Abstract
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.
Highlights
Zona incerta (ZI) is a functionally mysterious subthalamic nucleus containing mostly inhibitory neurons
The ZIr and ZIv/ZId injections revealed similar axonal labeling patterns in the midbrain, hindbrain, and thalamus (Fig. 1d and Supplementary Fig. 1a, b), while few projections were found in cortical regions or the amygdaloid complex (Fig. 1d)
In this study, by using combined anatomical tracing, electrophysiological recording and bidirectional optogenetic manipulations, we demonstrate that the rostral part of ZI can bidirectionally modulate defense behaviors, including both innate and learned defensive behaviors
Summary
Zona incerta (ZI) is a functionally mysterious subthalamic nucleus containing mostly inhibitory neurons. 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. Zona incerta (ZI), first described more than a century ago by Auguste Forel[1] as a “zone of uncertainty”, is a major subthalamic structure, functions of which remain largely unclear It has become a region of interest and studies have revealed some important features of this region[2,3,4,5]. We find that activation and suppression of ZIr reduces and enhances both innate and learned defensive behaviors respectively Consistent with these behavioral effects, we find that ZIr directly inhibits excitatory neurons in both the dorsolateral and ventrolateral compartments of PAG. Our data suggest that ZIr plays a role in modulating defense behaviors based on experience or contexts
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