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bioRxiv · 10.1101/2025.10.16.682741

KF/parabrachial complex PACAP - glutamate pathway to the extended amygdala couples rapid autonomic and delayed endocrine responses to acute hypotension

Hernandez, V. S.·Segura-Chama, P. D.·Zhang, L.
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Abstract

The calyx of Held is a giant axo-somatic synapse classically confined to the auditory brainstem. We recently identified morphologically similar calyx-like terminals in the extended amygdala (EA) that arise from the ventrolateral parabrachial complex and co-express PACAP, CGRP, VAChT, VGluT1, and VGluT2, targeting PKC{delta}+/GluD1+ EA neurons. Here we asked whether this parabrachial-EA pathway participates in compensation during acute hypotension. In rats given hydralazine (10 mg/kg, i.p.), we quantified Fos protein during an early phase (60 min) and a late phase (120 min). Early after hypotension, Fos surged in a discrete subpopulation of the parabrachial Kolliker-Fuse (KF) region and in the EA, whereas magnocellular neurons of the supraoptic and paraventricular nuclei (SON/PVN) remained largely silent. By 120 min, magnocellular SON/PVN neurons were robustly Fos-positive. Confocal immunohistochemistry showed that most Fos+ PKC{delta}/GluD1 EA neurons were encircled by PACAP+ perisomatic terminals (80.8%), of which the majority co-expressed VGluT1 (88.1%). RNAscope in situ hybridization further identified a selective KF population co-expressing Adcyap1 (PACAP) and Slc17a7 (VGluT1) that became Fos-positive during the early phase. Together these data suggest that a KFPACAP/VGluT1 projection forms calyceal terminals around PKC{delta}/GluD1 EA neurons, providing a high-fidelity route for rapid autonomic rebound to falling blood pressure, while slower endocrine support is subsequently recruited via neurohormone-magnocellular activation. This work links multimodal parabrachial output to temporally layered autonomic-neuroendocrine control. Short abstractAcute hypotension triggers rapid autonomic compensation followed by slower endocrine support. We identify a Kolliker-Fuse (KF) PACAP/VGluT1 pathway to the extended amygdala (EA) that initiates the fast limb. In hydralazine-treated rats, Fos rose at 60 min in KF and EA but not in magnocellular SON/PVN; by 120 min SON/PVN were strongly Fos-positive. Confocal microscopy showed that [~]81% of Fos+ PKC{delta}/GluD1 EA neurons were surrounded by PACAP+ calyceal terminals, [~]88% of which co-expressed VGluT1. RNAscope revealed a selective KF Adcyap1/Slc17a7 population that became Fos-positive early. We conclude that KF PACAP/VGluT1 calyces onto PKC{delta}/GluD1 EA neurons provide a high-fidelity autonomic pathway that precedes vasopressin-mediated endocrine compensation.

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Hernandez, V. S., Segura-Chama, P. D., Zhang, L.. 2025-10-16. KF/parabrachial complex PACAP - glutamate pathway to the extended amygdala couples rapid autonomic and delayed endocrine responses to acute hypotension. https://doi.org/10.1101/2025.10.16.682741

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