A Brainstem-Spinal Circuit Controlling Nocifensive Behavior

Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord circuits for simple reflexive responses, but the mechanisms underlying more complex behaviors remain poorly understood. We now describe a brainstem circuit that controls escape responses to select noxious stimuli. Tracing experiments characterized a highly interconnected excitatory circuit involving the dorsal spinal cord, parabrachial nucleus (PBNI), and reticular formation (MdD). A combination of chemogenetic, optogenetic, and genetic ablation approaches revealed that PBNITac1 neurons are activated by noxious stimuli and trigger robust escape responses to heat through connections to the MdD. Remarkably, MdDTac1 neurons receive excitatory input from the PBN and target both the spinal cord and PBN; activation of these neurons phenocopies the behavioral effects of PBNITac1 neuron stimulation. These findings identify a substrate for controlling appropriate behavioral responses to painful stimuli.