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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No. of hippo.neuronsper 100 sq.microns oftissue
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)
• 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)
• 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.• 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, CA4Conclude: - 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
- hypoglycemia
- hypoxia-ischemia
• GCs inhibit glucose transport
into hippocampal neurons
Cell Death
Energy Depletion
Additional Energy Depletion
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.)
• Inject Kainic acid into the hippocampus
• Euthanize three hours later
• Examine neuron damage in the hippocampus
RESULTS:
- Stress exacerbated kainic acid damage*
High levels of GCs
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-pituitary-adrenal 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.
• 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 levelsRESULTS:• 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 delayed memory deficit
- increasing/high group 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). MRI-based 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