CGRP inhibition in the PBN shifts defensive strategy from freezing to active avoidance in a platform-based active avoidance paradigm

Elucidating the neural circuits that govern the selection between passive freezing and active avoidance can provide insights into maladaptive defensive behaviours. One candidate neural substrate is calcitonin gene-related peptide (CGRP) expressing neurons in the parabrachial nucleus, which process aversive unconditioned stimulus (US) signals and encode threat intensity to promote passive defensive behaviours. Given their role in processing US signals, their disruption may influence active defensive strategies as well, yet whether CGRP neurons contribute to active avoidance remains uninvestigated.

In this study, we developed a platform-based active avoidance paradigm that models a naturalistic framework by providing a permanent safe zone to isolate threat-driven actions. Systematic variation of footshock intensity ranging from 0.1 to 0.5 mA revealed that low shock intensities yield weak avoidance acquisition and high-intensity shocks promote excessive freezing that suppresses action, with 0.3 mA providing the optimal window for robust active avoidance expression. Critically, silencing CGRP neurons did not impair associative active avoidance learning.

Instead, CGRP disruption inhibited passive freezing and successfully expanded the range of active avoidance to high intensity footshocks. Building on previous evidence that CGRP neurons are required for associative learning in Pavlovian fear conditioning, our findings suggest that their role differs in an operant active avoidance paradigm, where they bias defensive response selection toward passive freezing under high-threat conditions by regulating defensive behavioural output rather than by driving associative learning itself. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government, Ministry of Science and ICT (RS-2026-25600714).

We thank members of the Korea University BioPsychology Laboratory for thoughtful comments and feedback on earlier drafts of this manuscript. These authors contributed equally: Hanny Hayeon Lee, Eul Han. School of Psychology, Korea University, Seoul, Republic of Korea Hanny Hayeon Lee, Eul Han & Yong Sang Jo Neuroscience and Behavior Program, University of Massachusetts Amherst, Amherst, MA, USA The authors declare no competing interests.

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