Topographic representation of current and future threats in the mouse nociceptive amygdala.

Adaptive behaviors arise from an integration of current sensory context and internal representations of past experiences. The central amygdala (CeA) is positioned as a key integrator of cognitive and affective signals, yet it remains unknown whether individual populations simultaneously carry current- and future-state representations. We find that a primary nociceptive population within the CeA of mice, defined by CGRP-receptor (Calcrl) expression, receives topographic sensory information, with spatially defined representations of internal and external stimuli. While Calcrl+ neurons in both the rostral and caudal CeA respond to noxious stimuli, rostral neurons promote locomotor responses to externally sourced threats, while caudal CeA Calcrl+ neurons are activated by internal threats and promote passive coping behaviors and associative valence coding. During associative fear learning, rostral CeA Calcrl+ neurons stably encode noxious stimulus occurrence, while caudal CeA Calcrl+ neurons acquire predictive responses. This arrangement supports valence-aligned representations of current and future threats for the generation of adaptive behaviors.

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.