Transcript 5104_b3

The General Adaptation Syndrome
Figure 18.21
Flow-sheet of Stress
Response
“INPUT”
“Cortex”
“OUTPUT”
Hypo
“Stressors”:
temperature
sounds
images
smells
tastes
pressure
O2/CO2
sexual
PNS
Pit
Adrenals
PNS
“Motor Targets”
heart
blood vessels
lungs
adrenal glands
sweat glands
kidneys
tissue enzymes
others
Allostasis: achieving stability through change.
Coping with stress, habituation
15.17 Autonomic Activation during a Stress Situation (Part 1)
15.17 Autonomic Activation during a Stress Situation (Part 3)
Triad of systems mediate response to stress
Stimulation of the HPA-axis by cytokines
Consequences of persistant stress and allostatic load:
negative cortisol feedback dwindles (receptor downregulation?) +
a subpopulation of CRF secreting cells begin to synthesize and secrete
vasopressin as a co-existing releasing factor
Control of ACTH secretion:
- regulated by hypothalamic neurons secreting two releasing factors: CRH-41
(corticotropin releasing hormone) ± AVP (arginine vasopressin).
- various pathways utilizing different transmitters (5-HT, serotonin; NA,
noradrenaline; NO, nitric oxide) provide excitatory inputs that define the
magnitude of the CRH /AVP neuronal response, thus the quantity of peptides
delivered into the pituitary portal plexus
Stress (immobilization) up-regulates vasopressin synthesizing genes in
a population of hypothalamic CRF-synthesizing neurons, and increases
AVP in CRF immunoreactive terminals in the median eminence
from Bartanusz et al., Endocrinology 132: 895-902, 1993.
Summary: Chronic stress changes induced
in the hypothalamic CRF system
• Prolonged exposure of the hippocampus to elevated cortisol
levels impairs inhibitory feedback to CRF cells
• Add: reductions in the impact of negative cortisol feedback, so
CRF cells more active → more drive on HPA axis
• Add: re-activation of vasopressin genes in a subpopulation of
CRF cells, so they now produce two (stimulatory) peptides for
secretion into the portal plexus
• Add: upregulation of vasopressin V1b type receptors in
anterior pituitary corticotrophs (double whammy → more
ACTH→more drive on HPA axis)
• Add: additional drive to PVN from other sites e.g.amygdala
Cushing’s Syndrome
Cushing’s Syndrome
DN Orth, NEJM 332:791-803, 1995
Figure 1. Physiologic and Pathophysiologic Features of the Hypothalamic–
Pituitary–Adrenal Axis in Normal Subjects and Patients with Cushing's
Syndrome (Top Panels) and the Effect of Dexamethasone (Bottom
Panels).
Stimulation of the hypothalamus by other central nervous system centers,
such as the locus caeruleus, regulates the secretion of CRH; corticotropin
stimulates adrenal secretion of cortisol; and cortisol inhibits the secretion of
both CRH and corticotropin. Adrenal (i.e., corticotropin-independent)
Cushing's syndrome is caused by adrenal tumors and corticotropinindependent bilateral micronodular and macronodular adrenal hyperplasia.
Low doses of dexamethasone are shown by thin blue arrows, and high
doses by thick blue arrows. Normal hormone secretion is shown by thin
purple lines, suppressed secretion by dotted purple lines, and
hypersecretion by thick purple lines.
Neuron, Vol. 20, 1093–1102, June, 1998, Copyright ã1998 by Cell Press
Corticotropin Releasing Factor Receptor 1–Deficient
Mice Display Decreased Anxiety, Impaired Stress
Response, and Aberrant Neuroendocrine Development
Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to
stress. Two biochemically and pharmacologically distinct CRF receptor subtypes
(CRFR1 and CRFR2) have been described. We have generated mice null for the
CRFR1 gene to elucidate the specific developmental and physiological roles of CRF
receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1
displayed markedly reduced anxiety. Mutant mice also failed to exhibit the
characteristic hormonal response to stress due to a disruption of the hypothalamicpituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing
heterozygotes displayed low plasma corticosterone concentrations resulting from a
marked agenesis of the zona fasciculata region of the adrenal gland. The offspring
from homozygote crosses died within 48 hr after birth due to a pronounced lung
dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient
adrenocorticotropic hormone (ACTH) production during the neonatal period and was
rescued by ACTH replacement. These results suggest that CRFR1 plays an important
role both in the development of a functional HPA axis and in mediating behavioral
changes associated with anxiety.