The anatomy of the baroreceptor reflex

Abstract

Soohong et al. (2019) reveal a class of vagal afferents—defined by Piezo2 expression—that innervate the aorta and function to sense blood pressure fluctuations. Their study describes the morphologies and role of these neurons in vascular regulation.

Whether standing up from a desk, ascending a flight of stairs, or sprinting across campus to a forgotten meeting, the physiological demands of our body for blood place ever changing burdens on our vascular system. Failure to adapt quickly can lead to the common experience of orthostatic hypotension (i.e., a headrush) or can be indicative of more serious health problems. Stabilized circulation relies on a neural surveillance system that responds to changing pressure within the vasculature and triggers appropriate counteractive changes to heart rate, vascular tone, and respiration. In this issue of Cell Reports, Soohong et al. (2019) have used genetic approaches to reveal a class of vagal sensory neurons involved in this process, known as the baroreceptor reflex, and demonstrate how the form and function of these neurons help to maintain homeostasis.

The arch of the aorta resides just above the heart and has a specialized region with a thin and elastic blood vessel wall that swells and shrinks with changing blood pressure (Figure 1). Intriguingly, this section of the aorta is heavily innervated by vagal afferents arising from the nodose ganglion via the aortic depressor nerve that are activated by stretch (Kumada et al., 1990). Previous anatomical studies found three types of morphologically distinct sensory nerve endings innervating this region: end-net endings, flower spray endings, and glomus contacts (Cheng et al., 1997). Such distinct and elaborate terminal specializations are highly suggestive of sensory adaptions, although what these might be has remained mysterious. Very recently, in a major breakthrough, the Liberles and Patapoutian groups identified Piezo ion channels as forming the transduction machinery crucial for baroreception (Zeng et al., 2018). But which vagal neurons express these stretch-gated ion channels and how do their role in the baroreflex relate to the anatomical architecture of their endings in the aorta?

Figure 1. The Anatomy of the Baroreceptor.

The baroreflex is mediated by pressure sensitive vagal afferents that make specialized end-net endings in the aortic arch and express the stretch-gated ion channel Piezo2.

In their current study, Soohong et al. (2019) used an optogenetic approach to study how excitation of vagal neurons impacts the baroreflex. They began by targeting Channelrhodopsin2 (ChR2) to all vagal neurons and used pulsed blue light to optogenetically excite them while measuring cardio-vasculature outcomes. As expected, this type of optical vagal nerve stimulation evoked responses indicative of the baroreflex. More importantly, these exact same effects were seen when ChR2 was selectively targeted to just the neurons expressing Piezo2 and no other vagal cell types. For example, the stimulation of another class of neurons marked by expression of the MC4R gene had no impact on heart rate and blood pressure despite these cells also projecting to the aorta. In a series of complementary experiments, Soohong et al. (2019) also performed targeted ablation of both classes of aorta projecting vagal neurons and found that only loss of Piezo2 neurons abolished baroreceptor activity, showing they are both sufficient and necessary.

A commonality across all sensory systems tasked with transduction of mechanical force to electrical signals is the evolution of anatomical specializations that work in concert with the force transducing molecule(s). A precise description of anatomical specializations, for example, for the tip links of inner hair cells (Pickles, 1992), the muscle spindle organ (Proske and Gandevia, 2012), or various types of endings associated with hair follicles in the skin (Rutlin et al., 2014), has provided insight into how specialized structures aid the transduction of force. This beautiful marriage of form and function is also now found for aorta projecting Piezo2 neurons, a feature that is elegantly demonstrated by Soohong et al. (2019) using a battery of anatomical approaches. Using targeted fluorescence labeling, they showed that Piezo2 neurons form the end-net endings in the caudal region of the aortic arch previously seen using more classical anatomical approaches (Cheng et al., 1997). On the other hand, the MC4R-expressing vagal neurons, which do not participate in baroreceptor activity, innervate the “saddle” region and form the morphologically distinct “flower spray” endings. Intriguingly, the complete loss of baroreceptor activity in the absence of Piezo2 neurons demonstrated that other aorta projecting vagal afferents spared by the ablation procedure (flower spray and glomus endings) must have other unknown roles. It will be very exciting to learn more about what these neural types are sensing and how their activity might impact the cardiovascular or other organ systems.

The detailed description of anatomical organization of the end-net endings of the Piezo2 vagal afferents in the aorta are notable in a few ways. As the authors point out, there is an interesting analogy between the claw-like innervation of vagal Piezo2 neurons which wrap around the aortic arch and lanceolate endings made by low threshold mechanoreceptors (LTMRs) that are found around hair shafts in the skin. The finger-like lanceolate endings have been found to play a key role in tuning the responses of these neurons to gentle touch (Rutlin et al., 2014). Furthermore, electron microscopy revealed that Piezo2 end-net terminals in the ligament region of the aortic base were unmyelinated and closely associated with Schwann cells. Very recently, there has been a growing appreciation that these types of non-neuronal cells are also critical for mechanosensation (Abdo et al., 2019). The significance of similar types of associations in interoception is rapidly becoming an important topic (Alcaino et al., 2018).

The genetic identification of neurons involved in the baroreceptor reflex offers the exciting opportunity to investigate the specific neural connections in the brain that are involved. Vagal neurons project to the nucleus of the solitary tract (NTS) where they engage central circuits involved in many homeostatic and sensory functions in response to organ stretch and chemical cues (Umans and Liberles, 2018). Uncovering the organization of this downstream circuity will be particularly fascinating and should help us better understand links between our state of mind (e.g., fear, anxiety, or depression) and our physiology (and vice versa).