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层的大规模扩张，这是一种系统发育上的现代结构。尽管我们对大脑皮层的感觉处理能力有丰富的了解，但我们对大脑皮层如何影响行为，尤其是反射，知之甚少。反射性行为，比如逃避威胁，是一种本能的、无意识的运动行为，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。虽然先天反射是由硬连接的皮层下结构（如脑干）介导的，但根据当时的条件和过去的经验，先天反射也可以由皮层调节。这种皮层对反射的调节代表了一种基本的进化适应，因为它允许生物体调整其反射行为，否则这些行为将是刻板的，以响应动态变化的环境。一个典型的例子是自适应皮层对光动力反射（OKR）的控制，这是一种天生的眼球运动，当动物在环境中移动时，它能稳定视网膜上的图像。OKR是高度塑性的；事实上，当其他动眼肌反射受损时，其振幅可以自适应增强。包括我最近的研究在内的许多研究揭示了视觉皮层在先天行为可塑性模型中的突出作用。我们的数据支持，视觉皮层通过投射到脑干的下行皮质通路来增强其活动，从而提高脑干介导的OKR行为的表现。然而，这种皮层功能的确切机制仍有待阐明。我的研究项目旨在确定突触、细胞和电路机制，使皮层能够自适应地调节先天反射行为。

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.