F O C U S O N P S Y C H I AT R I C D I S O R D E R S C O M M E N TA R Y

Psychiatric distress in animals versus

animal models of psychiatric distress
Robert M Sapolsky
The realm of human uniqueness steadily shrinks; reflecting this, other primates suffer from states closer to
© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.

depression or anxiety than ‘depressive-like’ or ‘anxiety-like behavior’. Nonetheless, there remain psychiatric domains
unique to humans. Appreciating these continuities and discontinuities must inform the choice of neurobiological
approach used in studying any animal model of psychiatric disorders. More fundamentally, the continuities reveal
how aspects of psychiatric malaise run deeper than our species’ history.

Primatology research suggests that other
primates suffer from crippling depression or
anxiety, implying that these diseases’ roots pre-
date human history. At the same time, some
realms of psychiatry remain uniquely human.
Recognizing the similarities and dissimilarities
between us and other primates is essential in
studying animal models of psychiatric disease.
A cornerstone of evolution is the continu-
ity of traits across species as a result of shared
ancestry. Such continuity is the reason why we,
chimps and bonobos share more than 98% of
our DNA or why we and warthogs both have
four limbs and two nostrils; it is the reason for
our vague and distant relatedness to both T.
rex and crabgrass.
This continuity obviously extends to ner-
vous systems; if nothing else, if you want to
accurately predict a neuron’s resting poten-
tial, whether it is from a human or an Aplysia,
you’re going to have to relearn the Nernst equa-
tion (or was it the Goldman equation?). And,
of course, it extends to the principle output of
the nervous system, namely, behavior and the
internal life that can be inferred from it.
The narrowing range of human
uniqueness
Behavioral continuity has repeatedly forced a
narrowing of the definition of what it is to be
Robert M. Sapolsky is in the Departments of
Biological Sciences, Neurology and Neurosurgery,
Stanford University, Stanford, California, USA;
and the Institute of Primate Research, National
Museums of Kenya, Nairobi, Kenya.
e-mail: sapolsky@stanford.edu.
human, as one “we are the only species that…”
after another has fallen. As first documented
by Jane Goodall with her chimpanzees in
Gombe, Tanzania, we are not the only species
that makes and uses tools. Instead, such mate-
rial culture is widespread among other spe-
cies; moreover, some species utilize multiple
tools in sequential manners and make, store or
transport tools in anticipation of future use1.
We are most definitely no longer the only
animal that kills members of its own species.
Instead, other animals inflict lethal harm on
others in ways that can be highly strategic.
Chimps, for example, will kill each other in
an organized manner that can involve the use
of physical objects to do harm. Moreover, they
are capable of something resembling genocide,
in which individuals are killed, not for who
they are, but for what category they belong to
(i.e., males of a neighboring group)2. As pio-
neered by Frans de Waal and expanded by oth-
ers, we are not the only species that shows the
rudiments of a range of prosocial behaviors,
including reconciliation, empathy, third-party
consolation, an aversion to inequality and a
sense of justice (c.f. 3).
Many attributes once thought to be human-
specific even need to be extended to rodents.
For example, consider a rat in an arena leading
to a number of corridors, each giving a particu-
lar food reward after a time delay. Upon enter-
ing a corridor and hearing a tone that indicates
the duration of the delay, it can choose to stay
or switch to another corridor. When rats forgo
a reward with a moderate delay, in order to
choose a corridor that turns out to require an
even longer wait, they show evidence of ‘regret’.
This includes a characteristic profile of activa-
tion in the frontal cortex and ventral striatum,
frequent glancing at the corridor not taken and
a greater likelihood of persevering with a first
corridor choice in the future4. Moreover, rats
show temperamental differences in degree of
optimism, in that some tend to interpret an
ambiguous cue as a reward contingency, oth-
ers as a punishment contingency5.
Rodents also show elements of empathy and
proactive compassion. A mouse’s pain thresh-
old will be lowered when in the presence of
another mouse in pain, but this only occurs if
the other mouse is a cagemate6. As in humans,
the circle of such shared pain is expanded to
include strangers if the glucocorticoid stress-
response to the presence of a stranger is phar-
macologically blocked7. Moreover, rats will
work proactively to release a distressed cage-
mate from a restrainer and will even forgo a
desirable food reward to do so8. In addition,
pair-bonded prairie voles will increase their
rate of licking and grooming of a mate who is
stressed, but not of a stranger who is stressed;
this behavior is dependent upon oxytocin
actions in the anterior cingulate cortex9.
Finally, on a level that initially seems play-
ful but is ultimately profound, we are not even
the only species that enjoys being tickled. Apes
tickle each other in naturalistic settings, trig-
gering rapid exhalations and vocalizations
that are similar to human laughter. Moreover,
“tickle me” is a phrase learned early by apes in
various symbolic language studies (as a stu-
dent, I worked on one such project and spent a
large percentage of a summer being requested
to do so by a chimp). Remarkably, manual

NATURE NEUROSCIENCE VOLUME 19 | NUMBER 11 | NOVEMBER 2016 1387

 C O M M E N TA R Y
© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.
Figure 1 Affective experiences on a continuum
with humans; subjects are olive baboons (Papio
anubis) living in the Serengeti ecosystem of
East Africa. Top: an adolescent male who had
spent much of the previous months closely
following an adolescent female (arrow), in entirely
unsuccessful attempts to be groomed by her.
Bottom: an adult male who, one hour before, had
been toppled from the alpha position, having lost
a fight and being forced to give a subordinating
gesture to the beta male.
somatosensory stimulation—tickling—by
humans induces a positive affective state in
rats, elicits a characteristic chirping vocaliza-
tion in the 50 kHz range that is also elicited by
sex, appetitive social situations and dopamine
agonists, and is dependent upon mesolimbic
dopamine activation10. Moreover, such tick-
ling makes rats more optimistic in the ambigu-
ous cue test just described5.
If we prick them, do they not bleed? If we
tickle them, do they not do something that
is on a phylogenetic continuum with laugh-
ing? What are we to make of continuity of
behavior and affect among us and other ani-
mals when it comes to mental illness? At one
extreme, psychiatric disorders can be viewed
as so intrinsically human that any similarities
in other species constitute merely a model. At
the other, some other species can be viewed
as potentially suffering from psychiatric disor-
ders as surely as do humans. To approach this
issue, it is worth examining what the homologs
of certain types of psychiatric distress look like
in other primates navigating the vicissitudes of
life in their natural habitats.
Mood disorders and anxiety in free-living
primates
What might anxiety or depression look like
in another primate in the wild? Here would
1388 VOLUME 19 | NUMBER 11 | NOVEMBER 2016 NATURE NEUROSCIENCE
be a scenario that would occur with a clarity
never observed in actual field observations: a
low-ranking male baboon stumbles upon and
predates a highly prized prey item, a young
gazelle. Were this to have happened in the
middle of the troop, he would barely have
managed a bite before being displaced by a
higher-ranking male. Instead, he is at a dis-
tance from everyone else and has some time
to eat before a higher-ranking male arrives.
A clean, quantitative index of anxiety would
be how often the baboon would stop eating
to look back over his shoulder to see who is
approaching; in contrast, an index of depres-
sion of the learned helplessness type would be
if his displacement from the kill would seem
so inevitable that he walks away before anyone
is even close, perhaps even before taking a bite.
While such clarity is rare, nonhuman pri-
mates in their natural habitats do display
‘depression-like’ and ‘anxiety-like’ behavior
(see Fig. 1). The former is most common after
the death of particular group members. Among
Chacma baboons, for example, the predation of
an adult female produces a month-long increase
in glucocorticoid levels among her close rela-
tives (but not among unrelated individuals).
Moreover, such relatives seek social support,
initiating grooming at a higher frequency and
with a larger number of grooming partners11.
Less adaptive responses to the death of a
relative are seen as well. One that has long
intrigued and puzzled primatologists occurs in
chimpanzees and various monkey species (for
example, macaques and baboons). Specifically,
when an infant dies, the mother will often
carry and groom the corpse for a long period
afterward; among Japanese macaques, for
example, nearly 30% of females show this
behavior when an infant under a month of age
dies12. The behavior is typically accompanied
by decreased feeding and by social withdrawal
by the female, such as decreased grooming,
contact or other social interactions. Some pri-
matologists have proposed that the behavior is
adaptive, insofar as it would prevent the fatal
abandonment of an infant who is transiently in
an unresponsive state, rather than dead. This
seems an implausible selective force, in that
mothers will carry infant corpses for astonish-
ingly long periods of time—numerous species
show corpse carrying on the order of weeks to
months, during which time corpses decay or
mummify13,14.
Moreover, primates in their natural habitats
show pathological reactions to loss. Probably
the best documented is the case of Flint, an
eight-year-old chimpanzee studied from birth
by Goodall. Flint was the son of Flo, a matri-
arch in the group, and as her final living child,
he was atypically dependent on her, showing
an array of neotenized behaviors as a juvenile
(for example, continued attempts to nurse).
Upon Flo’s death of old age in 1972, Flint was
unable to function independently, withdrew
from all social activities, stayed near her body
continuously and died within a month15.
Thus, other primates respond to loss with
behavioral and/or endocrine indices of dis-
tress; most respond with increased seeking
of social support and affiliation; a substantial
minority respond instead with a prolonged
period of social withdrawal and maladaptive
behavior; a tiny subset are pathologically, even
fatally, incapacitated by loss. The similarities
to human grief, reactive depression and severe
major depression are striking. Moreover, stud-
ies of captive primates demonstrate neurobio-
logical underpinnings to these affective states
that are the same as with human depression
(for example, gene–environment interactions
concerning vulnerability and the serotonin
transporter16). Appropriately, primatologists
who study such ‘comparative thanatology’
typically transition from thinking that they are
examining ‘grieving behavior’ or ‘depression-
like behavior’ to, instead, ‘grief ’ and ‘depres-
sion’ in a closely related species.
We and other primates are also on a con-
tinuum when it comes to anxiety. There are
broad similarities in the circumstances of
ambiguity about threat that provoke it (for
example, proximity of an aggressive alpha
male for a monkey or of a hostile boss for a
human). There is also continuity in terms of
the behavioral stereotypies that occur: an anx-
ious monkey, for example, will show bursts of
repetitive self-grooming and scratching, teeth
grinding, nose wiping, assuming of a vigilant
stance, slapping at the ground or purposeless
breaking of branches or pulling up of grass;
the similarities to displacement behaviors in
anxious humans is striking.
There is also a continuum of the physiol-
ogy underlying anxiety; for example, as in
humans, the frequency of anxiety-related
behaviors among wild baboons increases
dramatically when benzodiazepine recep-
tors are blocked with a b-carboline receptor
antagonist. Moreover, endogenous benzodi-
azepine tone varies with social setting: that
b-carboline effect is most pronounced in low-
ranking baboons but only in troops in which
such subordinate animals are subject to high
rates of displacement aggression at the teeth
of dominant individuals17. Furthermore, indi-
vidual differences in anxiety-related behavior
can be long lasting in other primates; male
baboons differ dramatically as to how read-
ily they perceive neutral social situations to be
threatening (as assessed by how close a higher
ranking male, in a nonthreatening state, has

to be in order to disrupt a subject’s ongoing
behavior). These temperamental differences
are stable over years, and a propensity toward
reacting to the neutral presence of a rival as
if he is threatening is highly predictive of ele-
vated basal glucocorticoid levels18.
Thus, there is a striking continuum between
humans and other primates in their natural
habitats when it comes to mood and anxiety
disorders. Of course, at the same time, the
qualitative differences between humans and
other primates are enormous. A chimp may
feel a malignant sadness because of the death
of her child; a human may do so because of the
death of a child in a distant refugee camp, in
a novel, or because of a Mahlerian song cycle
about the death of children. A baboon may be
© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.
made anxious by the proximity of an alpha
male; a human by thoughts of mortality or the
I.R.S. or by wondering if their research will be
replicated. Even the motoric stereotypies that
can be shared with us by other primates have
striking human-specific features. Consider
the first-person account of a tic by a character
with Tourette’s syndrome in Jonathan Letham’s
novel, Motherless Brooklyn19:
“I left the notebook beside the [bag of fast
food hamburgers] on the seat between us and
slapped the compartment door shut again,
then delivered six redundant slaps to the same
spot to ventilate my brain’s pressure by repro-
ducing the hollow thump I’d liked. Six was a
lucky number tonight, six burgers, six forty-
five. So six slaps.”
Moreover, there is a wide range of psychiat-
ric maladies for which there is no nonhuman
primate equivalent, and this is not surprising.
Psychotic thought disorder and florid hal-
lucinations are not particularly compatible
with long-term survival in a wild primate and
likewise for a manic state of grandiosity, if it
involves repeated challenges to a predator or
high-ranking individual. Nonhuman primate
anorexics will leave few copies of their genes.
And furthermore, I would be mighty surprised
NATURE NEUROSCIENCE VOLUME 19 | NUMBER 11 | NOVEMBER 2016 1389
if there are primate homologs of Capgras
delusion (the belief that loved ones have
been replaced by imposters), acrotomophilia
(sexual arousal by amputees) or Stendhal
syndrome (ecstatic agitation and autonomic
arousal when first experiencing artwork in
Florence). All species are unique, but some
are unique in particularly unique ways.
What is one to make of animal models for
psychiatric disorders that seem deeply specific
to humans? In such cases, it is appropriate to
cautiously study well-defined, narrow and
reductive endpoints that model isolated pieces
of the disorder. This is the world of endophe-
notypes, signal transduction pathways, epi-
genetic modification of gene regulation and so
on; the enormous and exciting progress with
such approaches is highlighted in many of the
papers in this issue.
What is one to make of the similarities
between some cases of psychiatric disease
in humans and psychiatric disease and dis-
tress in other primates? One direction that
I often find to be unfruitful is questioning
whether, say, a ‘depressed’ nonhuman pri-
mate is really feeling the same things as a
depressed human. This readily turns into a
debate floating somewhere between Skinner’s
famed, dogmatic assertion that “emotions are
fictional causes to which we attribute animal
behavior”20 and college dorm discussions of
whether someone else sees the color blue the
same way that you do. When a highly depen-
dent chimpanzee sits alone by the corpse
of his mother for so long that he starves to
death, the similarities with the human experi-
ence far outweigh the differences.
This strengthens the validity of some animal
‘models’ in psychiatry research while, at the
same time, often questioning their ethicality.
But the continuity raises a deeper point. Many
aspects of psychiatry research focus, appropri-
ately, on issues specific to the human condi-
tion—for example, cross-cultural differences
in symptomatology or the roles of urbaniza-
C O M M E N TA R Y
tion or socioeconomic status in increasing
incidences of certain types of mental illness.
There are also obviously human-specific ele-
ments to the far too common skepticism in the
lay public about the biological bases of mental
illness. This is the view of so many who have
been spared the reality of, say, depression, that
it is merely manipulation, self-indulgence or
lack of willpower—some sort of neurochemi-
cal depletion of Calvinist gumption. What
these studies of wild primates show is that
the biological roots of pathological sadness or
anxiety run much deeper than the inventions,
neuroses and artifices of human life.
COMPETING FINANCIAL INTERESTS
The author declares no competing financial interests.
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