Wednesday, April 2, 2025
4/2/2025
Molecular and organizational mechanisms that build the vagal sensory code for interoception - Project Summary The brain continuously surveys and regulates body physiology to maintain health through a robust system that senses, interprets, and responds to diverse signals from other organ systems. This sensory function, called interoception, is critical for survival, and many prevalent disorders of the cardiovascular, respiratory, digestive, immune, and cognitive systems are associated with interoceptive dysfunction. A key body-brain axis for intero-ception is the vagus nerve which connects the brain with many organs and records diverse stimuli related to their functions and responses to environmental or pathological challenges. Vagus nerve directed treatments such as vagus nerve stimulation have emerged as promising therapies for patients experiencing depression, epilepsy, or stroke but have shown minimal efficacy in other conditions involving vagal dysfunction. Incomplete knowledge of how the vagus is functionally organized prevents development of more targeted, clinically efficacious inter-ventions. Despite this need, determining how the vagal sensory system can accommodate varied phenomena from multiple organs and communicate them to the brain represents a major challenge. Recent advancements have elucidated that the vagus achieves this through a multidimensional coding architecture consisting of genet-ically specialized subpopulations of sensory neurons in the nodose ganglia that identify the organ source, sen-sory modality, and other key features of body signals. However, the mechanisms through which these functional units for interoception are assembled in the nodose ganglia remain to be fully elucidated. The current objective is to examine how this coding architecture emerges in the nodose ganglia. First, the anatomical features that organize the vagal sensory system will be determined by defining the topography of functional units and organ representation within the nodose ganglia. This will be achieved using a novel strategy involving virus-based anatomical mapping and three-dimensional reconstruction of high-throughput spatial transcriptomics ap-proaches. Second, the molecular mechanisms that establish the interoceptive code in development will be re-solved by analyzing the transcriptional and regulatory landscape of the nodose ganglia throughout embryonic and early postnatal development. Single nucleus multi-omics approaches involving simultaneous gene expres-sion and epigenetic chromatin accessibility assays will be leveraged to examine the development of the vagal sensory code’s functional units. These studies will uncover the organization and functional assembly of vagal sensory neurons in the nodose ganglia. Understanding the cell types responsible for interoception in different organs and their spatial and molecular profiles is necessary to achieve fine tuning of parameters for vagus nerve stimulation or other interventions that specifically treat the neuronal subpopulations contributing to disease. The fundamental knowledge gained from this work will lay the groundwork for future research to examine how the organization and development of the vagal sensory system is disrupted in disease and provide novel insights into our understanding of how mind-body interventions may exert their potential therapeutic effects.
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