Available online at www.sciencedirect.com
Ominous odors: olfactory control of instinctive fear and
aggression in mice
Lisa Stowers1, Peter Cameron1 and Jason A Keller2
Aggression and fear are often thought to be distinct
behavioral states, yet they share several common output
responses. In the mouse, both can be initiated by specialized
odor cues. How these cues signal through the olfactory
system to promote behavior is largely unknown. Recent
experiments have started to uncover the relevant signaling
ligands, chemosensory receptors, and responsive sensory
neurons that together enable the precise manipulation of
behaviorally relevant neural circuits. Moreover, the use of
molecular genetics and new experimental strategies has
begun to reveal how the central nervous system processes
olfactory information to initiate aggression and fear. A
sensory-initiated comparative study of these two
fundamental threat reactions promises to offer new
mechanistic insight.
Addresses
1
The Scripps Research Institute, Department of Molecular and Cellular
Neuroscience, La Jolla, CA 92037, United States
2
University of California, San Diego, Neuroscience Graduate Program,
La Jolla, CA 92093, United States
Corresponding author: Stowers, Lisa (stowers@scripps.edu)
Current Opinion in Neurobiology 2013, 23:339–345
This review comes from a themed issue on Social and emotional
neuroscience
Edited by Ralph Adolphs and David Anderson
For a complete overview see the Issue and the Editorial
Available online 14th February 2013
0959-4388/$ – see front matter, # 2013 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.conb.2013.01.007
Introduction
Animals constantly encounter threats. Whether the
menace is a competitor of the same species or a hungry
predator, initiating an appropriate aggressive or fearful
response increases the individual’s chance of survival and
reproduction. These critical behaviors are displayed similarly across species, which suggests that they are generated by evolutionarily conserved neural mechanisms, as
Darwin first recognized well over a century ago [1].
Decades later, Cannon summarized the intricate relationship between the two main threat response states, fear
and aggression, as ‘fight or flight’ [2]. Even though both
fear and aggression have been extensively studied [3],
their underlying neural mechanisms remain largely
unknown.
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Fighting or fleeing may be promoted by stimuli that have
been previously associated with threat or by specialized
cues that have intrinsic meaning. Associative fear has
been intensively studied [4]. This paradigm has two
distinct facets: the generation and recall of a memory
as well as the display of fear. Innate fear presents an
alternate and simplified model to focus studies on behavioral output. Olfactory cues command instinctive behavior with especially high probability in a wide variety of
animals [5–8]. The mouse detects specialized odorants
emitted by conspecifics and heterospecifics, termed
pheromones and kairomones, respectively, which are
sufficient to robustly trigger the release of innate fearful
and aggressive behaviors [8,9]. Thus, olfaction can be
experimentally leveraged to control, manipulate, and
investigate the downstream neural circuits and mechanisms that promote innate behavior.
Fear and aggression are each complex behavioral states
that have proven difficult to ‘solve’ independently. However, when considered together, their similarities and
differences may provide mechanistic understanding
(Figure 1). At the circuit level, both require an intact
amygdala and hypothalamus [10,11]. Through neuroendocrine modulation, both tip the autonomic balance
to sympathetic domination. At the level of motor output
the two behavioral states may even seamlessly integrate,
as when a cornered animal suddenly turns ‘fear into fury’
[2]. However, the study of fear and aggression is often
approached separately because of numerous differences
in output: aggression is offensive (but see [12] for a more
detailed discussion), fear is defensive; aggression promotes piloerection and rearing to increase apparent size,
fear results in freezing and huddling to dissuade attention. Furthermore, fear and aggression are under differential developmental control. For example, territorial
aggression is not elicited before the onset of puberty,
whereas predator odor induces fear in juveniles [13,14].
These similarities and differences provide a comparative
framework to identify the common neural correlates that
enable mobilization to threats, as well as the particular
mechanisms that distinguish their separate but related
motor patterns.
Specialized odor cues promote fear and
aggression in the mouse
Almost any odorant can be conditioned to elicit fear or
aggression. In addition, the mouse detects a subset of
specialized odors that elicit behavior without prior associative conditioning. While the sources of many of these
Current Opinion in Neurobiology 2013, 23:339–345
340 Social and emotional neuroscience
Figure 1
pheromones & kairomones
aggression-specific
fear-specific
shared
Current Opinion in Neurobiology
Pheromones and kairomones influence fear and aggression in mice. Defensive responses to olfactory stimuli can be aggression-specific (blue), fearspecific (red), or shared by both fearful and aggressive behaviors (purple). The shared response primarily includes activation of the hypothalamicpituitary-adrenal axis (HPA) axis, which, for example, increases heart rate and decreases digestive secretions to deal with a threat. Facial expressions
[61] and other motor patterns [27] differ in fearful and aggressive contexts.
odorants are known, such as male mouse urine or predator
excretions, the identities of most of the bioactive ligands
remain unidentified. The ability of these cues to evoke
aggressive and fearful responses across individuals without previous experience and learning indicates that the
underlying neural correlates are in part genetically determined, which may provide experimental traction. For
example, these specialized ligands activate unknown
subsets of sensory receptors in the olfactory system,
but once such receptors are identified, they can be used
to study the neurons that are functionally relevant to
aggression and fear.
Mice detect odors through two primary olfactory sensory
organs: the main olfactory epithelium (MOE) and the
vomeronasal organ (VNO) (Figure 2a). The MOE mediates both associative olfactory learning and instinctive
responses, while the VNO is considered specialized for
innate behaviors. However, sensory neurons housed in
both the MOE and VNO promote innate aggression and
fear [8,9,15–20]. Mutant mice lacking sensory detection
in either the MOE or VNO have dramatically reduced
aggression [15,16,21]. Similarly, mice lacking sensory
detection in either the dorsal region of the MOE or
the VNO have severe reductions in freezing and avoidance to various predator odor sources such as fox feces and
cat fur, and even an anesthetized rat [8,19,20,22]. Olfactory sensory neurons generally express one out of approximately 1400 G protein coupled odorant receptors, which
tunes their response to a subset of odors. These odorant
receptors include roughly 1000 olfactory receptors (ORs)
and 15 trace amine associated receptors (TAARs) in the
MOE, as well as over 350 vomeronasal receptors (VRs) in
the VNO [23–25]. Complex odor sources such as those
emitted by other animals will likely activate many distinct
olfactory sensory neurons. With so many possible sensory
signals, how is the mouse olfactory system organized to
translate a particular sensory response into a reliable
reaction such as attack or fleeing? To investigate this,
Current Opinion in Neurobiology 2013, 23:339–345
several groups have begun to isolate the odorant sources
and in some cases the specific ligands that initiate these
stereotyped behaviors as well as their cognate receptors
and sensory neurons.
Significant headway in elucidating the identity of individual receptors tuned to aggression-inducing and fearinducing odors has now been made in both the MOE and
VNO. Isogai et al. performed a comprehensive investigation into the functional specificity of nearly 90 VRs
[22]. They exposed mice to ethologically relevant
ligand sources such as conspecific and heterospecific
bedding material and correlated sensory neural activity
with the functional identity of the VR. They found many
VRs activated selectively by either female or male mouse
odors (including putative aggression-promoting cues),
others activated by odors from other species (including
those of putative predators such as rats, snakes, and birds),
and a minority activated by both conspecific and heterospecific stimuli. This last class of sensory neurons could
form the basis of responses that are shared in both fear and
aggression (e.g., increased sympathetic outflow [26]),
while the male-conspecific and heterospecific specialized
sensory neurons may stimulate effectors that underlie the
differences between the behaviors [27].
In another study, Ferrero et al. took an alternative
approach by screening for biologically relevant ligand
sources that activate TAARs, noncanonical odorant
receptors in the MOE [28]. They found heterologously
expressed TAAR4 to be activated by urine from mountain
lions and bobcats. Further, 2-phenylethylamine, a volatile
compound enriched in carnivore urine, activates TAAR4
and promotes avoidance behavior as well as increases in
corticosterone stress hormone circulation. Thus, two distinct classes of odorant receptors operating in separate
olfactory structures, TAARs and VRs, detect cues that
induce aggression and fear. It is not known how distinct
signals from the MOE and VNO ultimately integrate with
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Ominous odors: olfactory control of instinctive fear and aggression in mice Stowers, Cameron and Keller 341
Figure 2
(a)
2nd order
neurons
MOE
MOB
AOB
forebrain & brainstem
BNST
MEA
COA
BAOT
NLOT
PAA
LA
PMD
VMHvl
VMHdm
PMV
MPOA
SC
PFC
PAGdl
AHA
PVN
effectors
motor neurons
pituitary gland
sympathetic
ganglia
VNO
(b)
< seconds minutes
ex. perception,
pheromones,
motor patterns
minutes hours
ex. hormones,
circadian cycle,
autonomic tone
hours days
ex. estrous cycle,
dominance relationships,
disease
months years
ex. sexual maturity,
photoperiod,
aging
Current Opinion in Neurobiology
Overlapping and distinct areas of the brain and modulating factors involved in pheromonal control of fear and aggression in mice. (a) Main areas of the
brain and periphery that have been implicated in olfactory-mediated unconditioned fear (red), aggression (blue), or both (purple), as determined by
lesions, microstimulation, and immediate early gene (IEG) expression. Areas shown in gray are only implicated by anatomy. Although braces depict the
forebrain regions receiving direct projections from both second order olfactory areas, most anatomical details between brain regions are not shown for
clarity. Many areas are bidirectionally connected through both excitatory and inhibitory projections. This gross anatomical view neglects
heterogeneous cell types and subcircuits within areas, and is based on experiments in both rats and mice. Additionally, non-olfactory contextual
information must enter the circuits through various routes, some of which are shown with dashed gray arrows. (b) Many factors dynamically regulate
information flow through the circuits in (a) and thus affect the probability of olfactory-mediated fear and aggression over several timescales.
Abbreviations: AHA, anterior hypothalamic area; AOB, accessory olfactory bulb; BAOT, bed nucleus of the accessory olfactory tract; BNST, bed
nucleus of the stria terminalis; COA, cortical amygdala; LA, lateral amygdala; MEA, medial amygdalar nucleus; MOB, main olfactory bulb; MOE, main
olfactory epithelium; MPOA, medial preoptic area; NLOT, nucleus of the lateral olfactory tract; PAA, piriform-amygdalar area; PAGdl, periaqueductal
gray, dorsolateral column; PFC, prefrontal cortex; PMD, dorsal premammillary nucleus; PMV, ventral premammillary nucleus; PVN, hypothalamic
paraventricular nucleus; SC: superior colliculus; VMHdm, ventromedial hypothalamus, dorsomedial portion; VMHvl, ventromedial hypothalamus,
ventrolateral portion; VNO, vomeronasal organ.
information from other sensory modalities including
vision, audition, and touch, to promote behaviors such
as attack or freezing. The identification of the relevant
odorant receptors provides a molecular handle to genetically label, visualize, and ultimately manipulate the
downstream neural circuits.
Circuits mediating aggressive and fearful
behaviors: overlapping and distinct
Aggressive and fearful behaviors are complex motor
sequences that typically employ the coordination of
multiple muscle groups, and yet they are highly stereotyped across mice [11,29], implying the existence of
‘hard-wiring’ to tie the coordinated actions together.
While recent work has revealed many of the details of
associative fear circuits [4,30–33], the identification of the
neurons in the central nervous system that are necessary
and sufficient for instinctive fear and aggression, how they
are genetically specified, and how they fit into the overall
control of behavior in an animal remains a challenge.
Recently, several excellent reviews have independently
considered the circuits underlying a single threat behavior
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[3,10,11,27], but the relationships between fear, aggression, and the olfactory system have not been jointly
explored.
Following sensory stimulation of either the MOE or
VNO, which excite the main olfactory bulb (MOB) and
accessory olfactory bulb (AOB), respectively, the circuits
mediating fear or aggression become less apparent as the
anatomy of second order projections becomes more complicated [34,35] (Figure 2a). The circuit involves other
brain regions that have been functionally identified
through lesions, microstimulation, and IEG expression.
These gross anatomical regions display both overlapping
and mutually exclusive functional contributions to fear
and aggression. At this stage even the anatomical details
of the threat-responsive circuits have not been well
established and the neural mechanisms are largely
unknown. However, as the signals progress closer to
the motor periphery a more concrete understanding of
the regions driving these behaviors emerges again. Functional studies show that the periaqueductal gray (PAG)
plays a key role in the generation of fear-related motor
Current Opinion in Neurobiology 2013, 23:339–345
342 Social and emotional neuroscience
patterns [11]. Perhaps the best-studied effector output
involved in both fear and aggression is the secretion of
corticotropin-releasing hormone and vasopressin by parvocellular neurons of the hypothalamic paraventricular
nucleus (PVN) in order to kick off the hypothalamicpituitary-adrenal axis (HPA) axis response to stress [36].
This output can be engaged simply by an olfactory
stimulus such as conspecific urine [26]. However, since
afferent projection patterns to the PVN are highly complex, little is known about how olfactory information
releases the HPA response.
Several groups have recently compiled a detailed
anatomy of MOB and AOB projections in the mouse
[34,37,38]. Further work has highlighted the preponderance of bidirectional connections between many areas
[39,40] and the overlap of projections from the main and
accessory olfactory systems [35]. One particular study
[41] employed engineered viruses to reveal that mitral
cells localized in the dorsal MOB preferentially project
their axons to the cortical amygdala, raising the tantalizing
possibility that this topography directs MOE-initiated
instinctive responses [19,20]. Such anatomical work is
essential to determine the focus of mechanistic studies
that will bridge the gap between behavioral and molecular understanding. Accordingly, Choi et al. [42] revealed
important anatomical details of the projection from the
medial amygdala (MEA), which is widely innervated by
the AOB, to the ventromedial nucleus of the hypothalamus (VMH), an area implicated in both innate fear and
aggression. They found molecularly distinct populations
of excitatory and inhibitory neurons within the MEA that
differentially project to regions of the VMH implicated in
separate innate behaviors. These results provide testable
models of how these circuits may interact to ‘gate’ output.
Bian et al. [43] expanded these results by combining
anatomical tracing with slice electrophysiology to highlight possible cellular mechanisms of olfactory-mediated
fear and aggression. They show that the VMH-projecting
neurons in the MEA have unexpected ‘cortical-like’
properties such as ion channels that allow burst coding,
thus inviting future studies of the behavioral significance
of such mechanisms.
Recently, Lin et al. utilized IEG analysis, optogenetics,
and electrophysiology to confirm the ventrolateral part of
the VMH (VMHvl) as a critical node in the aggressionproducing circuit [44]. By taking a genetic approach,
this investigation disambiguated classical studies of
microstimulation-induced aggression in other animals,
which could have recruited fibers of passage, and
extended their striking results to the mouse model.
The dorsomedial part of this same nucleus (VMHdm)
has also been implicated in unconditioned olfactory fear
responses by IEG expression analyses [42,45]. Interestingly, photostimulation of the VMHdm resulted in freezing and fleeing [44], suggesting a spatial segregation of
Current Opinion in Neurobiology 2013, 23:339–345
aggression and fear motor commands in the VMH. Does
the proximity of aggression-related and fear-related
neurons in the VMHvl and VMHdm, respectively, contribute to the shared threat response elicited by pheromones and kairomones or the seamless switch from ‘fear
to fury’? The potential intermingling of relevant neurons
highlights the need for sophisticated approaches to verify
and investigate the function of specific microcircuit connections.
Genetic and molecular control of fear and
aggression
Many of the brain regions implicated in fear and aggression are functionally and molecularly heterogeneous. The
absence of methods to disentangle them has impeded a
mechanistic study of the microcircuits involved. However, knowledge of the developmental mechanisms and
neuromodulatory influences underlying innate aggression
and fear may be exploited to dissect and delineate the
relevant neural circuits with genetic techniques. Indeed,
this strategy has been elegantly demonstrated in studies
of the neural pathways governing reproduction in nematodes, courtship in fruit flies, and the regulation of feeding
behavior in mice [46–48].
In addition to being elicited without experience, a striking feature of many instinctive behaviors is their
tendency to vary dramatically and stereotypically over
several timescales according to an animal’s age, sex, state,
or various other factors (Figure 2b). For instance, olfactory-initiated aggressive behavior is elicited with much
higher probability in adult versus juvenile or castrated
males, as well as in lactating versus virgin females
[9,14,21]. In mammals, sex hormones released from the
gonads during both development and adulthood play a
fundamental role in directing the display of aggression.
More specifically, a male-specific conversion of testosterone to estrogen at birth masculinizes neural circuits that
promote male-typical aggressive behaviors, while subsequent testosterone signaling ‘amplifies’ these circuits
in the adult [49–51]. Steroid responsive estrogen and
androgen receptors, as well as aromatase, are expressed
in sexually dimorphic, partially overlapping patterns in
subcortical nuclei implicated in aggressive behavior
[49,50]. Thus, these genes may delineate a functionally
unified neural pathway, and offer a logical entry point for
a genetically guided deconstruction of aggression circuits.
To identify additional molecular components underlying
sexually dimorphic behavior, Xu et al. examined gene
expression differences in males compared to females with
microarray and in situ hybridization techniques [52].
They identified a cohort of 16 genes differentially
expressed according to gender in the hypothalamus
and MEA, regions previously implicated in the display
of aggressive behavior. Loss-of-function mutants were
obtained for four of the identified genes, and behavioral
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Ominous odors: olfactory control of instinctive fear and aggression in mice Stowers, Cameron and Keller 343
testing implicated two sex hormone responsive genes,
Bombesin receptor subtype-3 (Brs-3) and Insulin receptor
substrate-4 (Irs-4), in the control of aggression. It is
currently unclear how Brs-3 or Irs-4 act to control attack
behavior, or to what extent the additional genes regulate
aggressive behavior in general. Future work aimed at
clarifying the cellular actions and potential epistatic
interactions of the identified genes, as well as the functional roles of the neurons that express them, will likely
advance our understanding of how the nervous system
generates sex-specific behaviors such as odor-mediated
aggression.
Can a similar approach yield insight into fear behavior?
Although predator odor fear is not considered a canonical
male or female typical behavior, hormonal and sex effects
have been reported [13,53]. Traction in dissecting fear
circuits may also come from considering additional developmental programs, hormones, and neuromodulatory
influences. For instance, Choi et al. performed amygdalar
gene expression analyses to find molecular markers that
demarcate neural populations responsive to predator odor
[42]. Studies in rats have also begun to detail how corticosterone may control the emergence of conspecific predator odor fear in juveniles as well as how noradrenergic
release in the dorsal premammillary nucleus may modulate the aversive response to cat odor [54,55]. Considering
these modulatory systems will likely provide an entry
point toward investigating olfactory initiated fear circuits.
Concluding remarks
Even in a simplified experimental environment, a mouse
faces an uncertain and complicated world, and thus any
behavior may be viewed as flexible, probabilistic, and
dynamic. Although the abovementioned genetic
approaches offer a clear entry point to deconstruct the
relevant neural circuits, it is worth noting that a large body
of work has suggested that additional molecular and
neuromodulatory sources [10,56–59] and even the birth
of new olfactory cells [60] contribute to the control of
aggression and fear. Understanding how all of these
elements ultimately converge to instruct a mouse
whether to fight or flee will be necessary to achieve a
systems level description of behavior (Figure 2). Amidst
such complexity, the olfactory system offers an excellent
opportunity to use clearly defined sensory stimuli and
genetic tools to identify, manipulate and study the mechanisms that promote threat-initiated survival behavior.
Acknowledgements
We would like to thank C. Dulac, F. Papes, and N. Shah for helpful
comments on the text. LS is supported by grants from the NIH-NIDCD,
Ellison Medical Foundation, and Skaggs Trust.
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