Fermat's Library | Why Stress Is Bad for Your Brain annotated/explained version.

#### TL;DR > ***"But if you get chronically, psychosocially stre...

Robert M. Sapolsky is an American neuroendocrinology researcher and...

Here is a great lecture by Robert Sapolsky recorded on September 22...

A long period of exposure to stress is long: - 1000 days = 2.7 yea...

### Glucocorticoids Glucocorticoids are a type of corticosteroid...

Alternatively, there is some evidence suggesting the atrophy is not...

> ***They have found significant reductions in the volume of both h...

More literature on this topic: - Here is a Review Article publis...

Do methods exist to reduce GC secretion? Would they hinder ability ...

Why

Stress Is

Bad

for Your

Brain

Robert

Sapolsky

Sustained stress can have numerous ~ath-

ologic effects. Among the molecules that

mediate such effects are the adrenal steroid

hormones, including the human glucocorti-

coid (GC) hydrocortisone. Along with epi-

nephrine (adrenaline) and norepinephrine,

GCs are essential for surviving acute physical

stress (evading a predator, for example) but

they may cause adverse effects when secre-

tion is sustained, such as when waiting to

hear about a grant renewal

Excessive exDosure to GCs has adverse

effects in the rodent brain, particularly in the

hippocampus, a structure vital to learning and

memory and possessing high concentrations

of receDtors for GCs

(2).

A few davs of stress

or GC overexposure "endangers" hippocam-

pal neurons, compromising their ability to sur-

vive seizures or ischemia; as the likely under-

pinning of this, the steroids worsen the poor

regulation of glutamate and calcium that oc-

curs during such neurologic insults. Over the

course of weeks, excess GC reversibly causes

atrophy of hippocampal dendrites, whereas

GC overexvosure for months can cause ver-

manent loss of hippocampal neurons. Al-

though a few studies suggest that similar ef-

fects occur in the brains of primates

(3),

there

has been virtually no evidence for GC-in-

duced damage in the human. Some new, ex-

citing studies present the first such evidence.

A first example, recently published by

Sheline and colleagues at Washington Uni-

versity School of Medicine, concerns major

depression

(4).

Approximately half of depres-

sive patients studied secrete abnormally high

amounts of GCs. Although investigators had

searched with magnetic resonance imaging

(MRI) for hippocampal atrophy in depres-

sives, these studies could not distineuish the

hippocampus from neighboring structures or

used geriatric de~ressives with brain-wide

atropgy from an ;nay of diseases. The au-

thors of the new studv reDort MRIs with far

more resolution than in previous studies and

have excluded individuals with neurologic,

metabolic, or endocrine diseases. They have

found significant reductions in the volume

of both hippocampi (12% in the right and

15% in the left) when comparing individuals

with a history of depression to age-, educa-

tion-, gender-, and height-matched controls.

No change in overall brain volume was ob-

sewed. The individuals studied had been

The author is in the Department of Biological Sciences,

Stanford University, Stanford, CA

94305,

USA.

de~ression-free for months or decades and. at

thi time of the study, had normal GC con-

centrations. The investieators ruled out sev-

era1 confounding variables: alcohol or sub-

stance abuse, electroconvulsive therapy, and

current use of antidepressants. Remarkably,

there was a significant correlation between

the duration of the depression and the ex-

tent of atrophy (see figure, top panel).

A similar relation is seen in patients with

Cushing's syndrome: GCs are overproduced

as a result of a hypothalamic, pituitary, adre-

nal, or pulmonary tumor, and there is bilat-

eral hippocampal atrophy

(5).

Unfortunately,

for control values the authors of

this

study

had to relv on com~arisons with ~ublished

data from MRI scans. However, as an impres-

sive internal control, among the Cushing-

oid individuals, the extent of GC hyperse-

cretion correlated with the extent of hippo-

campal atrophy (which also correlated

with

the extent of impairment in hippocampal-de-

pendent cognition) (see figure, middle panel).

No atrophy occurred in the caudate nucleus,

a brain region with few GC receptors

(6).

Additional evidence of the relation be-

tween GCs and hippocampal function has

emerged from studies of individuals with

posttraumatic stress disorder (PTSD). In

Vietnam combat veterans with PTSD,

Bremner and colleagues found

significant

atrophy of the right hippocampus (and

near significant atrophy of the left)

(7).

In a

study in

Biological Psychiany

(in press),

Guwits, Pitman, and colleagues also exam-

ined Vietnam veterans with PTSD and found

significant 22 and 26% reductions in volumes

of the right and left hippocampi, respectively

(8).

Finally, in another study, also in press in

Biological Psychiatry,

Bremner

al.

found a

12% atrophy of the left hippocampus in

adults with PTSD associated with childhood

abuse (with near significant atrophy in the

right hippocampus)

(9).

The studies con-

trolled for age, gender, education, and alco-

hol abuse-and the Bremner studie-ruled

out depression as a confounding variable as

well. There is some uncertainty

to the ana-

tomical specificity of the effect. In the studies

by Bremner, the results were only presented

as absolute hippocampal volume, and there

were nearly as large (but nonsignificant) re-

ductions in volumes of the amygdala, cau-

date nucleus, and temporal lobe. However,

the study by Guwits

al.

showed hippocam-

pal atrophy after correction for whole-brain

volume, with no atrophy in the amygdala.

ndrome

brain atrophy? Fielati& between hippocampal

volume and (top) duration of depression among

individuals with a history of major depression

[from

(41,

(mlddle) extent of cortisol hypersecre-

tion among Cushingoid patients [adapted from

(5)], and (bottom) duration of combat exposure

among veterans with or without a history of post-

traumatic stress disorder [from (a]. Cortisol is

another term for the human

hydrocortisone.

It is not clear whether the atrophy is asso-

ciated with trauma (combat or abuse) or with

succumbing to PTSD (which occurs in

20% of such traumatized individuals). In the

Gurvits study, control groups consisted of

healthy volunteers (matched for age, educa-

tion, and other characteristics) and matched

veterans with a history of combat exposure

but no PTSD. In the combat veterans, both

with and without PTSD, longer durations of

combat were associated with smaller hippo-

campi (see figure, bottom panel). However,

because the PTSD patients sustained longer

combat exposure than did the controls who

had experienced combat but did not have

PTSD, it was impossible to dissociate combat

from PTSD as a predictor of atrophy. In con-

trast, in the Bremner combat study (in which

there was no non-PTSD combat control

group), combat duration did not predict ex-

tent

atrophy. Finally,

the childhood abuse

study (in which there were no non-PTSD

childhood abuse controls), it was not pos-

SCIENCE

VOL.

273

AUGUST

1996

sible to dissociate the PTSD from the trauma.

Each of these studies has some weak-

nesses, but they are countered by comple-

mentary strengths in the other studies.

Are

GCs the damaging agents? Depres-

sion is accompanied by numerous physio-

logical abnormalities, and it has not been

demonstrated that the hippocampal atrophy

occurs only among depressives who overpro-

duce

GCs. Moreover, among individuals with

PTSD, there is no information as to the ex-

tent of the

stress response during the

trauma (or what additional physiological

changes occur then). Thus, in these cases, it

is not clear whether

GCs mediate the atro-

phy. However, as noted, the defining abnor-

mality in Cushing syndrome is GC excess,

making it a likely culprit in causing atrophy.

How persistent are the changes? Although

the Cushingoid atrophy reverses with correc-

tion of the endocrine abnormality

(6), in the

PTSD and depression studies, the atrophy

occurred months to years after the trauma or

the last depressive episode, and at a time

when patients did not hypersecrete

GCs.

Thus, these long-standing changes could con-

ceivably represent irreversible neuron loss.

The PTSD and depression studies present

a problem of causality. Given the cognitive

role of the hippocampus, a smaller hippo-

campus might be more likely to lead to being

assigned frontline combat duty rather than

a skilled task at headquarters. Furthermore,

eiven the evidence of

de~ression as a disorder

of "learned helplessness," a smaller hippo-

campus might predispose toward depression

(that is, less cognitive capacity to detect effi-

cacious coping responses and thus greater

vulnerability to learned helplessness). Final-

ly, PTSD individuals, before joining the mili-

tary, had high rates of learning disorders

and delayed developmental landmarks that

could reflect cerebral atrophy (10). Thus, a

small hippocampus could be a cause, rather

than a consequence, of the trauma or

stressor

in these studies. However. there is no ~lau-

sible way in which a small hippocampus' pre-

disposes one toward the pituitary or adrenal

abnormalities of the Cushingoid patients, or

toward being a victim of childhood abuse.

Should this literature ultimatelv show

that sustained stress or GC excess

can dam-

age the human hippocampus, the implica-

tions are considerable. It would then become

STATs Find That Hanging Together

Can Be Stimulating

Stewart Leung, Xiaoxia Li, George

Stark

Transcription factors~ctivate the synthesis

messenger RNAs from DNA, therebv

changing

;he function of cells. A few year;

ago, a new family of transcription

factors-

the STATs (signal transducers and activa-

tors of transcription)-was described that

mediates the action of a

large and vastlv im-

portant class of signaling molecules, the cyto-

kines and

growth factors. Each cvtokine or

growth

fac;or activates a distinct skt of genes

to produce very distinct effects on the cell,

yet there are only a limited number of

STATs to mediate these signals. How do

these few STATs generate a specific response

for each cytokine or growth factor? Part of

the answer to this puzzle is provided in a report

by Xu

al.

in this week's issue of

Science

)

The STATs exist as latent transcription

factors in the cytoplasm. After binding of

the growth factor or cytokine to its receptor,

the STAT is activated by

tyrosine phospho-

The authors are n the Department of Molecular B-

oogy Research lnsttute, Cleveland Clinic Founda-

tlon, Cleveland,

44195,

USA. E-mail. starkg@

cesmtp.ccf org

rylation

(24);

it then migrates to the nu-

cleus, binds to

s~ecific DNA elements. and

activates the transcription

ofnearby genes.

The six STAT family members form

homo-

or heterodimers in which the phosphotyr-

osine of one partner binds to the SH2 (SRC

homology 2) domain of the other

(5).

These dimers bind to palindromic GAS

sequences that have similar affinities for

different STATs.

The new work by Xu

al.

(1) describes

how each cytokine elicits a specific transcrip-

tional response when each must use a limited

number of factors and when the

target DNA

elements distinguish relatively poorly among

these factors. In investigating a region of the

human

interferon-y (IFN-y) gene that con-

tains clusters of GAS elements, these au-

thors found that homodimers of STATs

1,4,

5, and 6 all bind, but with different foot-

prints. Their observations suggest that STAT

dimers may cooperate in binding to clustered

GAS elements and that the details of this

cooperation may help to determine the cyto-

kine specificity of the response.

The STAT proteins share blocks of

ho-

relevant to question whether the high-dose

GC reeimes used to control manv autoim-

mune

akd inflammatory diseases have neuro-

pathological consequences. (Both therapeu-

tic and experimental administration of

GCs

to humans results in memory impairment.)

In addition, in the rodent the extent of life-

time GC exposure can influence the likeli-

hood of "successful" hippocampal and cogni-

tive aging (1

);

similar issues must be exam-

ined concerning our own dramatic differ-

ences in cognitive aging.

References

A Munck eta/. Endocr Rev

25 (1984)

B. McEwen, Prog. Brain Res

93,

365 (1992),

Saoolskv. Semin Neurosci

323 11994)

Sapolsky et a/, ibid.

10,

2897 (1990);

Magar~nos eta/, ibid

16,

3534 (1996)

Sheline eta/., Proc. Natl Acad. Sci U.S.A

93,

3908 (1 996).

M Starkman el a/, Biol Psychiatry

32,

756 (1 992).

M. Starkman, personal communlcaton

Bremner eta/, Am

Psychiatry

152,

973 (1995)

T. Gurvits eta/, Bin/ Psychiatry, in press

Bremner eta/., ibid in press.

10.

T Gurv~ts eta/,

Neuropsychiatry Ciin Neuroscl

183 119931.

11.

~eaney el a/., Science

239,

766 (1988);

ssa eta/.,

Neuroscl

10,

3247 (1990).

mology, arrayed over their entire 800-amino

acid length, and it is likely that similar do-

mains have similar functions: (i) The SH2

domain near residue 600 is highly conserved,

as is a

tyrosine near residue 700, which be-

comes phosphorylated upon activation. In

addition to binding the phosphotyrosine of

another STAT, the SH2 domain also medi-

ates the binding of STATs to specific

phos-

photyrosine residues of activated cytokine

receptors

(6-8).

(ii) The COOH-termini of

STATs mediate transcriptional activation,

and phosphorylation of a serine residue in

this region of STATs

la,

4, and 5 en-

hances this activity (9). In contrast, the

acidic COOH-terminal region of STAT2 can

activate transcription without

phosphoryla-

tion (1 0). (iii) STATs contain a DNA bind-

ing domain near residues 400 to 500 (1 1).

(iv)

STAT2-STAT1 heterodimers bind to

an additional protein,

p48, to form the major

transcription factor generated in response to

IFN-a. The region comprising residues 150

to 250 of

STAT1 interacts with p48 (1

2).

Other STAT dimers may also interact with

p48 (or similar proteins) to form more com-

plex

oligomeric transcription factors.

al.

)

have found a new function

for the

NH2-terminal domains of STATs

and 4: Mediating cooperative binding of

these STATs to tandem GAS sites. Deletion

of 90 amino acids from the

NH2-terminus of

STAT4 did not affect its binding to a single

GAS site but abolished the cooperative

binding of two STAT4 dimers to a double

site. Furthermore, a

peptide representing the

SCIENCE

VOL.

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AUGUST

1996

Discussion

Here is a great lecture by Robert Sapolsky recorded on September 22, 2016: [!["sapolsky"](https://i.imgur.com/B1OiH7S.png)](https://youtu.be/D9H9qTdserM?t=95) A long period of exposure to stress is long: - 1000 days = 2.7 years - 2000 days = 5.5 years - 3000 days = 8.2 years - 4000 days = 10.9 years (Depression timeline) #### TL;DR > ***"But if you get chronically, psychosocially stressed, you're going to compromise your health. So, essentially, we've evolved to be smart enough to make ourselves sick."*** Stress is defined as existing or anticipated threat of well-being. Our bodies' stress response evolved to help us get out of short-term physical emergencies - like if a lion is chasing you, you run. Such reactions compromise long-term physical health in favor of immediate self-preservation. Unfortunately, when confronted with non-life-threatening stressors, such as troubleshooting the internet connection worrying about money etc, modern humans turn on the same stress response. Modern lifestyles represent challenges that render individuals susceptible to physical and mental disorders. An individual's vulnerability and resilience may be determined by both genetic and epigenetic factors which influence our ability to cope with stress - ex: gender, early life experiences. The most easily measureable and critical physiological response to stress involves the release of glucocorticoids (GCs). GCs can exert profound modulatory effects on a variety of brain functions from early development through to late life. The hypothalamus, pituitary, and adrenal glands play an essential role in the adaptive response to psychogenic (ex: fear) and physical stressors (ex: cellular lesion or pathogen invasion). In this paper Sapolsky points out to the effects that prolonged exposure to GCs could have on the hypothalamus - ***"If you turn your stress response on for too long you get sick." *** > ***"Furthermore, if you're chronically stressed, all sorts of aspects of brain function are impaired, including, at an extreme, making it harder for some neurons to survive neurological insults," [...] "Also, neurons in the parts of the brain relating to learning, memory and judgment don't function as well under stress. That particular piece is what my lab has spent the last 20 years on."*** Alternatively, there is some evidence suggesting the atrophy is not a consequence of the trauma, but the reverse: "Some studies shows correlation of reduced hippocampus volume and posttraumatic stress disorder (PTSD) [...] This finding was not replicated in chronic PTSD patients traumatized at an air show plane crash in 1988 (Ramstein, Germany).[141] It is also the case that non-combat twin brothers of Vietnam veterans with PTSD also had smaller hippocampi than other controls, raising questions about the nature of the correlation.[142] A 2016 study strengthened theory that a smaller hippocampus increases the risk for post-traumatic stress disorder, and a larger hippocampus increases the likelihood of efficacious treatment.[143]" > ***They have found significant reductions in the volume of both hippocampi (12% in the right and 15% in the left) when comparing individuals with a history of depression to age-, educa- tion-, gender-, and height-matched controls. No change in overall brain volume was ob- sewed.*** Robert M. Sapolsky is an American neuroendocrinology researcher and the recipient of a MacArthur Foundation genius grant. He is currently a professor of biology, and professor of neurology and neurological sciences and, by courtesy, neurosurgery, at Stanford University. He is also the author of several works of nonfiction such as "Why Zebras Don't Get Ulcers", "Behave", "A Primate's Memoir". !["sapolsky"](https://news-media.stanford.edu/wp-content/uploads/2017/05/08115014/sapolsky_qa.jpg) Robert Sapolsky Stanford page: [Robert Sapolsky Webpage](https://profiles.stanford.edu/robert-sapolsky) More literature on this topic: - Here is a Review Article published in 2016: [Chronic Stress and Glucocorticoids](https://downloads.hindawi.com/journals/np/2016/6391686.pdf) - Here is an 2007 interview with Robert Sapolsky [Robert Sapolsky discusses physiological effects of stress](https://news.stanford.edu/news/2007/march7/sapolskysr-030707.html) Do methods exist to reduce GC secretion? Would they hinder ability to handle stress? ### Glucocorticoids Glucocorticoids are a type of corticosteroid hormone that is very effective at reducing inflammation and suppressing the immune system. Inflammation is the way our immune system responds to harmful substances and trauma and is part of our healing process. However, if the usual control mechanisms that turn the process of inflammation off aren’t functioning properly and it continues unabated, our tissues can become damaged. Continued inflammation is associated with many chronic conditions. Hormones such as GCs and adrenaline are released by primates to respond to stressful situations. These hormones which instantaneously increase the heart rate and energy level. The stress response is incredibly ancient evolutionarily. In the short term stress hormones are brilliantly adapted to help you survive an unexpected threat. According to the author of this paper: ***"You mobilize energy in your thigh muscles, you increase your blood pressure and you turn off everything that's not essential to surviving, such as digestion, growth and reproduction. You think more clearly, and certain aspects of learning and memory are enhanced. All of that is spectacularly adapted if you're dealing with an acute physical stressor—a real one."*** > ***"Fish, birds and reptiles secrete the same stress hormones we do, yet their metabolism doesn't get messed up the way it does in people and other primates."***

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