Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: A model for animal phobias

doi:10.1016/j.neubiorev.2008.05.006

Neuroscience & Biobehavioral Reviews

Volume 32, Issue 7, September 2008, Pages 1267-1276

https://doi.org/10.1016/j.neubiorev.2008.05.006 Get rights and content

Abstract

Specific phobias, including animal phobias, are the most common anxiety disorders, and have a strong innate and genetic component. Research on the neurobiology and environmental constraints of innate fear of predators in rodents may be useful in elucidating mechanisms of animal phobias in humans. The present article reviews research on innate fear in rats to trimethylthiazoline (TMT), an odor originally isolated from fox feces. TMT induces unconditioned freezing and other defensive responses that are regulated by the dose of TMT and the shape of the testing environment. Contextual conditioning induced by TMT occurs, but is constrained by the environment. Lesion studies indicate the amygdala circuitry subserving fear conditioning is not necessary for unconditioned fear to TMT. Additionally, a medial hypothalamic defensive circuit also appears not necessary for unconditioned freezing to TMT, whereas circuits that include the medial nucleus of the amygdala and the bed nucleus of the stria terminalis are essential. The importance of these findings of innate predator odor fear in rodents to animal phobias in humans is discussed.

Section snippets

Environmental constraints of TMT-induced behavior

Although the perception of TMT and other predator odors appears to be innate, defensive responses are not simply reflexive, but are complex behaviors shaped by environmental demands and situations (Bolles, 1970). For predator odors the most comprehensive analyses have been done by Blanchard and Blanchard, 1989, Blanchard and Blanchard, 2003; Blanchard et al., 1990, Blanchard et al., 1997, Blanchard et al., 2001) in a visible burrow system and other environments, and Dielenberg and McGregor

Neuroanatomy of predator odor fear

It is well accepted that an amygdala circuit is necessary for fear conditioning (Amorapanth et al., 2000, Campeau and Davis, 1995, Fanselow and Kim, 1994, Goosens and Maren, 2001, Hitchcock and Davis, 1986, Kapp et al., 1979, Kim et al., 1992, Kim et al., 1993, LeDoux et al., 1990, Malkani and Rosen, 2001, Maren et al., 1996, Maren, 1999, Miserendino et al., 1990, Nader et al., 2001, Wallace and Rosen, 2001). The lateral and basal nuclei of the amygdala together comprise the basolateral

Conclusions

We started this article by discussing the strong genetic and biological underpinnings of specific phobic disorders in humans, including animal phobias. Genetics appear to play a primary role (Kendler et al., 1999, Kendler et al., 2001, Kendler et al., 2002a), with associative conditioning processes being secondary (Hettema et al., 2007, Kendler et al., 2002b, Poulton and Menzies, 2002, Rachman, 2002). The studies described in this article on fear of TMT in rats demonstrate strong innate

Acknowledgements

The research was supported by a grant from the National Science Foundation IBN-0129809 to Jeffrey B. Rosen. Jerome H. Pagani was partially supported by a graduate student stipend from University of Delaware. Cameron Davis was supported by a Delaware INBRE grant from the National Institutes of Health.

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Citation Excerpt :
The olfactory bulb sends excitatoty project to the brain regions modulating innate fear physiologically and behaviorally (Takahashi, 2014). Thus TMT can be used to study the neurobiology of innate fear (Hacquemand et al., 2013; Rosen et al., 2008). In this study, we found that TMT expose significantly increase the c-Fos expression in LH, and sniffing TMT induced a significant increase in the activity of LH glutamatergic neurons, while inhibiting these neurons suppressed the avoidance behavior promoted by TMT.
The glutamatergic lateral hypothalamus (LH) has been implicated in a variety of behaviors, such as evasion and feeding, while its role in defensive behaviors and relevant neurocircuits remains unclear. Here, we demonstrated that the glutamatergic LH is a critical structure regulating defensive behaviors. Trimethylthiazole (TMT), the odor of mice predator, significantly increased c-Fos expression in the LH. Using fiber photometry technology, we found that TMT exposure increased the activity of LH glutamatergic neurons. Selective activation of LH glutamatergic neurons with optogenetics and chemogenetics promoted a series of defense-related behaviors, including fleeing, avoidance, and hiding, while selective inhibition of LH glutamatergic neurons suppressed the avoidance provoked by TMT. Activation of both the glutamatergic LH terminals in the hypothalamic paraventricular nucleus (PVN) and the glutamatergic projection from the basolateral amygdala (BLA) to the LH elicited defensive behaviors. Finally, by combining the viral-mediated retrograde tracing with anterograde activation, we found that PVN-projecting glutamatergic neurons in the LH were activated by BLA glutamatergic inputs. Taken together, our results illustrate that the glutamatergic LH is a pivotal relay of defensive behaviors and possibly promotes these behaviors through the BLA→LH→PVN pathway.

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ReviewAnalysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: A model for animal phobias

Abstract

Section snippets

Environmental constraints of TMT-induced behavior

Neuroanatomy of predator odor fear

Conclusions

Acknowledgements

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neurosci. Lett.

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Physiol. Behav.

Brain Res. Bull.

Neurosci. Biobehav. Rev.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Clin. Psychol. Rev.

Biol. Psychiatry

Brain Res.

Biol. Psychol.

Brain Res.

Brain Res.

Neuroscience

Neurosci. Biobehav. Rev.

Neurosci. Lett.

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Brain Res.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Brain Res.

Brain Res.

Physiol. Behav.

Brain Res.

Biol. Psychiatry

Behav. Res. Ther.

Neuroscience

Neurosci. Lett.

Physiol. Behav.

Prog. Neurobiol.

Behav. Brain Res.

Behav. Brain Res.

Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus

Nat. Neurosci.

Behavioural aspects of fear

Anxiety and its Disorders: the Nature and Treatment of Anxiety and Panic

Are emotions natural kinds?

Perspect. Psychol. Sci.

Neural systems for the expression of hypoalgesia during nonassociatiave fear

Behav. Neurosci.

Crouching as an index of fear

J. Comp. Physiol. Psychol.

Innate and conditioned reactions to threat in rats with amygdaloid lesions

J. Comp. Physiol. Psychol.

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

Behav. Neurosci.

Antipredator defensive behaviors in a visible burrow system

J. Comp. Psychol.

An ethoexperimental approach to the study of defense

Species-specific defensive reactions and avoidance learning

Psychol. Rev.

Comparative behavioral effects between synthetic 2,4,5-trimethylthiazoline (TMT) and the odor of natural fox (Vulpes vulpes) feces in mice

Behav. Neurosci.

Involvement of the central and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli

J. Neurosci.

Review
Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: A model for animal phobias