Integrated cardio-behavioral responses to threat define defensive states

Abstract

Fear and anxiety are brain states that evolved to mediate defensive responses to threats. 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—freezing as measured by immobility—is part of an integrated cardio-behavioral microstate mediated by Chx10+ 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.

Cerebellar contribution to the regulation of defensive states

“…Defensive states are multimodal, highly dynamic processes that crucially depend on brain-body interactions, including behavioral, cardio-respiratory, and endocrine responses that enable the expression of proper responses in reaction to threat. These complex, integrated defensive responses were recently studied by Signoret-Genest et al who developed a novel framework for combined analysis of defensive behaviors and their associated cardiac responses, i.e., heart rate changes in different anxiety and fear-related assays (Signoret-Genest et al, 2023). This study emphasizes the integrated nature of defensive states and puts forth the concept of short-lasting microstates and long-lasting macrostates, which interact with each other to generate complex defensive state dynamics.…”

“…Thus, FN output impinges onto an already known defense-related pathway, in which inhibitory interneurons within the vlPAG control glutamatergic outputs to pre-motor neurons in the magnocellular nucleus of the medulla that drive conditioned and innate freezing behavior (Tovote et al, 2016). These Chx10expressing vlPAG neurons have recently been demonstrated to mediate not only freezing behavior, but a short-lasting defensive microstate consisting of immobility concomitant with bradycardia (Signoret-Genest et al, 2023). The FN-PAG axis could therefore present a pathway through which the cerebellum contributes to the regulation of cardiac function during defensive states.…”

“…This means, for example, that identical threat-related behaviors can be associated with different cardiac outputs, depending on the preexisting state of the animal. Importantly, the dynamic heart rate responses are a highly sensitive indicator of integrated defensive microstates, which include behavioral and cardiac compounds, rather than just a mere result of behavioral responses (Signoret-Genest et al, 2023).…”

“…Recently, cerebellar outputs have been demonstrated to affect vlPAG neuronal activity, and specifically modulating the activity of Chx10-positive neurons. Because of the suggested role of these neurons as freezingbradycardia microstate generator elements (Signoret-Genest et al, 2023), it is conceivable that the cerebellum plays a role in defensive state regulation through the FN-vlPAG pathway. The precise underlying circuit mechanisms putatively involving functionally distinct FN modules (Fujita et al, 2020) need to be investigated in the future.…”

“…Whereas there is evidence for further functional specificity of FN-vlPAG pathways in that other FN glutamatergic inputs to the PAG subserve learned, but not innate defensive behaviors, FN projections to the parafascicular thalamic nucleus were shown to modulate defensive behaviors in classical rodent assays for anxiety (Frontera et al, 2020). These behavioral patterns are associated with specific cardiac dynamics, thereby constituting a defensive state space defined by combinations of multimodal, adaptive threat responses (Signoret-Genest et al, 2023). 10.3389/fnsys.2023 The precise mechanisms underlying integration of these multidimensional and highly dynamic states are largely unexplored.…”