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Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior

Nature Neuroscience volume 6, pages 168–174 (2003)Cite this article

Abstract

Although neuronal stress circuits have been identified, little is known about the mechanisms that underlie the stress-induced neuronal plasticity leading to fear and anxiety. Here we found that the serine protease tissue-plasminogen activator (tPA) was upregulated in the central and medial amygdala by acute restraint stress, where it promoted stress-related neuronal remodeling and was subsequently inhibited by plasminogen activator inhibitor-1 (PAI-1). These events preceded stress-induced increases in anxiety-like behavior of mice. Mice in which the tPA gene has been disrupted did not show anxiety after up to three weeks of daily restraint and showed attenuated neuronal remodeling as well as a maladaptive hormonal response. These studies support the idea that tPA is critical for the development of anxiety-like behavior after stress.

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Figure 1: The expression of tissue plasminogen activator (tPA) in the amygdala.
Figure 2: The regulation of extracellular tissue plasminogen activator (tPA) activity by restraint stress in the hippocampus and amygdala.
Figure 3: Stress increases total tPA activity in the amygdala.
Figure 4: tPA mediates synaptic plasticity in the amygdala.
Figure 5: Lack of stress-induced anxiety in the absence of tPA but not in the absence of plasminogen.
Figure 6: Acute stress does not affect tPA, uPA or GAP-43 levels in the hippocampus.
Figure 7: The effect of acute and chronic stress on plasma corticosterone (CORT) levels (ng/ml) in tPA+/+ and tPA−/− mice.

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Acknowledgements

This study was supported by National Institutes of Health grants NS-35704 and NS-38472. We thank Z-L. Chen for sharing his expertise in immunohisto-chemistry, P. Mercado and Y. Keptsi for technical assistance, and the members of Strickland Lab for discussion.

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Authors and Affiliations

  1. Laboratory of Neurobiology and Genetics, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Robert Pawlak, Jerry Melchor & Sidney Strickland

  2. Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Ana Maria Magarinos & Bruce McEwen

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Correspondence to Sidney Strickland.

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Pawlak, R., Magarinos, A., Melchor, J. et al. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat Neurosci 6, 168–174 (2003). https://doi.org/10.1038/nn998

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