Repeated exposure to the smell of innate fear, trimethylthiazoline, promotes fear habituation and hippocampal cell proliferation in rats.

Abstract

Synthetic predator scents such as trimethylthiazoline (TMT) evoke innate fear responses in rodents, reflecting evolutionarily conserved defense mechanisms. Previous studies have shown that after repeated exposure to innate fear stimuli would induce adaptive processes, including habituation and desensitization, which may involve additional neural circuits apart from the amygdala, particularly the hippocampus, which is involved in various forms of learning and memory. To elucidate whether the habituation induced by repeated exposure to innate fear stress is associated with plasticity in the hippocampus, the present study examined whether repeated exposure to TMT (i) attenuates innate fear responses and (ii) affects hippocampal neurogenesis. Twenty male Sprague Dawley rats were randomly assigned to the control (distilled water) or TMT-exposed groups for 14 days. Behavioral assays on anxiety- and depression-like behaviors were assessed after the exposure period. Serum samples were collected 2-3 days following the exposure, while neurogenesis and cell differentiation in brain tissues were analyzed. The results demonstrated that repeated TMT exposure facilitated fear habituation. Interestingly, no significant changes in anxiety- or depression-like behaviors were found even when exposure to TMT is regarded as a stressful stimulation. Additionally, hippocampal cell proliferation increased, and the total number of immature neurons decreased after repeated exposure to TMT. Instead of neurons, there is a significant increase in the proportion of new cells that adopt an astrocytic fate. The current results support that stress due to predator odor promotes hippocampal proliferation, inhibits neurogenesis, and alters glial cell fate adoption, which reveals a complex structural remodeling under repeated TMT exposure and fear habituation.