Thalamus-midbrain Circuits Mediate Defense Behaviors In Mice

Animal defensive behavior is the basis for its survival in nature.It is a natural and instinctive reaction to increase the chances and possibilities of survival for the predator.Defense behaviors include freezing,escapes or fighting a variety of different performance.Previous studies have demonstrated that the classical pathway of defensive behavior is the amygdala-PAG pathway.Based on some preliminary work in our laboratory,we have made a new exploration of the inner neural circuits and regulation of defensive behaviors,and studied the changes of the sensory responses under defensive conditions.Freezing is one of the most common defensive behaviors and is important for animals' survival.How the sensory responses would change during the freezing state is still unknown.Previous studies have shown that superior colliculus(SC)is engaged in freezing initiation.In this study,we found that activation of superficial SC(SCs)could both induce freezing and decrease the responses in layer 2/3 neurons of primary visual cortex(?).In addition,SCs provided direct excitatory inputs to lateral posterior thalamus(LP),and activation of either LP or the LP neurons receiving SCs input could reduce the sensory responses in ? as well.This suppression effect could be due to the direct excitation of layer 1 inhibitory neurons in V1 by LP activation.We also observed similar modulation of auditory responses by activation of SCs or LP.Taken together,these results demonstrated a novel sensory modulation pathway during freezing through LP.Zona incerta(ZI)is a functionally mysterious subthalamic nucleus containing mostly inhibitory neurons.Here,we discovered that GABAergic neurons in the rostral sector of ZI(ZIr)directly innervated 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 reduced both sound-induced innate flight response and conditioned freezing response,while optogenetic suppression of these neurons enhanced these defense behaviors,likely in a gain control manner.ZIr activity was progressively increased during extinction of conditioned freezing response,and suppressing ZIr activity impaired the expression of fear extinction.Furthermore,ZIr was found to be innervated by the medial prefrontal cortex(mPFC),and silencing mPFC prevented the increase of ZIr activity during extinction.Together,our results suggested that ZIr may be engaged in globally modulating defense behaviors.In summary,we used circuit-based optogenetic,in vivo and in vitro electrophysiological,and neuroanatomical tracing methods to study defense behaviors.our study found a novel pathway that regulates the sensory response of the cortex through the midbrain-thalamic(SC-LP)during the freezing reaction.In addition,a new medial prefrontal cortex-thalamic-medullary(mPFC-ZI-PAG)pathway that parallels the classical amygdala pathway is identified.The above studies have revealed that the thalamus serves as a bridge to mediate defense behaviors.It not only can connect the cortex with midbrain through the top-down control to mediate defense behaviors but also can feedback the information of the midbrain to cortex,thus changing the response state of the cortex through a bottom-up regulation.Taken together,our studies provided new evidence that the thalamus plays an important role in defensive behaviors,so in the future we can further explore the function of different thalamic nuclei in other defensive behaviors.