#### 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
M.
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
(1
).
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
a
significant
8%
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
et
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
as
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
et
al.
showed hippocam-
pal atrophy after correction for whole-brain
volume, with no atrophy in the amygdala.
ndrome
1
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
GC
hydrocortisone.
It is not clear whether the atrophy is asso-
ciated with trauma (combat or abuse) or with
succumbing to PTSD (which occurs in
5
to
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
of
atrophy. Finally,
in
the childhood abuse
study (in which there were no non-PTSD
childhood abuse controls), it was not pos-
SCIENCE
VOL.
273
9
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
GC
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
R.
Stark
Transcription factors~ctivate the synthesis
of
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
et
al.
in this week's issue of
Science
(1
)
.
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,
OH
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
et
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
1
);
similar issues must be exam-
ined concerning our own dramatic differ-
ences in cognitive aging.
References
1
A Munck eta/. Endocr Rev
5,
25 (1984)
2
B. McEwen, Prog. Brain Res
93,
365 (1992),
R
Saoolskv. Semin Neurosci
6
323 11994)
Sapolsky et a/, ibid.
10,
2897 (1990);
A
Magar~nos eta/, ibid
16,
3534 (1996)
4
Y.
Sheline eta/., Proc. Natl Acad. Sci U.S.A
93,
3908 (1 996).
5
M Starkman el a/, Biol Psychiatry
32,
756 (1 992).
6.
M. Starkman, personal communlcaton
7
J,
Bremner eta/, Am
J
Psychiatry
152,
973 (1995)
8.
T. Gurvits eta/, Bin/ Psychiatry, in press
9
J
Bremner eta/., ibid in press.
10.
T Gurv~ts eta/,
J
Neuropsychiatry Ciin Neuroscl
5.
183 119931.
11.
M
J
~eaney el a/., Science
239,
766 (1988);
A.
ssa eta/.,
J
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,
3,
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.
Xu
et
al.
(1
)
have found a new function
for the
NH2-terminal domains of STATs
1
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.
273
9
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) Do methods exist to reduce GC secretion? Would they hinder ability to handle stress? 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) ### 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."***