervous system

• analgesia: to decrease the perception of pain

• inhibition of behaviors and processes that might threaten the survival of the

individual:

– inhibition of mating behavior

– inhibition of feeding

– inhibition of gastrointestinal processes

– inhibition of inflammation and the immune system

Stress-ResponseChronic Stress Response:

• considered maladaptive--detrimental affects on the body

• chronic stress can lead to physical disease:

– metabolic changes, increased risk for coronary heart disease, formation of gastric ulcers,

inhibition of growth, immunosuppression

• chronic stress can also affect behavior:

– inhibition of reproduction, development of a state of learned helplessness, drug-seeking

behavior, increased anxiety, impairment in learning and memory

• in addition, chronic stress has been linked to psychiatric illness in humans

– depression

– anxiety

Stress-ResponseChronic Stress Response: Metabolic

• “stress-induced diabetes”

– decreased ability to utilize elevated blood glucose levels--hyperglycemia (elevated levels of

blood glucose) and insulin resistance

– result: fatigue

– result: muscle weakness (loss of protein--atrophy of muscle fibers)

• “stress-induced obesity”

– increasing accumulation of fat as adipose tissue within the intra-abdominal area

– in adipose tissue, glucocorticoids inhibit the fat-releasing effect of insulin and promote the

storage of fat as triglycerides

Stress-ResponseChronic Stress Response: Cardiovascular

• increased risk of coronary heart disease

– chronic hypertension (elevated blood pressure)

– damage to heart muscle

– weakened blood vessels (increased likelihood of stroke)

– deposition of cholesteral and the formation of atherosclerotic plaques

Stress-ResponseChronic Stress Response: Gastrointestinal Tract

• formation of gastric ulcers

– stomach expends considerable energy in building and thickening stomach walls and

secreting mucus--effects that protect the stomach walls from the ulcerative effects of gastric

acids

– prolonged exposure to stress can result in a reduction in the thickening of stomach walls

and in secreting mucus (in addition to the secretion of digestive enzymes)--when stressor

abates, acid secretion may damage the stomach walls before the walls can thicken and

mucus levels can increase

– also, prostaglandins aid in repairing stomach ulcers; glucocorticoids inhibit prostaglandin

synthesis and this may increse the likelihood that gastric ulcers will form

Stress-ResponseChronic Stress Response: Reproduction

• chronic stress can inhibit sex behavior, sexual desire and reproductive physiology

• Ex. stress of social subordination

– a high-ranking female monkey can ensure that she is the only member of her group to

reproduce by physically harassing subordinates into anovulation

– in males, exposure to multiple defeat experiences in social interactions can suppress

testosterone secretion

• mechanism?

– HYPOTHALAMUS: CRH and B-endorphin (released within the brain during stress) can

inhibit release of GnRH

– PITUITARY: glucocorticoids act at the pituitary to decrease responsiveness to GnRH

(fewer receptors); as a result, less LH and FSH will be secreted

– GONAD: glucocorticoids act at the level of the gonad to decrease responsiveness to LH

and FSH (fewer receptors); as a result, lower levels of gonadal steroids will be secreted

Stress-Response

Chronic Stress Response: Growth & Repair

• HYPOTHALAMUS: neurons within the hypothalamus secrete growth hormone

releasing factor (GHRH) and other neurons that secrete somatostatin

• PITUITARY: GHRH stimulates release of growth hormone (GH) from the anterior

pituitary; in contrast, somatostatin acts to inhibit release of growth hormone

• LIVER: growth hormone stimulates the release of somatomedins from the liver

• somatomedins are growth factors that directly stimulate bone and cartilage growth

• chronic stress inhibits secretion of growth hormone due to increased release of

somatostatin

• in children, stress-induced inhibition of GH can impair physical growth:

– “psychosocial dwarfism”--children are half the expected height for their age and secrete

very little GH; this condition is associated with severe emotional stress

Stress-Response

Chronic Stress Response: Growth & Repair

– removal of children from stressful environment is associated with increased secretion of

GH and increased rate of growth

• in adults, chronic elevations in glucocorticoids are associated with a loss of bone

density and an increase in the likelihood for bone fractures

Stress-Response

Chronic Stress Response: Nonspecific & Specific Defense Systems

• chronic exposure to stress can lead to immunosuppression--decreased ability to

defend the body against pathogens

• acutely, glucocorticoids act to inhibit inflammation and to limit proliferation of

nonspecific and specific defense systems during an infection; an effect associated

with decreased synthesis and release of interleukins and decreased synthesis of

interleukin receptors

• chronically, the effects of glucocorticoids are more profound:

– decreased proliferation of nonspecific and specific defense systems in response to an

infectious agent--decreases in NK cells, in cell-mediated immunity and humoral-mediated

immunity

– decreased maturation of developing lymphocyte associated with involution of immune

tissue during chronic stress (e.g., decrease in size of the thymus gland)

Stress-Response

Chronic Stress Response: Nonspecific & Specific Defense Systems

• immunosuppression has been linked to in an increase in disease

– in animals, clear link between chronic stress and cancer; chronic stress can increase the

likelihood that tumors will develop in animals and also speed the growth of tumors

– in humans, some limited evidence suggesting a relationship between life stressors and

increased cancer risk: one episode of major depression can increase cancer risk for decades

afterward (independent of age, diet, smoking and other risk factors)

– however, other studies have not shown a consistent relationship between stress in humans

and the development of cancer; it has been suggested that not all tumors may respond

favorably to stress, and that many of the human studies are limited by requiring either the

sick individual or their families to recall the individual’s history of stressors (retrospective

analyses)

– in humans, though, there is reasonably good evidence that chronic stress can increase the

likelihood of developing the common cold

Stress-Response

Chronic Stress Response: Central Nervous System

chronicstress

dysregulationof

HPA axis

increased levels of CRHpresent within the brain

PVN

other brain areas(e.g., amygdala)

elevated levels ofglucocorticoids basally(also see an increase in size ofadrenal gland--hypertrophy)

Stress-Response

HIPPOCAMPUS

• Hippocampus possesses high levels of receptors for glucocorticoids

• it is important for glucocorticoid negative feedback (limiting HPA axis)

• lesioning the hippocampus will increase activity of HPA axis

• chronic exposure to glucocorticoids leads to damage of neurons within hippocampus (even loss of neurons) and to decreased glucocorticoid negative feedback

• decreased negative feedback leads to dysregulation of HPA axis and increased HPA axis activity

chronic exposure toglucocorticoids

decreased glucocorticoidnegative feedback

damage tohippocampus

increased activityof HPA axis

•increase in CRH in brain•increase in basal glucocorticoids•increase in adrenal gland size

Stress-Response

Chronic Stress Response: Central Nervous System

dysregulationof

HPA axis

drug-seeking behavior

impairment of memory

(damage to hippocampus)

increased anxiety

development of a state of learnedhelplessness (animal model ofdepression)

•increase in CRH in brain•increase in basal glucocorticoids•increase in adrenal gland size

Stress-Response

Chronic Stress Response: Central Nervous System

• chronic stress and HPA axis dysregulation most likely interacts with a number of

neurotransmitter systems in the brain:

– serotonin and norepinephrine--neurotransmitters linked to depression; drugs that increase

the levels of serotonin and/or norepinephrine are used to treat depression

– GABA/benzodiazepines--neurotransmitters linked to anxiety; drugs that increase

GABAergic neurotransmission are used to treat anxiety (or panic attacks)

• most recently, research efforts have focused on developing antagonists to CRH

receptors to treat depression and anxiety

– general idea is that if one can limit HPA axis dysregulation it may be possible to limit

development of depression and anxiety

Stress-Response

Chronic Stress Response:

• Who will develop stress-related diseases?

– Some individuals may be more prone than others!

• How we cope or react to stress may be critical variable!!

– genetic predisposition--brain chemistry, personalities

– previous experiences with stress--early in development or later as adults

– these factors likely interact to influence how we cope with stress or react to stress, and

whether we will develop stress-related disease

Stress-Response

Role of multiple factors on response to stress:

• Ex. relationship between dominant and subordinate monkeys

– in a stable environment (where rank doesn’t change), dominant males have lower resting

levels of glucocorticoids than subordinate males; dominant males are less stressed

– however, in unstable environments, dominant males can have basal levels of

glucocorticoids that are as high if not higher than the levels observed in subordinate males;

dominant males are stress when they are actively fighting for their social rank

– in addition to social rank and stability of the environment, low glucocorticoid levels

mirrored the personality of the dominant male even bettern than rank and stability of the

social environment

– dominant males with specific personality traits have the lowest basal levels of

glucocorticoids than dominant males without these traits

Stress-Response

Role of multiple factors on response to stress:

• Good Personality Traits: (“good state of mind”)

– developed social support groups--formed nonsexual friendships with the opposite sex

– they could differentiate between neutral and threatening social situations, and initiated

fights only when the situations were indeed threatening--predicability and taking control

– when they lost a fight they showed displacement behavior-->they showed aggression

toward an innocent bystander; we might consider exercise (raquetball) as a way to release

tension associated with stress

Stress-Response

Role of multiple factors on response to stress:

• It is possible to see similar effects in humans.

– Ex. Parents of childrn dying of cancer have been shown to hypersecrete glucocorticoids

(clearly a stressful situation). However, some parents secrete much higher levels of

glucocorticoids than others.

– Why? It appears that parents with certain coping strategies had lower levels of

glucocortocoids: 1) religious backgroun, 2) ability to ignore facts of the disease, and 3) an

ability to lose themselves in the details of managing the disease.

– These responses can be viewed in terms of taking control--prayer, reaching out to others

with similar experiences (social support network) and also learning what’s next--

predictability.