Genetic Dissection of Vagal Motor Circuits Controlling Heart Function

Neuroscience and Neurobiology; Behavioral Neurobiology

Our project will define the synaptic circuitry and functional role of three novel neuron types in the nucleus ambiguous, the major parasympathetic input to the cardiovascular and respiratory systems.

Our projectwill define the synaptic circuitry and functional role of three novel neurontypes in the nucleus ambiguous. The nucleus ambiguous (nAmb), a highly conservedregion of the mammalian brainstem, is the primary source of parasympathetic inputto the heart and respiratory tract. Previous studies have raised thepossibility that distinct subsets of nAmb neurons connect with its differentorgan targets and so may represent “functional units” with distinct physiologicalroles (e.g., cardiac inhibition, pharyngeal contraction). Yet, since the neuronswhich comprise the nAmb are mostly unknown, it is unclear how to identify andaccess the nAmb’s functional units, greatly limiting progress in this area ofresearch. To address this issue, we recently characterized nAmb neuron subtypesand their genetic markers in mouse brain using single-cell transcriptomics. Our analysisidentified three nAmb neuron subtypes which are highly distinct in terms oftheir gene expression profiles: Vipr2 neurons, Crhr2 neurons, and Tbx3 neurons,each named for specific genetic markers that distinguish them from neighboringneurons. We will now use existing Cre/lox genetic technology and mouse models to access eachnAmb neuron subtype, map its projections to the heart and respiratory tract,and determine its role in cardiovascular function by optogenetically activating each neuron subtype while recordingcardiovascular output. This highly interdisciplinary, new research projectbrings together experts in diverse areas, from single-neuron transcriptomics tooptogenetics and neuro-cardiovascular control, to whole organ clearing andlight-sheet microscopy. Importantly, the results of this collaborative project willreveal cellular and molecular mechanisms for parasympathetic cardiovascular control.

Desired outcomes

The proposed study will accomplish thefollowing aims

  1. Characterize the molecular, anatomical, functional organization of the nucleus ambiguous (nAmb), the primary source of parasympathetic input to the heart and respiratory tract
  2. Define the synaptic projections of three novel subtypes of nAmb neurons to different organs and tissues of the respiratory and cardiovascular systems
  3. Determine the role of three novel subtypes of nAmb neurons in cardiovascular control
  4. Provide the methodological foundation and key preliminary data for an R01 grant application to the National Institutes of Health