Glia Accumulate Evidence that Actions Are Futile and Suppress Unsuccessful Behavior

When a behavior repeatedly fails to achieve its goal, animals often give up and become passive, which can be strategic for preserving energy or regrouping between attempts. It is unknown how the brain identifies behavioral failures and mediates this behavioral-state switch. In larval zebrafish swimming in virtual reality, visual feedback can be withheld so that swim attempts fail to trigger expected visual flow. After tens of seconds of such motor futility, animals became passive for similar durations. Whole-brain calcium imaging revealed noradrenergic neurons that responded specifically to failed swim attempts and radial astrocytes whose calcium levels accumulated with increasing numbers of failed attempts. Using cell ablation and optogenetic or chemogenetic activation, we found that noradrenergic neurons progressively activated brainstem radial astrocytes, which then suppressed swimming. Thus, radial astrocytes perform a computation critical for behavior: they accumulate evidence that current actions are ineffective and consequently drive changes in behavioral states.

当某一行为反复无法达成目标时，动物通常会放弃并进入被动状态，该策略有助于保存能量或在各次尝试间隙完成状态重整。目前学界尚未明确大脑如何识别行为失败，并介导此种行为状态的转换。在虚拟现实环境中游动的幼体斑马鱼（larval zebrafish）模型中，可通过阻断视觉反馈，使得游动尝试无法触发预期的视觉流动（visual flow）。在经历数十秒的此类运动无效尝试后，动物会进入与该时长相近的被动状态。全脑钙成像（whole-brain calcium imaging）结果显示，存在两类特异性响应细胞：一类是仅对失败的游动尝试产生反应的去甲肾上腺素能神经元（noradrenergic neurons），另一类是其钙水平随失败尝试次数增加而逐渐累积的放射状星形胶质细胞（radial astrocytes）。通过细胞消融（cell ablation）以及光遗传（optogenetic）或化学遗传（chemogenetic）激活实验，我们发现去甲肾上腺素能神经元会逐步激活脑干中的放射状星形胶质细胞，而后者随后会抑制游动行为。综上，放射状星形胶质细胞承担了对行为至关重要的计算功能：它们会累积“当前行动无效”的证据，并据此驱动行为状态的改变。