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

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

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...

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

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

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

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

Acute stress can improve immune function

3 . G C s i n t o t h e b r a i n

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”)

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

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 )

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

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