Rap1b but not Rap1a in the forebrain is required for learned fear
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Cell & Bioscience Open Access
RESEARCH
Rap1b but not Rap1a in the forebrain is required for learned fear Wen‑Bing Chen1,2†, Han‑Qing Pan1,2†, Ye He2,3, Xue‑Hui Wang1,2, Wen‑Hua Zhang2 and Bing‑Xing Pan1,2,4*
Abstract Background: Fear is an adaptive response across species in the face of threatening cues. It can be either innate or learned through postnatal experience. We have previously shown that genetic deletion of both Rap1a and Rap1b, two isoforms of small GTPase Rap1 in forebrain, causes impairment in auditory fear conditioning. However, the spe‑ cific roles of these two isoforms are not yet known. Results: In the present study, employing mice with forebrain-restricted deletion of Rap1a or Rap1b, we found that they are both dispensable for normal acquisition of fear learning. However, Rap1b but not Rap1a knockout (KO) mice displayed impairment in the retrieval of learned fear. Subsequently, we found that the expression of c-Fos, a marker of neuronal activity, is specifically decreased in prelimbic cortex (PL) of Rap1b KO mice after auditory fear conditioning, while remained unaltered in the amygdala and infralimbic cortex (IL). On the other hand, neither Rap1a nor Rap1b knockout altered the innate fear of mice in response to their predator odor, 2,5-Dihydro-2,4,5-Trimethylthiazoline (TMT). Conclusion: Thus, our results indicate that it is Rap1b but not Rap1a involved in the retrieval process of fear learning, and the learned but not innate fear requires Rap1 signaling in forebrain. Keywords: Rap1, Learned fear, Innate fear, Amygdala, mPFC Background Fear is an adaptive response across species upon the emergence of threatening cues in environment and is critical for survival [1]. It can be either inherited (known as innate fear) or achieved through learning during postnatal life (learned fear) [2]. In the past decades, understanding how fearful response is formed in the face of threat has attracted wide attention, partly due to the increasing prevalence of fear-related neuropsychiatric disorders [1, 3]. Studies in both human being and animals have shown that innate and learned fear share much in the circuit mechanisms that mediate fear-related behaviors like “fight-or-flight” [1, 4]. However, the roles of specific molecules in these two forms of behaviors may vary *Correspondence: [email protected] † Wen-Bing Chen and Han-Qing Pan contributed equally to this work 1 School of Life Sciences, Nanchang University, Nanchang 330031, China Full list of author information is available at the end of the article
dramatically. For example, stathmin and acid-sensing ion channel 1, two amygdala-enriched genes, were shown to be critical for both innate and learned fear [5, 6]. In contrast, zinc transporter 3, another amygdala-concentrated gene, was only required for learned but not innate fear [7]. Furthermore, BDNF in prelimbic cortex, a region critical for fear behavior, was also shown to be required selectively for learned fear [8]. Rap1, an important member of small GTPase Ras family, is ubiquitously expresse
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