Understanding the stress response Hormonal response to stress The two-waves response Concentrating on Glucocorticoids (GCs) GCs into the brain Mood and depression Reproduction

1. Stress and adaptation
Prof. Ferran Suay
Universitat de València
1.Understanding the stress response
2.Hormonal response to stress
1. The two-waves response
2.Concentrating on Glucocorticoids (GCs)
3.GCs into the brain
1. Mood and depression
2.Reproduction
Please, write down...
1. Your own definition of stress
2. The 3 main characteristics of stress
3. The most stressful situation you've experienced ever
4. The 3 clearest signs of stress you can see in other
people
5. The most intriguing (for you) aspect of stress
1. Intro: Evolutionary Perspective
• Life is challenging: competition, survival, environmental
changes...
• Perturbations of homeostasis➔ energy expenditure to
restore steady state.
• Energy for
• Cellular metabolism
• Growth
• Immune function
• Reproduction
• Thermogenesis
• Movement

2. Cardiac deaths in and around Los Angeles, California What is Stress?
Stressor is “anything that throws your body out of
homeostatic balance” (1994)
STRESS IN THE ANIMAL KINGDOM: WHAT WE CAN LEARN (ROBERT
SAPOLSKY) 8 MIN
http://www.youtube.com/watch?v=Z-3qqJhSetc
Intro: The Stress Response
Physiological and behavioral
reactions that help to
reestablish homeostasis.
Nonspecific = different stressors ➔ same response
Three-part definition (Kim & Diamond 2002)
1.Condition in which individuals
are aroused by aversive stimuli
2.Individuals must perceive the
event as aversive (threatening)
3.Control and predictibility

3. Limitations to the homeostatic concept
1. Psychological stressors elicit full
physiological responses that cause (and
not restore) homeostasis.
2. Individual differences in perception of
stressors are not explained.
3. Activation of SNS and HPA may also be
produced by pleasurable events
Allostasis
The process of achieving homeostasis, through
physiological or behavioral change.
Carried out by means of alteration in HPA axis
hormones, ANS, cytokines, or other systems
Generally adaptive in the short term.
Essential to maintain internal viability amid changing
conditions
Allostatic load
• = cumulative cost incurred during allostasis.
Chronic stressors➔ allostatic overload
Stressors
• Sources of stressors:
• Environment: temperature changes, noise....
• Physiological: lack of aliment, water...
• Psychosocial: conflict, lack of control,
novelty...

4. 2. The hormonal response to stress
14
Stress triggers two complementary
pathways
!
• HPA axis
• SNS
• Individual differences (i.e.:
attitude) affect the magnitude of
the stress response
Neuroendocrine response

5. Two-waves stress response
1st Wave 2nd Wave
Gonadal Steroids
FIRST WAVE (SECONDS)
Catechol Adrenal Medulla Release
CRH Hypothal Release
(+10”) ACTH Pituitary Release
GnRH Pituitary Decrease
PRL + GH (primates) Pituitary Release
Glucagon Pancreas Release
AVP Pituitary massive secretion
only if
haemorrhageRenin Kidney
SECOND WAVE (MINUTES)
GCs Adrenal Cortex Release
Sex Steroids Gonads Decrease
Timing of the stress responses
Seconds to a few minutes
✓Diversion of energy to exercising muscle
✓ Mobilization of stored energy
✓ Inhibition of subsequent storage
✓ Gluconeogenesis
✓Enhanced substrate delivery to muscle (via ↑ cardiovascular tone)
✓Stimulation of Immune function
✓Inhibition of reproductive physiology and behavior
✓Decreased feeding and appetite
✓Sharpened cognition and ↑ cerebral perfusion rates and ↑
glucose utilization.
20

6. Catecholamine concentrations peaked on the day of a PhD exam
Fight or Fight Response Degree of Control
Blood hormone concentrations are altered by the stress of parachute jumps
Focusing on Glucocorticoids
•EPI does not cross BBB
•Stress must affect behavior through
brain effects
•Glucocorticoids
• Respond to many stressors
• Easily pass the BBB
• Find receptors in many brain
areas
Adaptive effects of the stress response
• ↑ energy availability
• ↑ oxygen intake
• ↓ blood flow to organs not involved in movement
• ↓ pain perception
• Inhibition of costly processes not involved in
immediate survival
• Enhanced senses and memory

7. 3. Physiological effects of the stress response: GLUCOCORTICOIDS
• Released within minutes
• Affect behavioral stress responses via nongenomic
pathways
• Mediate long-term effects of stressors via genomic
pathways
• During acute stress response:
• Some components of Immune function are supressed
• Others (sending immune cells to skin) are enhanced
Glucocorticoid (GC) actions
MODULATING PREPARATIVE
Alter response to stressor • A f f e c t r e s p o n s e t o
subsequent stressors
1. PERMISSIVE • Aid adaptation to chronic
stressors
2. SUPRESSIVE
3. STIMULATING
MODULATING ACTIONS OF GCs
PERMISSIVE SUPRESSIVE STIMULATING
GCs present before
the stressor
Depend on stress-
induced GCs’ increase
Depend on stress-
induced GCs’ increase
Prime defense
mechanisms
Onset 1 hour after
stressor (aprox)
Onset 1 hour after
stressor (aprox)
Prevent defense reactions
from overshooting
Counteract supressive
actions
PREPARATIVE ACTIONS OF GCs
• Do not affect immediate response
• Modulate response to future stressors
• Can be mediating or supressive

8. Acute stress can improve immune function
3. GCs into the brain
HYPOTHALAMIC CRH
• Receptors in
• Hypothalamus ➔ HPA axis regulation
• Amygdala ➔ anxiety responses
• Two receptor types mediate different aspects of the stress
response
• CRH-R1: involved in negative feedback, anxiety (knockout mice
less anxious) and mediation of hormonal, behavioral and
nociceptive responses to stress
• CRH-R2: anorexigenic effects of stress (activation supresses food
intake)
ENDOCANNABINOIDS
• Mediate effects of GCC on stress responses via synaptic
mechansims.
• Inhibit GABA secretion ➔ disinhibit NE secretion
• Affects food intake, emotion, energy balance, pain responsivity
and sexual behavior (“mellowing effects”)

9. PITUITARY HORMONES
•Other than ACTH: vasopressin (ADH); PRL; endorphins;
enkephalins
POMC
GLUCOCORTICOID RECEPTORS
• Hippocamus: 2 types of
receptors
• Type-I: MRs (mineralocorticoid)
• Higher affinity
• Baseline levels
• Homeostatic balance
Type-II: GRS (glucocorticoid)
• Lower affinity
• Provide negative feedback for high circulating levels
during stress
MOOD AND DEPRESSION
Inverted U-shaped relationship between Cortisol and mood

10. Cortisol and depression
• Impaired HPA axis negative
feedback
!
• [C] peacking 3-4 hours after
sleep onset and going down
during day time.
!
!
• Probable mechanism:
Down-regulation of GR
receptors in Hippocampus
Cortisol and depression
• Excessive [C] in 50% patients
• Hyperglycemic C !➔ Hypoglycemic
Insulin
• Depressed patients: Insulin test
- Blood glucose supression induced
by high doses of Insulin cannot be
restored by C
Failure of HPA axis negative feedback system
• Inappropriate response to DXMT ➔ Failure of neural
inhibiting mechanism for ACTH and C
• (5HT system and HPA axis) responsible for hypercortisolism
1. High basal [C]
2. DXMT failure to supress C
production
3. High [CRH] in CSF
4. Blunted ACTH response to CRH
5. Disturbed circadian C pattern
CSF= Cerebrospinal Fluid
Complementary hypothesis: Hormonal action of antidepressant drugs (Barden et al. 1994)
• AD drugs would stimulate genic expression of hippocampal GR
receptors
↑ sensitivity to inhibitory feedback signals from GCC
↓ HPA axis activity
(↓CRH- neurons expression )

11. 1.Reproduction
Reproductive disfunction
• Stress inhibits T production
• Low [T]➔ ↓ sexual drive
and performance
• GCC inhibit reproduction by:
• Suppressing GnRH and LH
• Inhibiting protein formation
needed for hormone receptors
• Inhibiting T secretion
• Suppressing spermatogenesis
•Stress disrupts estrous cycles
(i.e. human amenorrhea)
•Women with functional HPT
amenorrhea display high [C]
•Severe stress can interrupt
pregnancy or lactation
•High [C] affect size and
viablity of the litter (hares)
•Same GnRH, FSH and LH
impairments as in males
PITUITARY HORMONES: Prolactin
PRL supresses reproduction
Makes Leydig cells less responsive to LH
Enhances negative feedback from T
Low PRL levels
facilitate
T production
Estradiol
T
LH, FSH
GnRH
Target
tissues
Cortisol
ACTH
CRH
EXCITING
β-
endorphins
INHIBITING
HPA & HP-Gonadal Axis

12. Physical exercise
• [T]: sedentary < active > overtrained
(highly active)
Physical exercise
• Hypercortisolemia very common in runners
• Dysmenorrhea and amenorrhea prevalent in
some sports specialities
• Higher [β-endorphin] in trained women
• Fasting ➔ ↑ [C] = stressor
• Stress disrupts estrous cycles by metabolic
pathways