The cerebellum and reward-driven behavior Damage to the cerebellum manifests itself in various forms of cognitive impairment and abnormal social behavior. However, the exact role the cerebellum plays in these conditions is far from clear. Working in mice, Carta et al. found direct projections from the deep cerebellar nuclei to the brain's reward center, a region called the ventral tegmental area (see the Perspective by D'Angelo). These direct projections allowed the cerebellum to play a role in showing a social preference. Intriguingly, this pathway was not prosocial on its own. Cerebellar inputs into the ventral tegmental area were more active during social exploration. Depolarization of ventral tegmental area neurons thus represents a similar reward stimulus as social interaction for mice. Science, this issue p. eaav0581; see also p. 229 The cerebellum plays a role in cognitive and emotional control in mice. INTRODUCTION Although the cerebellum has long been considered to be a purely motor structure, recent studies have revealed that it also has critical nonmotor functions. Cerebellar dysfunction is implicated in addictive behavior and in mental disorders such as autism spectrum disorder (ASD), cognitive affective syndrome, and schizophrenia. The cerebellum is well poised to contribute to behavior because it receives a wide array of cortical and sensory information and is subject to control by a number of neuromodulators. To perform its function, the cerebellum is believed to integrate these diverse inputs to provide the rest of the brain with predictions required for optimal behavior. Although there are many pathways for this to occur in the motor domain, fewer exist for the nonmotor domain. RATIONALE There are no direct pathways emanating from the cerebellum that have been shown to serve nonmotor functions. We hypothesized that the cerebellum may contribute to motivated behavior by a direct projection to the ventral tegmental area (VTA), a structure that is critical for the perception of reward and control of social behaviors. Such a projection would explain why functional imaging experiments indicate that the cerebellum plays a role in addiction and would provide one potential mechanism by which cerebellar dysfunction might contribute to the symptoms of mental disorders. RESULTS In mice, we found that monosynaptic excitatory projections from the cerebellar nuclei to the VTA powerfully activate the reward circuitry and contribute to social behavior. Using anatomical tracing, we showed that axonal projections from the cerebellar nuclei form synapses with both dopaminergic and nondopaminergic neurons in the VTA. The cerebello-VTA (Cb-VTA) projections were powerful and their optogenetic stimulation robustly increased the activity of VTA neurons both in vivo and in vitro. Behavioral tests to examine reward processing showed that stimulation of the Cb-VTA projections was sufficient to cause short-term and long-term place preference, thereby demonstrating that the pathway was rewarding. Although optogenetic inhibition of Cb-VTA projections was not aversive, it completely abolished social preference in the three-chamber test for sociability, which suggests that the cerebellar input to the VTA is required for normal social behavior. A role for the cerebellum in social behavior was also indicated by correlation between calcium activity in these axons and performance in the three-chamber test. However, optogenetic activation of the Cb-VTA inputs was not prosocial, hence the pathway was not sufficient for social behavior. CONCLUSION The Cb-VTA pathway described here is a monosynaptic projection from the cerebellum to a structure known primarily for its nonmotor functions. Our data support a role for the cerebellum in reward processing and in control of social behavior. We propose that this Cb-VTA pathway may explain, at least in part, the association between the cerebellum and addictive behaviors, and provides a basis for a role for the cerebellum in other motivated and social behaviors. In addition to contributing to reward processing, the VTA also targets a number of other brain regions, such as the prefrontal cortex, that in turn sustain a large repertoire of motor and nonmotor behaviors. Direct cerebellar innervation of the VTA provides a pathway by which the cerebellum may modulate these diverse behaviors. The Cb-VTA pathway delineated here provides a mechanism by which cerebellar dysfunction, by adversely affecting the VTA and its targets, might contribute to mental disorders such as ASD and schizophrenia. The cerebellum sends direct excitatory projections to the ventral tegmental area (Cb-VTA). These projections likely play a role in reward processing and addictive behavior, are required (but not sufficient) for social behavior, and may constitute one of the major pathways by which cerebellar dysfunction contributes to mental disorders. The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to these disorders is not well understood. In mice, we found that the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward. Optogenetic activation of the cerebello-VTA projections was rewarding and, in a three-chamber social task, these projections were more active when the animal explored the social chamber. Intriguingly, activity in the cerebello-VTA pathway was required for the mice to show social preference in this task. Our data delineate a major, previously unappreciated role for the cerebellum in controlling the reward circuitry and social behavior.

中文翻译：

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奖励回路和社会行为的小脑调节

小脑和奖励驱动的行为 小脑的损伤表现为各种形式的认知障碍和异常的社会行为。然而，小脑在这些情况下所起的确切作用尚不清楚。在小鼠中工作，Carta 等人。发现从深小脑核到大脑奖励中心的直接投影，该区域称为腹侧被盖区（参见 D'Angelo 的观点）。这些直接投射允许小脑在表现出社会偏好方面发挥作用。有趣的是，这条途径本身并不亲社会。进入腹侧被盖区的小脑输入在社会探索过程​​中更为活跃。因此，腹侧被盖区神经元的去极化代表了与小鼠社交互动类似的奖励刺激。科学，这个问题 p。eaav0581; 另见第。229 小脑在小鼠的认知和情绪控制中起作用。引言 虽然小脑长期以来被认为是一个纯粹的运动结构，但最近的研究表明它也具有关键的非运动功能。小脑功能障碍与成瘾行为和精神障碍有关，例如自闭症谱系障碍 (ASD)、认知情感综合征和精神分裂症。小脑准备好对行为做出贡献，因为它接收大量的皮层和感觉信息，并受许多神经调节剂的控制。为了执行其功能，小脑被认为会整合这些不同的输入，为大脑的其余部分提供最佳行为所需的预测。虽然在运动领域有很多途径可以让这种情况发生，非运动领域的存在较少。基本原理 没有从小脑发出的直接通路已被证明具有非运动功能。我们假设小脑可能通过直接投射到腹侧被盖区 (VTA) 来促进动机行为，VTA 是一种对奖励感知和社会行为控制至关重要的结构。这样的预测将解释为什么功能成像实验表明小脑在成瘾中起作用，并将提供一种潜在的机制，小脑功能障碍可能通过该机制导致精神障碍的症状。结果 在小鼠中，我们发现从小脑核到 VTA 的单突触兴奋性投射有力地激活了奖励回路，并有助于社会行为。使用解剖学追踪，我们发现小脑核的轴突投射与 VTA 中的多巴胺能和非多巴胺能神经元形成突触。小脑-VTA (Cb-VTA) 预测是强大的，它们的光遗传学刺激在体内和体外都有力地增加了 VTA 神经元的活性。检查奖励处理的行为测试表明，Cb-VTA 预测的刺激足以引起短期和长期的位置偏好，从而证明该途径是有益的。尽管 Cb-VTA 预测的光遗传学抑制并不令人厌恶，但它在社交能力的三腔测试中完全消除了社会偏好，这表明小脑对 VTA 的输入是正常社会行为所必需的。这些轴突中的钙活性与三腔测试中的表现之间的相关性也表明了小脑在社会行为中的作用。然而，Cb-VTA 输入的光遗传学激活不是亲社会的，因此该途径不足以用于社会行为。结论 这里描述的 Cb-VTA 通路是从小脑到主要以其非运动功能而闻名的结构的单突触投射。我们的数据支持小脑在奖励处理和控制社会行为中的作用。我们认为这种 Cb-VTA 通路至少可以部分解释小脑和成瘾行为之间的关联，并为小脑在其他动机和社会行为中的作用提供基础。除了有助于奖励处理，VTA 还针对许多其他大脑区域，例如前额叶皮层，这些区域反过来维持大量的运动和非运动行为。VTA 的直接小脑神经支配提供了小脑可以调节这些不同行为的途径。此处描述的 Cb-VTA 通路提供了一种机制，小脑功能障碍通过对 VTA 及其靶标产生不利影响，可能导致 ASD 和精神分裂症等精神障碍。小脑将直接兴奋性投射发送到腹侧被盖区 (Cb-VTA)。这些预测可能在奖励处理和成瘾行为中发挥作用，是社会行为所必需的（但不是充分的），并且可能构成小脑功能障碍导致精神障碍的主要途径之一。小脑与许多非运动性精神障碍有关，例如自闭症谱系障碍、精神分裂症和成瘾。然而，它对这些疾病的贡献尚不清楚。在小鼠中，我们发现小脑将直接兴奋性投射发送到腹侧被盖区 (VTA)，这是处理和编码奖励的大脑区域之一。小脑-VTA 投影的光遗传学激活是有益的，在三腔社交任务中，当动物探索社交腔时，这些投影更加活跃。有趣的是，小鼠在这项任务中表现出社会偏好需要小脑-VTA 通路中的活动。我们的数据描绘了小脑在控制奖励回路和社会行为方面的重要的、以前未被重视的作用。