Review
The smell of danger: A behavioral and neural analysis of predator odor-induced fear

https://doi.org/10.1016/j.neubiorev.2005.04.008Get rights and content

Abstract

The odors of predators used in animal models provide, in addition to electric footshock, an important means to investigate the neurobiology of fear. Studies indicate that cat odor and trimethylthiazoline (TMT), a synthetic compound isolated from fox feces, are often presented to rodents to induce fear-related responses including freezing, avoidance, stress hormone and, in some tests, risk assessment behavior. Furthermore, we report that different amounts of cat odor impregnated on small-, medium-, or large-sized cloths impact the display of fear-related behavior when presented to rats. That is, rats exposed to a large cat odor containing cloth exhibit an increase in fear behavior, particularly freezing, which remains at high levels in habituation tests administered over a period of 7 days. The large cloth also induces a long-lasting increase in avoidance behavior during repeated habituation and extinction tests. A review of the brain regions involved in predator odor-induced fear behavior indicates a modulatory role of the medial amygdala, bed nucleus of the stria terminalis, and dorsal premammillary nucleus. In addition, the basolateral amygdala is involved in fear behavior induced by cat odor but not TMT, and the central amygdala does not appear to play a major behavioral role in predator odor-induced fear. Future research involving the use of predator odor is likely to rapidly expand knowledge on the neurobiology of fear, which has implications for understanding fear-related psychopathology.

Introduction

The ability to sense, analyze, and respond to olfactory information is a common function of all brains. The early neuroanatomists were keen in recognizing a link between olfactory processing and emotionality. Papez's proposed brain circuits of emotion (Papez, 1937), which Paul MacLean later termed the limbic system, has historical roots in Paul Broca's limbic lobe concept described in 1878 (Shepherd, 1994). Importantly, Broca emphasized that the limbic lobe had a strong relationship with the olfactory system (Isaacson, 1974). Nonetheless, current knowledge of the neurobiology of fear is based largely on the use of unconditioned stimuli such as electric footshock or physical restraint to provoke negative emotional states. A contemporary neurobiological analysis examining the relationship between odors and emotional behavior is likely to provide novel information on brain mechanisms involved in modulating fear.

This paper summarizes and presents new information on fear behavior induced by predator odor, a natural threat. Odors of predators trigger a range of unconditioned behavioral and physiological responses in rodents. Because odor-induced fear behavior is attracting increasing attention, we will discuss some of the major stimulus properties of predator odor, especially in relation to the effects of stimulus intensity on fear behavior and on behavioral habituation and extinction. The paper will also summarize the emerging work on the brain regions implicated in the modulation of predator-odor induced fear. Although both young and adult rodents exhibit fear behavior when exposed to particular odors associated with conspecifics, this important developmental (Moriceau et al., 2004, Shair et al., 1997, Takahashi, 1996, Wiedenmayer and Barr, 2001) and stress literature (Carr et al., 1970, Kikusui et al., 2001, Mackay-Sim and Laing, 1980, Valenta and Rigby, 1968) will not be the central focus of this review.

Section snippets

Stimulus properties of predator odors

Mammals respond readily to a variety of odors associated with predators both in the field (Apfelbach et al., this issue; Dickman and Doncaster, 1984, Jedrzejewski and Jedrzejewski, 1990, Müller-Schwarze, 1972, Stoddart, 1980, Weldon, 1990) and laboratory environment (Blanchard et al., 1989, Dell'Omo et al., 1994; Fendt et al., this issue; Zangrossi and File, 1992). In the laboratory, the odors of predators most frequently employed to analyze fear in rodents include cat odor and

Neural modulation of predator odor-induced fear

Within the last 5 years, a number of laboratories have begun to examine the neural correlates of predator odor-induced fear in the adult rodent. An emerging view is that some brain regions underlying predator odor-induced unconditioned fear may involve brain areas previously overlooked in the shock-induced fear conditioning literature. In addition, exposure to cat odor and TMT were shown to involve similar as well as different brain regions in the modulation of fear behavior.

Summary and conclusions

The use of predator odors such as cat odor and TMT provide researchers new opportunities to investigate the behavioral, endocrine, and neural basis of unconditioned fear. We have conducted studies in rats to determine the effects of different amounts of cat odor on behavior. These studies indicate that the amount of cat odor presented to rats has pronounced effects on fear-related behavioral habituation and extinction. High amounts of predator odor are more likely to elevate the state of fear,

Acknowledgements

Preparation of this review and research conducted in our laboratory were supported by NIH grants NS 39406, 5 R25 GM56930-07, the Richard H. and Mildred D. Kosaki Student Awards and the University Research Council.

References (84)

  • B.A. Kapp et al.

    Amygdala central nucleus lesions: effect of heart rate conditioning in the rabbit

    Physiol. Behav.

    (1979)
  • T. Kikusui et al.

    Alarm pheromone enhances stress-induced hyperthermia in rats

    Physiol. Behav.

    (2001)
  • S. Kollack-Walker et al.

    Mating and agonistic behavior produce different patterns of Fos immunolabeling in the male Syrian hamster brain

    Neuroscience

    (1995)
  • T.R. Laxmi et al.

    Generalisation of conditioned fear and its behavioral expression in mice

    Behav. Brain Res.

    (2003)
  • A. Mackay-Sim et al.

    Discrimination of odors from stressed rats by non-stressed rats

    Physiol. Behav.

    (1980)
  • C.M. Markham et al.

    Modulation of predatory odor processing following lesions to the dorsal premammillary nucleus

    Neurosci. Lett.

    (2004)
  • I.S. McGregor et al.

    Not all ‘predator odours’ are equal: cat odour but not 2,4,5 trimethylthiazoline (TMT; fox odour) elicits specific defensive behaviours in rats

    Behav. Brain Res.

    (2002)
  • S. Moriceau et al.

    Corticosterone controls the developmental emergence of fear and amygdala function to predator odors in infant rat pups

    Int. J. Dev. Neurosci.

    (2004)
  • B.A. Morrow et al.

    The predator odor, TMT, displays a unique, stress-like pattern of dopaminergic and endocrinological activation in the rat

    Brain Res.

    (2000)
  • B.A. Morrow et al.

    TMT, a predator odor, elevates mesoprefrontal dopamine metabolic activity and disrupts short-term working memory in the rat

    Brain Res. Bull.

    (2000)
  • K.M. Myers et al.

    Behavioral and neural analysis of extinction

    Neuron

    (2002)
  • S. Shibata et al.

    Differential effects of medial, central and basolateral amygdaloid lesions on four models of experimentally-induced aggression in rats

    Physiol. Behav.

    (1982)
  • A.M. Van der Poel

    A note of ‘stretched attention’, a behavioural element indicative of an approach-avoidance conflict in rats

    Anim. Behav.

    (1979)
  • K.L. Weller et al.

    Afferent connections to the bed nucleus of the stria terminalis

    Brain Res.

    (1982)
  • C.P. Wiedenmayer et al.

    Developmental changes in c-fos expression to an age-specific social stressor in infant rats

    Behav. Brain Res.

    (2001)
  • H. Zangrossi et al.

    Behavioral consequences in animal tests of anxiety and exploration of exposure to cat odor

    Brain Res. Bull.

    (1992)
  • H. Zangrossi et al.

    Habituation and generalization of phobic responses to cat odor

    Physiol. Behav.

    (1994)
  • J.X. Zhang et al.

    Cryogenic blockade of the central nucleus of the amygdala attenuates aversively conditioned blood pressure and respiratory responses

    Brain Res.

    (1986)
  • R.J. Blanchard et al.

    Crouching as an index of fear

    J. Comp. Physiol. Psychol.

    (1969)
  • R.J. Blanchard et al.

    Ethoexperimental approaches to the study of defensive behavior

  • D.C. Blanchard et al.

    Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli

    Behav. Neurosci.

    (2003)
  • D.C. Blanchard et al.

    Changes in defensive behavior with lesions of areas expressing c-fos to cat odor

    Int. Behav. Neurosci. Soc. Abstr.

    (2004)
  • N.S. Canteras et al.

    Organization of projections from the medial nucleus of the amygdala: a phal study in the rat

    J. Comp. Neurol.

    (1995)
  • W.J. Carr et al.

    Responses of mice to odors associated with stress

    J. Comp. Physiol. Psychol.

    (1970)
  • D. Champagne et al.

    CRFergic innervation of the paraventricular nucleus of the rat hypothalamus: a tract-tracing study

    J. Neuroendocrinol.

    (1998)
  • M. Davis

    Neurobiology of fear responses: the role of the amygdala

    J. Neuropsychiatry Clin. Neurosci.

    (1997)
  • M. Davis et al.

    The extended amygdala: are the central nucleus of the amygdala and the bed nucleus of the stria terminalis differentially involved in fear versus anxiety

    Ann. NY Acad. Sci.

    (1999)
  • M. Davis et al.

    The amygdala: vigilance and emotion

    Mol. Psychiatry

    (2001)
  • G. Dell'Omo et al.

    Strain differences in mouse response to odors of predator

    Behav. Proc.

    (1994)
  • C.R. Dickman et al.

    Responses of small mammals to red fox (Vulpes vulpes) odor

    J. Zool.

    (1984)
  • R.A. Dielenberg et al.

    Habituation of the hiding response to cat odor in rats (Rattus norvegicus)

    J. Comp. Psychol.

    (1999)
  • M.S. Fanselow et al.

    Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist, d,l-2-amino-5-phosphonovaleric acid, to the basolateral amygdala

    Behav. Neurosci.

    (1994)
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