Bervoets Sven, Jacob Miles Solomon, Devineni Anita V, Mahoney Brennan Dale, Sullivan Kaelan R, Butts Andrew R, Sung Hayeon, Einstein Jenifer, Metzstein Mark M, Dus Monica, Shepherd Jason D, Caron Sophie Jeanne Cécile
bioRxiv. 2024 Nov 8:2024.11.04.621761. doi: 10.1101/2024.11.04.621761.
The genes - which include and ( ) - evolved from Ty3 retrotransposons and encode proteins that form virus-like capsids. These capsids enable a novel form of intercellular communication by transferring RNAs between cells. However, the specific neuronal circuits and brain processes Arc intercellular signaling regulates remain unknown. Here, we show that loss of both genes in enhances associative learning in an appetitive conditioning paradigm, where flies associate an odor with sugar rewards. This increased learning performance arises from an increased valuation of sugar rewards: unlike wild-type flies, flies form abnormally strong associations even when the sugar reward is small or has no caloric value. We found that the γ5-dopaminergic neurons of the protocerebral anterior medial (PAM) cluster, which encode the positive valence of sugar rewards, show heightened activity in response to sucrose in flies. We further show that the learning phenotype of flies depends on the formation of capsids, underscoring a direct role for capsid-mediated Arc signaling in sugar valuation. Our findings establish genes as critical regulators of reward valuation in , acting through a non-cell autonomous mechanism that relies on capsid-mediated communication between cells.
这些基因——包括Arc和Arc2（CG17864）——从Ty3逆转座子进化而来，编码形成病毒样衣壳的蛋白质。这些衣壳通过在细胞间转移RNA实现一种新型的细胞间通讯形式。然而，Arc细胞间信号传导所调节的具体神经回路和大脑过程仍不清楚。在这里，我们表明，果蝇中这两个Arc基因的缺失在一种味觉条件范式中增强了联想学习，即果蝇将一种气味与糖分奖励联系起来。这种学习表现的提高源于对糖分奖励的估值增加：与野生型果蝇不同，即使糖分奖励很小或没有热量价值，Arc基因缺失的果蝇也会形成异常强烈的关联。我们发现，原脑前内侧（PAM）簇中的γ5-多巴胺能神经元编码糖分奖励的正价，在Arc基因缺失的果蝇中，它们对蔗糖的反应表现出增强的活性。我们进一步表明，Arc基因缺失的果蝇的学习表型取决于衣壳的形成，这突出了衣壳介导的Arc信号在糖分估值中的直接作用。我们的研究结果确立了Arc基因作为果蝇奖励估值的关键调节因子，通过一种非细胞自主机制发挥作用，该机制依赖于细胞间衣壳介导的通讯。
