線蟲制約迴避行為中的多巴胺神經調節作用

Abstract

動物藉由學習過往的經驗來適應環境，且這樣的行為可塑性(behavioral plasticity)被認為是動物在環境中生存並最佳化適應性的方式。感受刺激的效價(valence)則可以藉由同時發生的獎勵或是處罰而改變，並且神經調節作用(neuromodulation)在這個制約學習中扮演重要的角色。然而，目前對於此過程的分子及神經迴路機制還未完全暸解。秀麗隱桿線蟲(Caenorhabditis elegans)以細菌為食。而這樣天生的食物偏好，在受到藉由藥理，或是遺傳上的操弄所造成的粒線體(mitocondria)或著其他重要的生理功能損傷時，會轉變為迴避行為。我們發現多巴胺(dopamine)對於此制約迴避細菌的行為是重要的。此角色與已知多巴胺在關於學習獎勵上的功能大相逕庭。我們的研究顯示當抑制多巴胺生合成及再吸收時，可削弱制約迴避細菌的行為，並且透過補充多巴胺可回復此現象。七種被認為是多巴胺的受器中，dop-3可能在此迴避行為中扮演角色。此外，在dop-1，dop-2，dop-3等多巴胺受器的雙突變株或三突變株也可看到迴避行為的減少，暗示這三個多巴胺受器具有重複的功能來傳遞迴避行為中的多巴胺訊號。我們的表現形態分析暗示這些多巴胺受器可能表現在多個神經元中。闡明多巴胺傳遞的神經迴路機制將有助於理解制約迴避行為中的神經基礎。

Animals adapt to the environment by learning from past experience, and this behavioral plasticity is thought to optimize fitness and survival of the animals in the natural habitat. The valence of sensory cues can be modified by concurrent reward or penalty, and neuromodulation plays a critical role in this conditioned learning, but the molecular and circuit mechanisms are incompletely understood. In Caenorhabditis elegans, innate preference for nutritious bacterial food can switch to aversion when mitochondrial or other core physiological functions are concurrently disrupted by genetic or pharmacologic manipulation. We find that dopamine is important for this conditioned bacterial avoidance, a role that is distinct from its well-established function in learning associated with rewards. We show that inhibiting dopamine synthesis or reuptake weakens conditioned avoidance behavior, which can be restored by supplement of dopamine. Among seven putative dopamine receptors, dop-3 may play a role in avoidance behavior. In addition, double or triple mutations of dop-1, dop-2 and dop-3 receptor genes diminish avoidance behavior, suggesting that these three dopamine receptor genes act redundantly to transmit dopamine signal for avoidance. Our expression analyses suggest that these receptors may be expressed in several neurons. Elucidation of the circuit mechanisms of dopaminergic transmission will provide important insight into the neural basis of aversive conditioned learning.