Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors

Abstract

Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1−/− mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

“…Accordingly, two major brain strategies for behavioral control have been selected. In the first, developmentally specified neural circuits generate rapid innate responses to sensory stimuli that have remained relatively constant and predictable over evolutionary timescales (1)(2)(3)(4)(5). In the second, neural circuits generate flexible responses to stimuli that can change over an individual's lifespan, through learning and memory (6)(7)(8).…”

Enhanced sensory coding in mouse vibrissal and visual cortex through TRPA1

“…TRPA1 belongs to the superfamily of TRP channels, a group of non-selective cation channels that are widely preserved throughout evolution. In simpler organisms, such as invertebrates, TRP channels play a role in sensation of external stimuli including light, sound, chemicals, temperature, and touch [26][27][28][29][30] and are involved in generation of behavioral responses [27,[31][32][33][34]. Our findings indicate that, as in simpler nervous systems, TRPA1 may contribute to processing of sensory information in the rodent cortex.…”

Posterior subthalamic nucleus (PSTh) mediates innate fear-associated hypothermia

“…We compared the 2MT-induced thermoregulatory response between wild-type and Trpa1 -/mice using a behavior paradigm as previously described 33,35 . To study the effect of 2MT on the change of body temperature, we used infrared (IR) thermography combined with implanted telemetry transmitter to measure in real time the cutaneous and core body temperature, respectively (Fig.…”

“…On the other hand, potent stress or fear stimuli that threaten the survival of animals, such as long-lasting immobile stress and hypoxia, induces hypothermia 9,[28][29][30] . Moreover, potent innate fear odor 2MT can trigger acute hypothermia accompanying robust defensive behaviors, such as freezing 33,34,35 . Thus, it is plausible that extreme stress or fear stimuli may induce hypothermia to promote animal survival, although the biological significance of stress/fear-evoked hypothermia is unclear.…”

“…It has been shown that 2-methyl-2-thiazoline (2MT), a potent analog of predator odor 2,4,5trimethyl-3-thiazoline (TMT), elicits highly robust innate fear/defensive behaviors, such as freezing, in naïve mice 33,34 . Through forward genetics screening of randomly mutagenized mice, we identified the transient receptor potential A1 (Trpa1) mutant as deficient for 2MT/TMT-and snake skin-evoked innate defensive behaviors 33 .…”