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Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry

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Abstract

Amygdalar norepinephrine (NE) plays a key role in regulating neural responses to emotionally arousing stimuli and is involved in memory consolidation of emotionally charged events. Corticotropin-releasing factor (CRF) and dynorphin (DYN), two neuropeptides that mediate the physiological and behavioral responses to stress, are abundant in the central nucleus of the amygdala (CeA), and directly innervate brainstem noradrenergic locus coeruleus (LC) neurons. Whether the CRF- and DYN-containing amygdalar neurons receive direct noradrenergic innervation has not yet been elucidated. The present study sought to define cellular substrates underlying noradrenergic modulation of CRF- and DYN-containing neurons in the CeA using immunohistochemistry and electron microscopy. Ultrastructural analysis revealed that NE-labeled axon terminals form synapses with CRF- and DYN-containing neurons in the CeA. Semi-quantitative analysis showed that approximately 31 % of NET-labeled axon terminals targeted CeA neurons that co-expressed DYN and CRF. As a major source of CRF innervation to the LC, it is also not known whether CRF-containing CeA neurons are directly targeted by noradrenergic afferents. To test this, retrograde tract tracing using FluoroGold from the LC was combined with immunocytochemical detection of CRF and NET in the CeA. Our results revealed a population of LC-projecting CRF-containing CeA neurons that are directly innervated by NE afferents. Analysis showed that approximately 34 % of NET-labeled axon terminals targeted LC-projecting CeA neurons that contain CRF. Taken together, these results indicate significant interactions between NE, CRF and DYN in this critical limbic region and reveal direct synaptic interactions of NE with amygdalar CRF that influence the LC-NE arousal system.

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Acknowledgments

This project was supported by the National Institutes of Health grants DA009082 to E.J.V.B. and DA018326 to E.M.U. We acknowledge the experimental contributions of Mr. Nathan Heldt.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 S. 15th Street, Philadelphia, PA, 19102, USA

    J. L. Kravets, B. A. S. Reyes & E. J. Van Bockstaele

  2. Department of Pharmacology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA

    E. M. Unterwald

Authors
  1. J. L. Kravets
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  2. B. A. S. Reyes
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  3. E. M. Unterwald
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  4. E. J. Van Bockstaele
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Correspondence to B. A. S. Reyes.

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Kravets, J.L., Reyes, B.A.S., Unterwald, E.M. et al. Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry. Brain Struct Funct 220, 541–558 (2015). https://doi.org/10.1007/s00429-013-0674-8

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  • DOI: https://doi.org/10.1007/s00429-013-0674-8

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