Opposing manipulations of insular projections to the bed nuclei of the stria terminalis converge on behavioral passivity

Abstract

Adaptive stress coping involves flexible coordination of behavioral and neuroendocrine responses, yet how cortical regions orchestrate these outputs remains poorly understood. The insular cortex (IC) integrates interoceptive signals and projects to extended amygdala nuclei implicated in threat responses, including the anteroventral subdivision of the bed nuclei of the stria terminalis (avBST) and central amygdala (CeA). Here we used pathway-specific chemogenetics to bidirectionally manipulate IC-avBST projections in male rats during the shock probe defensive burying test (SPDB), which naturalistically measures active versus passive coping. Inhibition of avBST-projecting neurons resulted in a passive coping phenotype of increased immobility and elevated corticosterone levels. Excitation of these neurons unexpectedly shifted behavior in the same direction, reducing defensive burying without altering immobility or corticosterone responses. This convergence suggested that the effects might not be mediated by the avBST projection itself, prompting us to examine collateral targets. Anatomical tracing revealed that avBST-projecting IC neurons send dense collateral axons to CeA, and ex vivo recordings confirmed functional synaptic connectivity. Chemogenetic excitation of CeA-projecting IC neurons also reduced defensive burying, as did optogenetic stimulation of IC terminals in CeA but not avBST, implicating IC input to CeA. These findings suggest that reducing IC excitatory drive on avBST promotes behavioral and hormonal features of passive coping, consistent with avBST’s established role in constraining stress responses. By contrast, excitatory influences operate through collateral CeA projections suppress active defensive behavior without engaging neuroendocrine output, indicating that a projection's collaterals, not its defining target, can determine its functional impact. Significance statement Adaptive stress coping requires coordinated behavioral and hormonal responses, yet the neural circuits orchestrating these outputs remain poorly understood. We show that insular cortex neurons projecting to the bed nuclei of the stria terminalis (BST) send dense collateral axons to the central amygdala, enabling distributed control of stress responses. Inhibiting these neurons increases both behavioral passivity and adrenocortical activation— hallmark features of passive coping. Conversely, exciting these neurons suppresses active defensive behavior without affecting hormonal output, an effect mediated by collateral projections to the amygdala rather than the projection to BST itself. These findings demonstrate that insular cortex regulation of stress coping operates through a collateral architecture rather than simple point-to-point connectivity.

The authors' abstract, as published at the source. Journal of Neuroscience, 2026 · DOI ↗