Transcript BrainStress2001

STRESS,
GLUCOCORTICOIDS, AND
YOUR BRAIN
Stress Hormones:
Glucocorticoids
• Cortisol in the human
• Corticosterone in the rat
• Secreted by the cortex of the adrenal gland
Landfield et al.(1979,1981)
• Basal (resting) levels of glucocorticoids (GCs) rise
with age in rats
• The greater the basal level of GCs in old rats, the
greater the cell loss in the hippocampus
Landfield et al.- cont.
Middle Aged rats (12 months)
Removed the adrenal glands (Adx)
Replacement injections of GCs
(low concentration for life -1.0 yr)
Two years old
No cell loss in
hippocampus
Landfield et al. - results
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5
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2
Aged (1
yr),
Adx+GCs
0
Aged (2 yr)
1
Young
mature
No. of hippo.
neurons
per 100 sq.
microns of
tissue
Sapolsky et al. (1985 ff.)
• Young rats (3-5 months)
• Daily injections of stress levels of GCs
- Two weeks (acute)
or
- Three months (chronic)
RESULTS
- acute treatment
No hippocampal cell loss
- chronic treatment
significant hippocampal
cell loss*
What natural conditions
contribute to increased
glucocorticoid levels?
Sapolsky et al. (1989)
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Field studies - male baboons in Kenya
Measured basal levels of GCs (cortisol) - 6 years
determined social dominance rank
RESULTS:
- lowest ranking males subjected to unpredictable
stress
- lowest ranking males have highest GC levels*
Uno et al.(1989). Hippocampal
Damage Associated with
Prolonged and Fatal Stress in
Primates.
Uno et al. (1989)
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Observations under natural conditions
Eight vervet monkeys
Agricultural pests
primate center in Kenya
All died suddenly over two year period
Control group (n=5) of euthanized animals from the
center
• Autopsies upon death
• RESULTS:
- all eight from sudden death group had gastric ulcers
Uno et al. (1989) - cont.
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Enlarged adrenal gland cortex in each SD monkey
Enhanced numbers of bite scars on SD monkeys
Shrunken cells in hippocampus of all SD monkeys
Reduced numbers of cells in various cell layers of
the hippocanpus of males*
- pyramidal neurons in areas CA1, CA3, CA4
Conclude:
- SD animals subjected to prolonged stress
- Prolonged stress
increased GC secretion
- Increased GC secretion
hippocampal damage
Sapolsky et al. (1990) Hippocampal Damage
Associated with Prolonged
Glucocorticoid Exposure in
Primates
Sapolsky et al. (1990)
• Four vervet monkeys
• Cortisol pellets implanted into hippo. on one side
• Cholesterol(control) pellet into hippo. on other side
• One year later
examine hippo. for pathology
RESULTS:
- soma shrinkage on cortisol side*
- dendritic atrophy on cortisol side
Summary
• GC basal levels increase with age in rats
• GCs can cause hippocampal pathology in
rats and primates
How do glucocorticoids
damage hippocampal neurons?
• They endanger neurons by increasing their
vulnerability to metabolic insults
• Metabolic insults
Energy
- hypoglycemia
Depletion
- hypoxia-ischemia
• GCs inhibit glucose transport
Additional Energy
into hippocampal neurons
Depletion
Cell Death
What role does stress play in
hippocampal cell damage
during metabolic insults?
Stein-Behrens et al.(1994).
Stress Exacerbates Cell Loss in
the Hippocampus.
Stein-Behrens et al. (1994)
• Metabolic insult
Kainic acid
• Kainic acid
Glutamic acid agonist
• Kainic acid
excites neurons
depletes energy
EXPERIMENT 1:
• Five groups of ADX rats
1. 100% GCs
2. 60% GCs
3. 15% GCs
Replacement injections for
4. 0% GCs
3 days
5. Stress GC level
Stein-Behrens et al. – cont.
• Inject Kainic acid into the hippocampus
• Euthanize 3 hours later
• Examine neuron damage in the
hippocampus
• RESULTS:
- Increasing amounts of neuron damage with
increasing doses of GCs*
Will stress exacerbate
hippocampal damage produced
by Kainic acid?
Stein-Behrens et al. – cont.
EXPERIMENT 2:
• Normal rats, no ADX
• Subject to three days of different stressors (cold,
restraint, mix social grps.)
High levels of GCs
• Inject Kainic acid into the hippocampus
• Euthanize three hours later
• Examine neuron damage in the hippocampus
RESULTS:
- Stress exacerbated kainic acid damage*
What is the behavioral
significance of increased levels
of GCs?
• REMEMBER: Landfield’s results
- AGED RATS
HIGH GC LEVELS
- AGED RATS
HIPPO. CELL LOSS
• Hippocampal damage
Memory deficits
Do aged rats with high
glucocorticoid levels show
hippocampal pathology and
memory impairments?
Issa et al. (1990).
Hypothalamic-pituitaryadrenal activity in aged,
cognitively impaired and
cognitively unimpaired rats
Issa et al. (1990)
• Aged rats: 23-27 mos.
• Young controls: 6-7 mos.
• Behavioral screening in Morris Water maze
1. N=58 old rats
2. N=28 young rats
• Hippocampal cell counts
• Basal and stress-induced GC levels
• GC binding in hippocampus
Issa et al.(1990) - cont.
• RESULTS:
Behavioral screening*:
Started with 58 old rats
1. 16 (28%) = aged impaired
2. 20 (34%) = aged unimpaired
3. 22 (38%) = in between and excluded
Young control rats
Hippocampal cell counts:
Control > aged unimpaired > aged impaired*
Issa et al.- cont.
• Basal and stress GC levels*:
- basal: Aged impaired secrete higher levels
than aged unimpaired or young rats
- stress: Aged impaired secrete higher levels
than aged unimpaired or young rats
• GC binding in hippocampus*: Aged impaired
rats show less binding than other two groups
What are the implications of
this research for humans?
Non-elderly human populations with high GC levels
- Depressed patients
- Cushing’s syndrome
Elderly humans – some have high cortisol levels
Sheline et al. (1996, 1999).
Hippocampal atrophy in
recurrent major depression.
Sheline et al.
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Magnetic resonance imaging (MRI)
Humans with a prolonged history of depression
Image taken while patients were no longer depressed
RESULTS:
- Left and right hippocampus reduced in volume
compared to control group*
- The longer the time depressed, the less the
hippocampal volume*
Starkman et al. (1992).
Hippocampal formation
volume, memory dysfunction,
and cortisol levels in patients
with Cushing’s syndrome.
Starkman et al.(1992)
• Magnetic resonance imaging
• Memory tests
• Cortisol levels
RESULTS:
• The greater the cortisol level, the less the
hippocampal volume*
• Cushing’s syndrome patients demonstrate memory
impairments
- the less the hippocampal volume, the
greater the memory impairment
Lupien et al. (1998). Cortisol
levels during human aging
predict hippocampal atrophy
and memory deficits.
Lupien et al. (1998)
• Measured cortisol levels in the elderly for 5-6 years
• Two groups:
1. increasing/high levels of cortisol
2. decreasing/moderate levels of cortisol
• Memory test:
- line drawings
- immediate and delayed (24 hr.) recall
Lupien et al.-cont.
• RESULTS:
- increasing/high group
- increasing/high group
delayed memory deficit
decreased hippo.volume
Post Traumatic Stress Disorder
(PTSD)
• Combat veterans, victims of rape, childhood sexual
abuse, accidents, violent crimes
• Symptoms:
- flashbacks
- nightmares
- sleep disorders
- emotional disorders
- enhanced startle reflex
- disorders of memory and concentration
Bremner et al. (1995). MRIbased measurement of
hippocampal volume in
patients with combat-related
posttraumatic stress disorder
Bremner et al.(1995)
• Subjects:
- 26 Vietnam combat veterans with diagnosed
PTSD
- 22 matched controls (age, handedness, sex, race,
age, weight, height, SES, yrs. education, alcohol
abuse)
• MRI
• Assessed verbal memory (Wechsler Memory
Scale)
Bremner et al.(1995)
• RESULTS:
- Right hippocampal volume is reduced by 8% in
PTSDs*
- Reduction selective to the hippocampus
- PTSDs demonstrated memory impairments
- The less the volume of the right hippocampus,
the worse the memory
Bremner et al.(1997). Magnetic
resonance imaging-based
measurement of hippocampal
volume in postraumatic stress
disorder related to childhood
physical and sexual abuse – a
preliminary study
Bremner et al.(1997)
• 17 adult survivors of severe childhood physical/sexual
abuse diagnosed with PTSD
• 17 matched controls
• MRI
• Assessed verbal memory
RESULTS:
- Left hippocampal volume is reduced by 12% in PTSDs
- Reduction is selective to the hippocampus
- Impaired verbal memory
- The longer the history of abuse, the less the
hippocampal volume
Important Question
What brain circuits are activated by stress to
cause secretion of cortisol?
Fear of the bear (acute stress)
Activates the amygdala
Activates the hypothalamus
(Paraventricular nucleus)
Releases CRF into the anterior lobe of the pituitary gland
Releases ACTH
Adrenal gland
glucocorticoids
Amygdala
CRF - containing neurons
Hypothalamus
(paraventricular nucleus)
CRF - containing neurons
Pituitary Gland