Genetic Dissection of Nucleus Ambiguus Neurons Controlling Cardiorespiratory Functions - PROJECT SUMMARY
Heart rate is a well-established indicator of overall health and well-being, yet little is known about the neurons
that control it. Although the heart has its own pacemaker, heart rate is largely regulated by the autonomic nervous
system, subjecting it to the interplay between sympathetic neurons and parasympathetic neurons (i.e., cardiac
vagal preganglionic neurons (CVNs)). CVNs control many aspects of cardiac function, ranging from heart rate
and atrioventricular conductance (via nodal tissue) to contractility and excitability (via ventricular myocardium).
Furthermore, these neurons are highly relevant to heart health: cardiac mortality increases whenever cardiovagal
activity is diminished. The nucleus ambiguus (nAmb), a region in the medullary reticular formation of the
brainstem, houses the majority of CVNs, along with other neurons that are known to control respiratory functions
(bronchoconstriction, bronchosecretion) and innervate upper airway and esophageal muscles. This functional
diversity of neurons within the nAmb makes it challenging to isolate CVNs for study. This has greatly limited what
we know about their gene expression, synaptic circuitry, and specific roles in cardiac function—thus limiting our
ability to target these neurons in the context of cardiovascular diseases. To address these issues, I propose a
comprehensive approach to identify CVNs molecularly, anatomically, and functionally. I will characterize CVNs
based on transcriptome-wide mRNA expression, which will reveal transcriptional markers that provide genetic
access to each nAmb subtype. Leveraging the genetic differences between nAmb subtypes, I will trace each
subtype’s axonal projections to thoracic organs, revealing the anatomical organization of the CVNs. Our
preliminary studies have pointed to three molecularly distinct neuron subtypes localized in the nAmb, one of
which innervates multiple sites in the heart. Lastly, to uncover each subtype’s physiological role, I will activate
each subtype using intersectional optogenetics while assessing the effect on heart rate, respiration, and upper
airway motor function. Taken together, these studies will further uncover the molecular, anatomical, and
functional organization of CVNs, providing a multi-dimensional and comprehensive understanding of the neurons
that mediate heart rate.
