Chp. 6: Neuroendocrinology of the Stress-Response

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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--gtsecretes
  glucocorticoids
• activation of the ANS--gtsecretes 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!!

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Stress-Response
What is stress?
Physical
Psychological
no job promotion
grizzly bear
Negative
injury (hemorrhaging)
physical abuse
public speaking
meeting a deadline
exercise
Positive

• Definitions
• stressor anything that disrupts the bodys
  physiological balance
• stress-response the bodys adaptations designed
  to re-establish balance
• stress general state of stressors provoking a
  stress-response

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Stress-Response
Nervous System
Hormones
activation of the HPA axis
glucocorticoids
activation of the ANS (sympathetic division)
Fight or Flight Reactions
perception of an event as stressful
plasma catecholamines
activation of additional pathways in NS
motor responses (locomotion)
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HPA Axis
LIMBIC SYSTEM

• 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)

HYPO
CRH Neuron
CRH
ANT PIT
glucocorticoid negative feedback
ACTH
ADRENAL CORTEX
glucocorticoids
mobilize energy
CRH corticotrophin-releasing hormone ACTH
adrenocorticotrophin hormone
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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
• 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
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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
ganglion
brainstem
target tissue
hypothalamus
ACh
lower spinal cord
ACh
target tissue
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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 chain of ganglia
Sympathetic Division
IML of spinal cord
target tissue
hypothalamus
ACh
NE
E
(bloodstream)
Adrenal Medulla
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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)

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Stress-Response

• Acute 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)

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Stress-Response

• Acute 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

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Stress-Response

• Acute 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.

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Stress-Response

• Acute 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

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Stress-Response

• Acute 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

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Stress-Response

• Acute 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
  zebras 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 its 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

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Stress-Response

• Acute 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

activates behaviors associated with increased
state of fear (anxiety)
CRH release in brain
increased vigilance (attention)
increased freezing
inhibition of mating
inhibits behaviors not associated with stress
increased behavioral reactivity
inhibition of feeding
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Stress-Response

• Acute 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)

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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)

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Stress-Response

• Acute 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)

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Stress-Response

• Background--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)

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Stress-Response

• Background--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

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Stress-Response

• The 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)

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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

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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

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Stress-Response

• Chronic 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

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Stress-Response

• Chronic 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

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Stress-Response

• Chronic 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

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Stress-Response

• Chronic 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

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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

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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

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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)

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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
  individuals 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

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Stress-Response

• Chronic Stress Response Central Nervous System

increased levels of CRH present within the brain
PVN
dysregulation of HPA axis
chronic stress
other brain areas (e.g., amygdala)
elevated levels of glucocorticoids basally (also
see an increase in size of adrenal
gland--hypertrophy)
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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 to glucocorticoids
damage to hippocampus
decreased glucocorticoid negative feedback
increased activity of HPA axis

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

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Stress-Response

• Chronic Stress Response Central Nervous System

drug-seeking behavior
impairment of memory
dysregulation of HPA axis
(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)
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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

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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

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Stress-Response

• Role of multiple factors on response to stress
• Ex. relationship between dominant and
  subordinate monkeys
• in a stable environment (where rank doesnt
  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

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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--gtthey showed aggression toward an
  innocent bystander we might consider exercise
  (raquetball) as a way to release tension
  associated with stress

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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 whats next--predictability.

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