Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut 06001.
Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut 06001
J Neurosci. 2021 May 12;41(19):4262-4275. doi: 10.1523/JNEUROSCI.0027-21.2021. Epub 2021 Mar 31.
Animals, including humans, readily learn to avoid harmful and threatening situations by moving in response to cues that predict the threat (e.g., fire alarm, traffic light). During a negatively reinforced sensory-guided locomotor action, known as signaled active avoidance, animals learn to avoid a harmful unconditioned stimulus (US) by moving away when signaled by a harmless conditioned stimulus (CS) that predicts the threat. CaMKII-expressing neurons in the pedunculopontine tegmentum area (PPT) of the midbrain locomotor region have been shown to play a critical role in the expression of this learned behavior, but the activity of these neurons during learned behavior is unknown. Using calcium imaging fiber photometry in freely behaving mice, we show that PPT neurons sharply activate during presentation of the auditory CS that predicts the threat before onset of avoidance movement. PPT neurons activate further during the succeeding CS-driven avoidance movement, or during the faster US-driven escape movement. PPT neuron activation was weak during slow spontaneous movements but correlated sharply with movement speed and, therefore, with the urgency of the behavior. Moreover, using optogenetics, we found that these neurons must discharge during the signaled avoidance interval for naive mice to effectively learn the active avoidance behavior. As an essential hub for signaled active avoidance, neurons in the midbrain tegmentum process the conditioned cue that predicts the threat and discharge sharply relative to the speed or apparent urgency of the avoidance (learned) and escape (innate) responses. During signaled active avoidance behavior, subjects move away to avoid a threat when directed by an innocuous sensory stimulus. Using imaging methods in freely behaving mice, we found that the activity of neurons in a part of the midbrain, known as the pedunculopontime tegmentum, increases during the presentation of the innocuous sensory stimulus that predicts the threat and also during the expression of the learned behavior as mice move away to avoid the threat. In addition, inhibiting these neurons abolishes the ability of mice to learn the behavior. Thus, neurons in this part of the midbrain code and are essential for signaled active avoidance behavior.
动物（包括人类）通过对预测威胁的线索做出反应来避免有害和危险的情况，这一过程非常迅速。在一种被称为有信号的主动回避的负强化感觉引导运动行为中，动物通过在无害的条件刺激（CS）发出信号预测威胁时移动来避免有害的非条件刺激（US）。在中脑运动区域的被盖桥脑脚核区（PPT）中表达 CaMKII 的神经元已被证明在学习行为的表达中起着关键作用，但这些神经元在学习行为期间的活动尚不清楚。通过在自由活动的小鼠中使用钙成像光纤光度法，我们发现，在回避运动开始之前，PPT 神经元在听觉 CS 发出时会急剧激活，该 CS 预测威胁。PPT 神经元在随后的 CS 驱动的回避运动或更快的 US 驱动的逃避运动中进一步激活。PPT 神经元在缓慢的自发运动期间的激活较弱，但与运动速度高度相关，因此与行为的紧迫性相关。此外，使用光遗传学，我们发现，对于天真的小鼠来说，这些神经元必须在有信号的回避间隔内放电，才能有效地学习主动回避行为。作为有信号的主动回避的重要枢纽，中脑被盖区的神经元处理预测威胁的条件线索，并在回避（学习）和逃避（本能）反应的速度或明显紧迫性方面急剧放电。在有信号的主动回避行为中，当被指导时，动物会避开威胁，远离威胁。通过在自由活动的小鼠中使用成像方法，我们发现，中脑一部分（称为被盖桥脑脚核区）的神经元在预测威胁的无害感觉刺激呈现时以及在小鼠移动以回避威胁时的学习行为表达期间，其活动增加。此外，抑制这些神经元会使小鼠丧失学习该行为的能力。因此，中脑这一部分的神经元对有信号的主动回避行为进行编码，并对其必不可少。
