Vagal baro‐ and chemoreceptors in middle internal carotid artery and carotid body in rat

The Emx1-IRES-Cre transgenic mouse is commonly used to direct genetic recombination in forebrain excitatory neurons. However, the original study reported that Emx1-Cre is also expressed embryonically in peripheral autonomic ganglia, which could potentially affect the interpretation of targeted circuitry contributing to systemic phenotypes. Here, we report that Emx1-Cre is expressed in the afferent vagus nerve system involved in autonomic cardiorespiratory regulatory pathways. Our imaging studies revealed expression of Emx1-Cre driven tdtomato fluorescence in the afferent vagus nerve innervating the dorsal medulla of brainstem, cell bodies in the nodose ganglion, and their potential target structures at the carotid bifurcation such as the carotid sinus and the superior cervical ganglion (SCG). Photostimulation of the afferent terminals in the nucleus tractus solitarius (NTS) in vitro using Emx1-Cre driven ChR2 reliably evoked EPSCs in the postsynaptic neurons with electrophysiological characteristics consistent with the vagus afferent nerves. In addition, optogenetic stimulation targeting the Emx1-Cre expressing structures identified in this study, such as vagus nerve, carotid bifurcation, and the dorsal medulla surface transiently depressed cardiorespiratory rate in urethane anesthetized mice in vivo . Together, our study demonstrates that Emx1-IRES-Cre is expressed in the key peripheral autonomic nerve system and can modulate cardiorespiratory function independently of forebrain expression. These results raise caution when interpreting systemic phenotypes of Emx1-IRES-Cre conditional recombinant mice, and also suggest the utility of this line to investigate modulators of the afferent vagal system.

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Section: Resultsmentioning

confidence: 99%

Emx1-Cre Is Expressed in Peripheral Autonomic Ganglia That Regulate Central Cardiorespiratory Functions

Ning

Noebels

Aiba

2022

eNeuro

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“…In order to further characterize peripheral Emx1-Cre expression, we analyzed the Emx1-tdtomato signal in the neural tissue at the carotid bifurcation where the vagus nerve innervates the vascular sensory structures such as the carotid body, carotid sinus, as well as the superior cervical ganglion (SCG) (Wang et al, 2019). In the extracted whole-mount preparation ( Figure 4A ), blur Emx1-tdtomato fluorescence was identified at the carotid artery bifurcation and diffusely in the SCG ( Figure 4B&C ).…”

Section: Resultsmentioning

confidence: 99%

Emx1-Cre is expressed in peripheral autonomic ganglia that regulate central cardiorespiratory functions

Aiba

Ning

Noebels

2022

Preprint

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The Emx1-IRES-Cre transgenic mouse is commonly used to direct genetic recombination in forebrain excitatory neurons. However the original study reported that Emx1-Cre is also expressed in peripheral autonomic ganglia, which could potentially affect the interpretation of targeted circuitry contributing to systemic phenotypes. Here, we report that Emx1-Cre is expressed in nodose ganglion cells whose axon travel within afferent vagal nerves and terminate in the nucleus tractus solitarius (NTS), a critical central autonomic regulatory pathway located in the dorsal medulla. Optogenetic stimulation of Emx1-Cre+ fibers reliably evoked excitatory postsynaptic currents in the NTS in vitro and evoked a parasympathetic bradycardia reflex occasionally with irregular respirations in anesthetized mice in vivo. Our study clearly demonstrates that Emx1-IRES-Cre is expressed in the vagal nerve fibers traveling within the central autonomic system involving autonomic cardiorespiratory regulation. These results raise caution when interpreting the systemic phenotypes of Emx1-IRES-Cre conditional recombinant mice, and also suggest the utility of this line to investigate the modulators of afferent vagal system.Significance StatementEmx1-IRES-Cre mice are widely used to dissect critical circuitry underlying neurological disorders such as epilepsy. These studies often assume the Cre is expressed selectively only in forebrain excitatory neurons. However, earlier works reported that Emx1 is expressed in several peripheral tissues of the developing embryo and thus gene recombination may affect these peripheral structures. In this study, we characterized the expression and physiological functions of Emx1-Cre expressed in the afferent vagus nerve. Optogenetic stimulation of these Emx1-Cre+ vagus nerves activates the nucleus tractus solitarius neurons within the brainstem in vitro and induces brief bradycardia in vivo. This study confirmed that peripheral Emx1-Cre+ cells are involved in autonomic regulation and potentially affect transgenic mouse phenotypes.

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“…They also reported that the neurons in the vagus nerve represented between 1%–2% of all vagal sensory neurons. More recent histological studies identified a population of sparse pseudo‐unipolar cells that resembled vagal afferent neurons in cross‐sections of the porcine vagus nerve (Pelot et al, 2020 ; Settell et al, 2020 ) and rat whole vagal trunk (Wang et al, 2019 ). Whereas Plenat and colleagues (Plenat et al, 1988 ) described these neurons as “displaced sensory neurons ” , in this study, we have identified vagal afferent neurons with soma outside the NG and JG as extraganglionic neurons .…”

Section: Introductionmentioning

confidence: 99%

Evidence of extraganglionic vagal mechanoreceptors in the mouse vagus nerve

2023

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Vagal afferent neuronal somas are in the nodose and jugular ganglia. In this study, we identified extraganglionic neurons in whole‐mount preparations of the vagus nerves from Phox2b‐Cre‐ZsGreen transgenic mice. These neurons are typically arranged in small clusters and monolayers along the cervical vagus nerve. Although infrequent, these neurons were sometimes observed along the thoracic and esophageal vagus. We performed RNAscope in situ hybridization and confirmed that the extraganglionic neurons detected in this transgenic mouse strain expressed vagal afferent markers (i.e., Phox2b and Slc17a6) as well as markers that identify them as potential gastrointestinal mechanoreceptors (i.e., Tmc3 and Glp1r). We also identified extraganglionic neurons in the vagus nerves of wild‐type mice that were injected intraperitoneally with Fluoro‐Gold, thereby ruling out possible anatomical discrepancies specific for transgenic mice. In wild‐type mice, extraganglionic cells were positive for peripherin, confirming their neuronal nature. Taken together, our findings revealed a previously undiscovered population of extraganglionic neurons associated with the vagus nerve. Going forward, it is important to consider the possible existence of extraganglionic mechanoreceptors that transmit signals from the abdominal viscera in future studies related to vagal structure and function.

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Vagal baro‐ and chemoreceptors in middle internal carotid artery and carotid body in rat

Cited by 4 publications

References 34 publications

Emx1-Cre Is Expressed in Peripheral Autonomic Ganglia That Regulate Central Cardiorespiratory Functions

Emx1-Cre Is Expressed in Peripheral Autonomic Ganglia That Regulate Central Cardiorespiratory Functions

Emx1-Cre is expressed in peripheral autonomic ganglia that regulate central cardiorespiratory functions

Evidence of extraganglionic vagal mechanoreceptors in the mouse vagus nerve

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