A Central Amygdala-Globus Pallidus Circuit Conveys Unconditioned Stimulus-Related Information and Controls Fear Learning
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Abstract
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.
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Stress increases CeA activity.
“Elevated CeA→DMS activity following stress is consistent with evidence that stress increases CeA activity63–65.”
From A dual-pathway architecture for stress to disrupt agency and promote habit (2025) · cites this paper as [65]
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- Pavlov, I.P. (1927). Conditioned Reflexes (London: Oxford University Press).
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A dual-pathway architecture for stress to disrupt agency and promote habit
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- Authors
- Giovanniello, J., Yu, K., Furlan, A., Nachtrab, G. T., Sharma, R., Chen, X., & Li, B.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Stanford University (US)
- Corresponding author
- Li, Bo
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2020-10-16
- Volume
- 40
- Issue
- 47
- Pages
- 9043-9054
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7673004
- OpenAlex
- W3092873902
- Cited by
- 65
- References
- 62
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 27 · 2023: 16 · 2022: 7 · 2021: 5
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- HHS | NIH | National Institute of Mental Health (R01MH101214, R01MH108924)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS104944)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- central amygdala, fear conditioning, somatostatin neurons, tetanus toxin light chain, optogenetic inactivation, auditory fear, defensive behavior, circuit mapping
- MeSH terms
- Acoustic Stimulation, Animals, Conditioning, Classical, Fear, Female, Globus Pallidus, Learning, Male, Mice, Inbred C57BL, Nerve Net, Somatostatin, Tetanus Toxin, Mice, Optogenetics, Central Amygdaloid Nucleus
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