Rivi Veronica, Sarti Pierfrancesco, Fodor Istvan, Pirger Zsolt, Koene Joris M, Pani Luca, Batabyal Anuradha, Lukowiak Ken, Blom Johanna Maria Catharina, Tascedda Fabio, Benatti Cristina
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Department of Adult Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
Transl Psychiatry. 2025 May 22;15(1):177. doi: 10.1038/s41398-025-03399-z.
Anxiety, a behavioral consequence of stress, has been characterized in humans and some vertebrates but remains largely unexplored in invertebrates. Here, we demonstrate that after being exposed to fish water, which simulates the presence of predators, pond snails (Lymnaea stagnalis) exhibit a series of sustained fear responses. These include increased aerial respiration, changes in righting behavior, and reduced escape responses. Notably, these behaviors persist even after the stressor (fish water) is removed, indicating that they likely represent an anxiety-like state rather than a simple conditioned reflex. Additionally, exposure to fish water enhances long-term memory formation for the operant conditioning of aerial respiration, suggesting that the predator scent potentially induces a state of heightened alertness, which enhances memory consolidation processes. Furthermore, when snails experience fish water alongside an appetitive stimulus (carrot), they form configural learning-a higher form of learning - where the appetitive stimulus now triggers a fear response instead of eliciting feeding. Importantly, the anxiolytic drug alprazolam prevents these anxiety-like responses. Through dose-response experiments, we found that alprazolam at a concentration of 0.1 µM for 15 min effectively counteracts predator-induced anxiety without causing sedation. This treatment also prevents the effects of predator cues on learning and memory. However, consistent with data from vertebrates - alprazolam induces anterograde amnesia, impairing the formation of new memories for up to 3 h after treatment, though it does not cause long-term memory deficits. Overall, this is the first study showing that a molluscan model organism exhibits anxiety-like behaviors similar to those seen in vertebrates, and these behaviors can be mitigated by an anti-anxiety drug. This suggests that fundamental anxiety mechanisms are evolutionarily conserved across species. By using this simple invertebrate model, our research offers new insights into the biological basis of anxiety and sets the stage for future pharmacological studies.
焦虑是压力的一种行为后果，在人类和一些脊椎动物中已有描述，但在无脊椎动物中仍基本未被探索。在此，我们证明，暴露于模拟捕食者存在的鱼水后，池塘蜗牛（椎实螺）会表现出一系列持续的恐惧反应。这些反应包括空气呼吸增加、翻正行为改变和逃避反应减少。值得注意的是，即使在应激源（鱼水）被移除后，这些行为仍然持续，这表明它们可能代表一种类似焦虑的状态，而不是简单的条件反射。此外，暴露于鱼水会增强空气呼吸操作性条件反射的长期记忆形成，这表明捕食者的气味可能会诱导一种警觉性提高的状态，从而增强记忆巩固过程。此外，当蜗牛在接触鱼水的同时经历一种食欲刺激（胡萝卜）时，它们会形成构型学习——一种更高形式的学习——此时食欲刺激现在会引发恐惧反应而不是引发进食。重要的是，抗焦虑药物阿普唑仑可预防这些类似焦虑的反应。通过剂量反应实验，我们发现浓度为0.1µM的阿普唑仑作用15分钟可有效抵消捕食者诱导的焦虑，且不会引起镇静作用。这种治疗还可预防捕食者线索对学习和记忆的影响。然而，与脊椎动物的数据一致——阿普唑仑会诱导顺行性遗忘，在治疗后长达3小时内损害新记忆的形成，尽管它不会导致长期记忆缺陷。总体而言，这是第一项表明软体动物模型生物表现出与脊椎动物类似的焦虑样行为，且这些行为可通过抗焦虑药物减轻的研究。这表明基本的焦虑机制在物种间具有进化保守性。通过使用这种简单的无脊椎动物模型，我们的研究为焦虑的生物学基础提供了新的见解，并为未来的药理学研究奠定了基础。
