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Chp. 6: Neuroendocrinology of the Stress-Response
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What is stress? How do we define stress, stressors and the stress-response.
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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)
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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
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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
What is stress?
Physical
Psychological
no job
promotion
grizzly bear
Negative
injury
(hemorrhaging)
Positive
exercise
physical
abuse
public speaking
meeting a
deadline
Definitions:
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stressor: anything that disrupts the body’s physiological balance
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stress-response: the body’s adaptations designed to re-establish balance
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stress: general state of stressors provoking a stress-response
Stress-Response
Nervous System
Hormones
activation of
the HPA axis
perception
of an
event as
“stressful”
activation of
the ANS
(sympathetic
division)
activation of
additional
pathways
in NS
glucocorticoids
plasma
catecholamines
motor responses
(locomotion)
Fight
or
Flight
Reactions
HPA Axis
Hypothalamo-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)
LIMBIC
SYSTEM
HYPO
CRH Neuron
CRH
ANT
PIT
ACTH
ADRENAL
CORTEX
glucocorticoid
negative
feedback
glucocorticoids
CRH: corticotrophin-releasing hormone
ACTH: adrenocorticotrophin hormone
mobilize
energy
Autonomic Nervous System (ANS)
The ANS consists of two main divisions--the parasympathetic and sympathethic
divisions. These divisions have opposite effects on many physiological processes.
Parasympathetic Division
Sympathetic Division
“vegetative functions”
increased digestion
increased saliva
decreased heart rate
decreased breathing
increased blood flow to gut
“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
restful state
Neurons within the hypothalamus control the activity of neurons in the brainstem
and 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
brainstem
ganglion
target
tissue
hypothalamus
lower
spinal
cord
ACh
ACh
target
tissue
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
IML of
spinal cord
sympathetic
chain of
ganglia
target
tissue
hypothalamus
ACh
NE
E
(bloodstream)
Adrenal
Medulla
Autonomic Nervous System (ANS)
During a stress response, the sympathetic division of the ANS will be activated.
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norepinephrine (NE) will be released at target tissues (e.g., heart)
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epinephrine (E) will be released into the bloodstream to act throughout the body
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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-Response
Acute Stress Response:
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considered adaptive--it allows us to deal with an emergency situation (short-lived)
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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
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chronic stress can also affect behavior: inhibition of reproduction
•
in humans, chronic stress has been linked to psychiatric illness (depression)
Stress-Response
Acute Stress Response:
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metabolic: to increase levels of glucose within the bloodstream
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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
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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-Response
Acute Stress Response: Metabolic
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Purpose: to increase levels of glucose within the bloodstream
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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-Response
Acute Stress Response: Metabolic
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Purpose: to increase levels of glucose within the bloodstream
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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-Response
Acute Stress Response: Cardiovascular/Respiratory
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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
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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-Response
Acute Stress Response: Analgesia
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Purpose: to decrease the perception of pain
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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
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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-Response
Acute Stress Response: Alterations in behavior
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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 brain
inhibits
behaviors
not associated
with stress
activates
behaviors
associated with
increased state
of fear
(anxiety)
inhibition of
mating
inhibition of
feeding
increased
vigilance
(attention)
increased
freezing
increased
behavioral
reactivity
Stress-Response
Acute Stress Response: Gastrointestinal Tract
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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:
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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
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decreased blood flow to the GI tract
•
increased defecation (imbalance between parasympathetic and sympathetic control)
Stress-Response
Acute Stress Response: Nonspecific & Specific Defense Mechanisms
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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-Response
Acute Stress Response: Nonspecific & Specific Defense Mechanisms
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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 cellmediated immunity
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immune system activates the HPA axis which acts to inhibit the immune system
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why?
– adaptive significance: may protect the body from becoming too active and possibly
attacking self (autoimmune disease)
Stress-Response
Background--Defense against pathogens
The body has two systems to defend against pathogens, or infectious agents:
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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-Response
Background--Defense against pathogens
The body has two systems to defend against pathogens, or infectious agents:
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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-Response
The Basic Immune Response:
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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
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(see attached pages illustrating basic concept)
Stress-Response
Acute 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-Response
Chronic 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-Response
Chronic Stress Response: Metabolic
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“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-Response
Chronic Stress Response: Cardiovascular
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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-Response
Chronic Stress Response: Gastrointestinal Tract
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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-Response
Chronic Stress Response: Reproduction
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chronic stress can inhibit sex behavior, sexual desire and reproductive physiology
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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
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HYPOTHALAMUS: neurons within the hypothalamus secrete growth hormone
releasing factor (GHRH) and other neurons that secrete somatostatin
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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
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somatomedins are growth factors that directly stimulate bone and cartilage growth
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chronic stress inhibits secretion of growth hormone due to increased release of
somatostatin
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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
increased levels of CRH
present within the brain
chronic
stress
dysregulation
of
HPA axis
PVN
other brain areas
(e.g., amygdala)
elevated levels of
glucocorticoids basally
(also see an increase in size of
adrenal gland--hypertrophy)
Stress-Response
chronic exposure to
glucocorticoids
damage to
hippocampus
decreased glucocorticoid
negative feedback
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
increased activity
of HPA axis
•increase in CRH in brain
•increase in basal glucocorticoids
•increase in adrenal gland size
Stress-Response
Chronic Stress Response: Central Nervous System
drug-seeking behavior
dysregulation
of
HPA axis
impairment of memory
(damage to hippocampus)
increased anxiety
•increase in CRH in brain
•increase in basal glucocorticoids
•increase in adrenal gland size
development of a state of learned
helplessness (animal model of
depression)
Stress-Response
Chronic Stress Response: Central Nervous System
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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.