Cell-type-specific Connectivity of Brainstem Circuits Mediating the Cortical Control of Innate Reflexes

哺乳动物大脑的一个显著特征是新皮质的大规模扩张，这是一种系统发育学上的现代结构。尽管关于大脑皮层的感觉处理能力有丰富的知识，但我们对大脑皮层如何影响行为，尤其是反射，知之甚少。反身性行为，就像逃避威胁一样，是天生的非自愿运动动作，几乎是在瞬间对外部刺激做出反应，对动物的生存至关重要。尽管由脑干等硬连接的皮质下结构进行调节，但天然反射也可以由皮质调节，这取决于当时的情况和过去的经验。这种对反射的皮质调节代表了一种基本的进化适应，因为它允许有机体调整其反射行为，否则这些行为将是僵化的，以应对动态变化的环境。一个最好的例子是视动反射(OKR)的自适应皮质控制，这是一种与生俱来的眼睛运动，当动物在环境中移动时，它会稳定视网膜上的图像。OKR是高度可塑性的；事实上，当其他眼球运动反射受损时，它的幅度可以自适应地增强。许多研究，包括我最近的工作，都揭示了视觉皮质在这种先天行为可塑性模型中的突出作用。我们的数据支持，视觉皮质使用其下行的皮质分离通路投射到脑干，以增强其活动，这反过来又提高了脑干介导的OKR行为的表现。然而，这种皮质功能背后的确切机制仍有待明确阐明。我的研究项目旨在确定使大脑皮质能够自适应地调节天生反射行为的突触、细胞和电路机制。参与OKR的脑干结构由不同类型的神经元组成。由于电路的神经连接形成了信息流和电路操作的神经基础，在这项建议中，我们将使用现代综合方法来揭示参与OKR可塑性的皮质分离-脑干电路的解剖。我们将识别接受远程皮质激素输入的脑干神经元群体，并绘制脑干群体之间的局部突触连接图。这项研究将产生OKR行为的基本脑干电路的第一张线路图。最终，它将为脑干种群在大脑皮质控制先天行为中扮演的细胞类型特定角色提供洞察力。此外，技术和概念上的进步将激发科学家对大脑皮质功能感兴趣，特别是大脑皮质对先天行为的影响。最后，该研究项目还将为加拿大学术界和工业界培养高素质的年轻科学家。

A remarkable trait of the mammalian brain is the massive expansion of the neocortex, a phylogenetically modern structure. Despite the wealth of knowledge about its capability of sensory processing, we understand little of how the cortex contributes to behaviors, especially reflexes. Reflexive behaviors, like the escape from a threat, are innate involuntary motor actions that happen nearly instantaneously in response to external stimuli, and are critical for animals' survival. Although mediated by hardwired subcortical structures such as the brainstem, innate reflexes can also be modulated by the cortex, depending on prevailing condition and past experience. This cortical modulation of reflexes represents a fundamental evolutionary adaptation as it allows an organism to adjust its reflexive behaviors, which would be otherwise rigidly stereotyped, in response to dynamically changing environments. A prime example is the adaptive cortical control of the optokinetic reflex (OKR), an innate eye movement that stabilizes images on the retina as animals move through the environment. The OKR is highly plastic; in fact, its amplitude can be adaptively potentiated when other oculomotor reflexes are impaired. A number of studies including my recent work uncovered a prominent role of the visual cortex in this model of innate behavioral plasticity. Our data support that visual cortex uses its descending corticofugal pathway that projects to the brainstem to enhances it activity, which in turn boosts the performance of brainstem-mediated OKR behavior. However, the exact mechanisms underlying this cortical function remain to be clearly elucidated. My research program aims at identifying the synaptic, cellular, and circuit mechanisms that enable the cortex to adaptively modulate innate reflexive behaviors. The brainstem structure mediating the OKR consists of diverse types of neurons. Since neural wiring of a circuit forms the neural basis of information flow and circuit operation, in this proposal we will employ a modern integrative approach to uncover the anatomy of corticofugal-brainstem circuits involved in OKR plasticity. We will identify brainstem neuronal populations receiving long-range corticofugal input, and map local synaptic connectivity between brainstem populations. This study will give rise to the first wiring diagram of the fundamental brainstem circuit of OKR behavior. And ultimately it will provide insights into the cell-type specific roles of brainstem populations in the cortical control of innate behaviors. In addition, the technical and conceptual advancements will inspire scientists interested in cortical functions, especially in cortical influence on innate behaviors. Finally, this research program will also prepare highly qualified young scientists for both academia and industry in Canada.