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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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=19 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 sustained stress to cause hypersecretion of cortisol?

Fear of the bear

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