Central Amygdala Somatostatin Neurons Gate Passive and Active Defensive Behaviors.

The central amygdala (CeA) has a key role in learning and expression of defensive responses. Recent studies indicate that somatostatin-expressing (SOM(+)) neurons in the lateral division of the CeA (CeL) are essential for the acquisition and recall of conditioned freezing behavior, which has been used as an index of defensive response in laboratory animals during Pavlovian fear conditioning. However, how exactly these neurons participate in fear conditioning and whether they contribute to the generation of defensive responses other than freezing remain unknown. Here, using fiber-optic photometry combined with optogenetic and molecular techniques in behaving mice, we show that SOM(+) CeL neurons are activated by threat-predicting sensory cues after fear conditioning and that activation of these neurons suppresses ongoing actions and converts an active defensive behavior to a passive response. Furthermore, inhibition of these neurons using optogenetic or molecular methods promotes active defensive behaviors. Our results provide the first in vivo evidence that SOM(+) neurons represent a CeL population that acquires learning-dependent sensory responsiveness during fear conditioning and furthermore reveal an important role of these neurons in gating passive versus active defensive behaviors in animals confronted with threat. The ability to develop adaptive behavioral responses to threat is fundamental for survival. Recent studies indicate that the central lateral amygdala (CeL), in particular its somatostatin-expressing neurons, is crucial for both learning and the expression of defensive response. However, how exactly these neurons participate in such processes remains unclear. Here we show for the first time in behaving mice that the somatostatin-expressing neurons in the CeL acquire learning-dependent responsiveness to sensory cues predicting a threat. Furthermore, our results indicate that these neurons gate the behavioral output of an animal: whereas high activity in these neurons biases toward passive defensive responses, low activity in these neurons allows the expression of active defensive responses.

Yu K ，Garcia da Silva P ，Albeanu DF ，Li B ... -  《-》

A Central Amygdala-Globus Pallidus Circuit Conveys Unconditioned Stimulus-Related Information and Controls Fear Learning.

The central amygdala (CeA) is critically involved in a range of adaptive behaviors, including defensive behaviors. Neurons in the CeA send long-range projections to a number of extra-amygdala targets, but the functions of these projections remain elusive. Here, we report that a previously neglected CeA-to-globus pallidus external segment (GPe) circuit plays an essential role in classical fear conditioning. By anatomic tracing, in situ hybridization and channelrhodopsin (ChR2)-assisted circuit mapping in both male and female mice, we found that a subset of CeA neurons send projections to the GPe, and the majority of these GPe-projecting CeA neurons express the neuropeptide somatostatin. Notably, chronic inhibition of GPe-projecting CeA neurons with the tetanus toxin light chain (TeLC) completely blocks auditory fear conditioning. In vivo fiber photometry revealed that these neurons are selectively excited by the unconditioned stimulus (US) during fear conditioning. Furthermore, transient optogenetic inactivation or activation of these neurons selectively during US presentation impairs or promotes, respectively, fear learning. Our results suggest that a major function of GPe-projecting CeA neurons is to represent and convey US-related information through the CeA-GPe circuit, thereby regulating learning in fear conditioning.SIGNIFICANCE STATEMENT The central amygdala (CeA) has been implicated in the establishment of defensive behaviors toward threats, but the underlying circuit mechanisms remain unclear. Here, we found that a subpopulation of neurons in the CeA, which are mainly those that express the neuropeptide somatostatin, send projections to the globus pallidus external segment (GPe), and this CeA-GPe circuit conveys unconditioned stimulus (US)-related information during classical fear conditioning, thereby having an indispensable role in learning. Our results reveal a previously unknown circuit mechanism for fear learning.

Giovanniello J ，Yu K ，Furlan A ，Nachtrab GT ，Sharma R ，Chen X ，Li B ... -  《-》

Periaqueductal Gray Neuronal Activities Underlie Different Aspects of Defensive Behaviors.

Defense is a basic survival mechanism when animals face danger. Previous studies have suggested that the midbrain periaqueductal gray (PAG) is essential for the generation of defensive reactions. Here we showed that optogenetic activation of neurons in the PAG in mice was sufficient to induce a series of defensive responses (including running, freezing, and avoidance). However, the endogenous neural dynamics of the PAG underlying defensive behaviors still remain elusive. Using chronic extracellular recording, we recorded the spiking activities of PAG neurons in freely behaving mice exposed to natural threats (rats). We observed that there exist distinct neuronal subsets within the PAG participating in respective detection (risk assessment) and response (flight) aspects of defensive behaviors. Our results demonstrate the important role of PAG neuronal activities in the control of different aspects of defensive behaviors, and provide novel insights for investigating defense from an electrophysiological perspective. Defense is crucial for animals' survival in nature. Here, using optogenetic stimulation and in vivo recording in behaving mice reacting to threats, we explored the role of the midbrain periaqueductal gray (PAG) in defense. We show that optogenetic activation of PAG neurons is sufficient to elicit different aspects of defensive responses. Consistently, the present study provides in vivo evidence demonstrating that activity of the population of dorsal PAG neurons is activated during defense. Also, different subpopulations of units recorded in the dorsal PAG participate in distinct aspects of defensive behaviors. These findings help us understand the role of the PAG in animal behavior at the single neuron level.

Deng H ，Xiao X ，Wang Z 《-》

A competitive inhibitory circuit for selection of active and passive fear responses.

Fadok JP ，Krabbe S ，Markovic M ，Courtin J ，Xu C ，Massi L ，Botta P ，Bylund K ，Müller C ，Kovacevic A ，Tovote P ，Lüthi A ... -  《-》

Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala.

Penzo MA ，Robert V ，Li B 《-》