Parabrachial and central amygdala circuits for affective nociceptive processing

Abstract

The central amygdala (CeA) and parabrachial nucleus (PBN) are two crucial nodes in the nociceptive relay from the spinal cord to the forebrain. Recent work suggests that nociceptive neurons of the PBN expressing calcitonin gene-related peptide (CGRP) act as integrators, receiving multisensory aversive stimuli and relaying a scaled threat-signal to forebrain nuclei to affect defensive responses. The CeA, in contrast, is a striatum-like structure with multiple cross-inhibitory subnuclei that accomplishes hierarchical processing and action selection through antagonizing opposing stimuli. The purpose of this thesis is to delineate systems underpinning affective processing of aversive stimuli at the level of the PBN and CeA, focusing on the complementary roles played by PBN CGRP neurons, their various projections, and CGRP-receptor (Calcrl) neurons in the CeA. Using cell-type-specific tracing and optogenetics we identify distinctly collateralizing subpopulations of PBN CGRP neurons, with individual projections differentially promoting distinct unconditioned behavioral and physiological responses or associative fear learning to aversive stimuli. We also find that some responses generated by PBN CGRP neuron activation requires summed activity at multiple downstream nodes, suggesting that defensive responses do not occur exclusively through labeled-line circuit structure. At the level of the CeA, we use anatomical and functional analyses of connectivity, cell activity dynamics and behavioral and physiological response characteristics to reveal that CeA Calcrl+ neurons have biased influence over aversive processing based in part on their spatial location. In particular, rostral and caudal Calcrl+ neurons exert opposing effects on active vs passive defensive response strategies, and, while both have similar response profiles to external stimuli, caudal Calcrl+ neurons preferentially respond to and orchestrate responses to aversive internal states and profoundly affect stimulus valence. Importantly, both populations contribute to associative fear learning, highlighting their intersectional importance in affective processing.