Mar 18, 2023

Integrated cardio-behavioral responses to threat define defensive states

Signoret-Genest J, Schuhkraft N, Reis SL, Segebarth D, Deisseroth K, Tovote P.

Nat Neurosci 2023 Mar;26(3):447-457. Epub 2023 Feb 9.
doi: 10.1038/s41593-022-01252-w.

Panic, stress and anxiety are brain states that have evolved to mediate defensive responses to threats. The defensive response to threat – a central element of human fear or anxiety – involves multiple behavioural, autonomic and endocrine adjustments that are controlled and integrated by neural circuits. Parkinson’s disease can lead to enhanced sensitivity to perceived threats and reflexive defensive responses. However, the integrative nature of those defensive states is poorly understood. A better understanding of defensive state dynamics is needed for the refinement and new development of brain stimulation approaches for the treatment of network diseases.

In particular, although threat has been associated with various cardiac changes, there is no clear consensus on the relevance of these changes to the integrated defence response. In contrast to relatively robust defensive behaviours elicited under tightly controlled experimental conditions, studies of defensive autonomic responses have yielded complex, paradoxical observations and sometimes seemingly contradictory results. Indeed, both slowing (bradycardia) and acceleration (tachycardia) of heart rate (HR) have been reported under threat conditions.

In this study, we applied new analyses to a large dataset of simultaneous behavioural, HR and thermal measurements during different behavioural paradigms in freely moving mice.

Based on these analyses, we identify rapid microstates associated with specific behaviours and heart rate dynamics that are influenced by long-lasting macrostates reflecting context-dependent threat levels.In addition, we show that one of the most commonly used defensive behavioural responses – freezing measured by immobilisation – is part of an integrated cardio-behavioural microstate mediated by Chx10+ neurons in the periaqueductal gray. Our framework for the systematic integration of cardiac and behavioural readouts provides the basis for a better understanding of complex neural defence states and their associated systemic functions.

Tovote and colleagues present an analytical framework that integrates threat-evoked, interrelated behavioural and cardiac adaptations and allows the identification of short- and long-term defensive states and their midbrain neural mediators.

Dr. Jérémy Signoret-Genest

Jérémy Signoret-Genest is a postdoctoral research fellow in Prof. Tovote’s lab. His research is based on the computational analysis of multi-dimensional read-outs displayed during fear and anxiety in order to identify integrated defensive states.

Nina Schukraft

Nina Schukraft is a PhD student in Prof. Tovote’s lab with a focus on identifying neural brain circuitries underlying integrated defensive states.

Prof. Dr. Philip Tovote

Philip Tovote is head of the Defense Circuits Lab, chair of Systems Neurobiology and Co-director of the Institute of Clinical Neurobiology in Würzburg. His group aims at a better understanding of the neuronal circuits that underlie brain-body interactions in health and disease and to develop models for targeted ‘circuit therapy’ with enhanced specificity to treat systems neuropsychiatric disorders.