Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons

Parabrachial CGRP neurons receive diverse threat-related signals and
contribute to multiple phases of adaptive threat responses in mice, with
their inactivation attenuating both unconditioned behavioral responses to
somatic pain and fear-memory formation. Because CGRPPBN neurons respond
broadly to multi-modal threats, it remains unknown how these distinct
adaptive processes are individually engaged. We show that while three
partially separable subsets of CGRPPBN neurons broadly collateralize to
their respective downstream partners, individual projections accomplish
distinct functions: hypothalamic and extended amygdalar projections elicit
assorted unconditioned threat responses including autonomic arousal,
anxiety, and freezing behavior, while thalamic and basal forebrain
projections generate freezing behavior and, unexpectedly, contribute to
associative fear learning. Moreover, the unconditioned responses generated
by individual projections are complementary, with simultaneous activation
of multiple sites driving profound freezing behavior and bradycardia that
are not elicited by any individual projection. This semi-parallel,
scalable connectivity schema likely contributes to flexible control of
threat responses in unpredictable environments.