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Background Substantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD). Carriers of this deletion show divergent symptoms besides the core features of autism spectrum disorder, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. Methods We used mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) and their sex-matched wild-type littermates for the study and examined their anxiety-related behaviors, auditory perception, and central amygdala circuit function using behavioral, circuit tracing, and electrophysiological techniques. Results Mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) had sex-specific anxiety-related behavioral and neural circuit changes. Specifically, we found that female, but not male, 16p11.2 del/+ mice showed enhanced fear generalization—a hallmark of anxiety disorders—after auditory fear conditioning and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male, 16p11.2 del/+ mice. Conclusions Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.

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 situhybridization 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 vivofiber 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 STATEMENTThe 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.

The central amygdala (CeA) is critically involved in a range of adaptive behaviors. In particular, the somatostatin-expressing (Sst+) neurons in the CeA are essential for classic fear conditioning. These neurons send long-range projections to several extra-amygdala targets, but the functions of these projections remain elusive. Here, we found in mice that a subset of Sst+ CeA neurons send projections to the globus pallidus external segment (GPe), and constitute essentially the entire GPe-projecting CeA population. Notably, chronic inhibition of GPe-projecting CeA neurons completely blocks auditory fear conditioning. These neurons are selectively excited by the unconditioned stimulus (US) during fear conditioning, and transient inactivation or activation of these neurons during US presentation impairs or promotes, respectively, fear learning. Our results suggest that a major function of Sst+ CeA neurons is to represent and convey US information through the CeA-GPe circuit, thereby instructing learning in fear conditioning.