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The defense reaction includes multiple interacting behavioral, autonomic and endocrine adjustments, but their integrative nature is poorly understood. In particular, although threat has been associated with various cardiac changes, there is no clear consensus regarding the relevance of these changes for the integrated defense reaction. Here we identify rapid microstates that are associated with specific behaviors and heart rate dynamics, which are affected by long-lasting macrostates and reflect context-dependent threat levels. In addition, we demonstrate that one of the most commonly used defensive behavioral responses\u2014freezing as measured by immobility\u2014is part of an integrated cardio-behavioral microstate mediated by <jats:italic>Chx10<\/jats:italic><jats:sup>+<\/jats:sup> neurons in the periaqueductal gray. Our framework for systematic integration of cardiac and behavioral readouts presents the basis for a better understanding of complex neural defensive states and their associated systemic functions.<\/jats:p>","DOI":"10.1038\/s41593-022-01252-w","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T16:12:55Z","timestamp":1676045575000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Integrated cardio-behavioral responses to threat define defensive states"],"prefix":"10.1038","author":[{"given":"J\u00e9r\u00e9my","family":"Signoret-Genest","sequence":"first","affiliation":[]},{"given":"Nina","family":"Schukraft","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8126-2915","authenticated-orcid":false,"given":"Sara","family":"L. Reis","sequence":"additional","affiliation":[]},{"given":"Dennis","family":"Segebarth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9440-3967","authenticated-orcid":false,"given":"Karl","family":"Deisseroth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4598-722X","authenticated-orcid":false,"given":"Philip","family":"Tovote","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"1252_CR1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1146\/annurev.neuro.23.1.155","volume":"23","author":"JE LeDoux","year":"2000","unstructured":"LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155\u2013184 (2000).","journal-title":"Annu. Rev. 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