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Zona incerta (ZI) is a largely inhibitory subthalamic region connecting with many brain areas. Early studies have suggested involvement of ZI in various functions such as visceral activities, arousal, attention, and locomotion, but the specific roles of different ZI subdomains or cell types have not been well examined. Recent studies combining optogenetics, behavioral assays, neural tracing, and neural activity-recording reveal novel functional roles of ZI depending on specific input-output connectivity patterns. Here, we review these studies and summarize functions of ZI into four categories: sensory integration, behavioral output control, motivational drive, and neural plasticity. In view of these new findings, we propose that ZI serves as an integrative node for global modulation of behaviors and physiological states., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Zona incerta (ZI) is a functionally mysterious subthalamic nucleus containing mostly inhibitory neurons. Here, we discover that GABAergic neurons in the rostral sector of ZI (ZIr) directly innervate excitatory but not inhibitory neurons in the dorsolateral and ventrolateral compartments of periaqueductal gray (PAG), which can drive flight and freezing behaviors respectively. Optogenetic activation of ZIr neurons or their projections to PAG reduces both sound-induced innate flight response and conditioned freezing response, while optogenetic suppression of these neurons enhances these defensive behaviors, likely through a mechanism of gain modulation. ZIr activity progressively increases during extinction of conditioned freezing response, and suppressing ZIr activity impairs the expression of fear extinction. Furthermore, ZIr is innervated by the medial prefrontal cortex (mPFC), and silencing mPFC prevents the increase of ZIr activity during extinction and the expression of fear extinction. Together, our results suggest that ZIr is engaged in modulating defense behaviors.