Brainwide Circuits Underlying Territory Covering Micturition Behavior

Abstract

The brain guides the selection of specific motor actions based on sensory information in the environment, past experiences, and internal state. This sensorimotor transformation is a crucial process for any biological, or even an artificial, system that must react to the environment. A central goal of neuroscience research is to understand how the brain executes this action-selection process. Revealing the full circuitry underlying a sensorimotor transformation may now be tractable for a robust, simple behavior. To this end, we established a behavioral paradigm to observe context-dependent territory-covering micturition (TCM) in the laboratory setting. We found that mice display rank-dependent TCM, but most display “subordinate-like” TCM, likely due to complex social interactions. Therefore, we bypassed the social modulation and obtained a high-contrast TCM through prolonged social isolation (Chapter 2, Appendix A). In order to functionally understand how the brain controls TCM, we analyzed the Pontine Micturition Center (PMC), which forms the output from the brain to the bladder. We found that PMC contains corticotropin-releasing hormone (Crh)-expressing neurons that send command output to drive bladder contraction and receive converging pro- and anti-micturition signals (Appendix A). Using whole brain c-fos immunolabeling and electrophysiological analysis of synaptic transmission, we compared group-housed and isolated animals. We showed that distributed and coordinated brain-wide activity changes, as opposed to a single brain region, underlie the differences in context- and state-dependent TCM. Additionally, by combining whole-brain c-Fos labeling and whole-brain rabies input mapping, we discovered a putative upstream PMC micturition network that can modulate TCM in a context-dependent manner. Further, we find that chemogenetic modulation of one of the identified nodes of the putative PMC micturition network— the lateral hypothalamus—bidirectionally modulates TCM behavior (Chapter 2). Together with the discovery of previously unknown cell-types in the PMC via single-cell transcriptome profiling (Chapter 3), our work provides resources, circuit principles, and, proof-of-concept discoveries that will enable future studies to fully trace the sensorimotor transformation underlying innate territory covering micturition behavior.