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Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear

Molecular Psychiatry volume 23, pages 914–922 (2018)Cite this article

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Abstract

The lateral central nucleus of the amygdala (CeAL) and the dorsolateral bed nucleus of the stria terminalis (BNSTDL) coordinate the expression of shorter- and longer-lasting fears, respectively. Less is known about how these structures communicate with each other during fear acquisition. One pathway, from the CeAL to the BNSTDL, is thought to communicate via corticotropin-releasing factor (CRF), but studies have yet to examine its function in fear learning and memory. Thus, we developed an adeno-associated viral-based strategy to selectively target CRF neurons with the optogenetic silencer archaerhodopsin tp009 (CRF-ArchT) to examine the role of CeAL CRF neurons and projections to the BNSTDL during the acquisition of contextual fear. Expression of our CRF-ArchT vector injected into the amygdala was restricted to CeAL CRF neurons. Furthermore, CRF axonal projections from the CeAL clustered around BNSTDL CRF cells. Optogenetic silencing of CeAL CRF neurons during contextual fear acquisition disrupted retention test freezing 24 h later, but only at later time points (>6 min) during testing. Silencing CeAL CRF projections in the BNSTDL during contextual fear acquisition produced a similar effect. Baseline contextual freezing, the rate of fear acquisition, freezing in an alternate context after conditioning and responsivity to foot shock were unaffected by optogenetic silencing. Our results highlight how CeAL CRF neurons and projections to the BNSTDL consolidate longer-lasting components of a fear memory. Our findings have implications for understanding how discrete amygdalar CRF pathways modulate longer-lasting fear in anxiety- and trauma-related disorders.

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Acknowledgements

This work was supported by NIH grant R01HD07506603 to JBR, an APA grant to AA, and by the National Institute on Drug Abuse Intramural Research Program (AFH and CRL). Microscopy access was supported by grants from the NIH-NIGMS (P20 GM103446), the NSF (IIA-1301765) and the State of Delaware.

Author contributions

AA, JBR and JS designed the experiments; AA and AD performed the behavioral experiments. AA performed the molecular work. CRL and AFH performed the electrophysiology experiments. AA, JBR, JS, CRL and AFH analyzed the data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, USA

    A Asok, A Draper & J B Rosen

  2. Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA

    A F Hoffman & C R Lupica

  3. Department of Neuroscience, Georgetown University, Washington, DC, USA

    J Schulkin

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  1. A Asok
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  2. A Draper
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Correspondence to A Asok.

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Asok, A., Draper, A., Hoffman, A. et al. Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear. Mol Psychiatry 23, 914–922 (2018). https://doi.org/10.1038/mp.2017.79

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