Rostral ventrolateral medulla, retropontine region and autonomic regulations☆
Introduction
The autonomic nervous system comprises a highly diverse array of efferent sympathetic and parasympathetic pathways that collectively regulate every bodily organ. This review focuses on the role of the ventrolateral medulla and adjacent retropontine region (the latter defined as in (Watson et al., 2019) (RVLMRP) with particular emphasis on cardiorespiratory integration. The purpose is not to provide an exhaustive description of the myriad reflexes or feed-forward regulations mediated through the RVLMRP in health and disease (Coote and Spyer, 2018; Dampney, 2016; Guyenet et al., 2018; Guyenet et al., 2020; Schreihofer and Sved, 2011). Instead, we focus on a limited number of fundamental reasons why this region plays center stage in defining patterns of autonomic responses. In discussing these topics we refer to foundational papers while emphasizing the most recent developments. We address the cellular origin of the resting sympathetic tone to the cardiovascular system, the importance of disinhibition to the regulation of sympathetic nerve activity to the cardiovascular system and the most elemental mechanism for coordination of breathing and the circulation (central cardiorespiratory coupling). Finally, we highlight new research on three types of brain interoreceptors (proton receptors, hypoxia sensors and mechanoreceptors) located in this region of the brain and attempt to draw analogies with hypothalamic interoceptors implicated in detecting other circulating variables such as sodium.
Section snippets
The rostral ventrolateral medulla and retropontine region: general anatomy
The VLM extends from the spino-medullary junction to the facial motor nucleus (Fig. 1). The VLM has been variously subdivided depending on whether cardiovascular regulation (Schreihofer and Sved, 2011) or breathing (Del Negro et al., 2018; Smith et al., 2013) was the primary research focus (Fig. 1A). The dorsal half of the VLM harbors the ventral respiratory column (VRC) (Fig. 1A). The catecholaminergic neurons (C1 rostrally, A1 caudally), are found preferentially in the ventral half of the VLM
RVLM adrenergic and other presympathetic neurons
Reis et al. proposed that the bulbospinal C1 neurons maintain sympathetic vasomotor tone because they are located in a region whose integrity is required for the sympathetic vasomotor tone of anesthetized mammals (Dampney et al., 1982; Guertzenstein and Silver, 1974; Ross et al., 1981; Ross et al., 1983) and for recent reviews: (Dampney, 2016; Guyenet et al., 2018; Schreihofer and Sved, 2011). Roughly half of the C1 neurons indeed directly innervate spinal preganglionic neurons and therefore
RVLM and sympathetic tone to the cardiovascular system
Under anesthesia, the SNA to the heart, kidneys and blood vessels persists virtually unchanged after the brain is transected at the intercollicular level but it is eliminated by silencing RVLM neurons indiscriminately using local injections of neuroinhibitory chemicals such as glycine or muscimol (Dampney et al., 2003; Dampney, 1981; Dampney, 1994). These seminal observations combined with the unit-recording data discussed above suggest that, under anesthesia, the sympathetic tone is largely
Origin of the sympathetic tone to the cardiovascular system
Vast portions of the neuraxis contribute to state- or behavior-related adjustments of SNA and BP. This topic is beyond the scope of this chapter (Dampney, 2016). However, SNA persists in all mammalian preparations in the absence of the brain rostral to the pons. The following section deals with the generation of this activity which has fascinated scientists for generations (for a historical perspective see (Seller, 1996)).
At present, given the preeminence of the RVLM in maintaining sympathetic
The C3 neurons, an ectopic subgroup of C1 cells?
Located in the dorsomedial medulla, the C3 cluster of adrenergic neurons presents many similarities with the C1 cells. They express VGlut2, hence use glutamate as a fast transmitter, they synthesize similar neuropeptides (NPY, PACAP, ENK, CART), separate subgroups project rostrally vs. to the spinal cord, those with spinal projections contact directly the preganglionic neurons and selective C3 stimulation increases SNA and breathing frequency, albeit to a lesser extent than C1 (Menuet et al.,
Other functions of the C1 cells: breathing, immune regulation, appetite regulation, parasympathetic regulation
The possibility that C1 neurons could have many other functions besides BP regulation was evoked very early based on the brain distribution of PNMT-immunoreactive cell bodies and terminals (Hokfelt et al., 1974). The effect of the C1 cells on breathing, the level of vigilance, immune responses and glucoregulation are currently among the best documented. Several of these effects are at least partly mediated via the sympathetic system (e.g., anti-inflammatory effect, effect on glucose
VLM and the baroreflex
In the field of neural control of BP, the term caudal VLM (CVLM) refers to a portion of the ventrolateral medullary reticular formation that contains another major nodal point of the baroreflex. Activation of this area by a microinjection of glutamate lowers BP hence the name ventrolateral medullary “depressor” region originally given to it by Sapru and colleagues (Willette et al., 1983; Willette et al., 1984). We prefer to call it IVLM (intermediate VLM) since it overlaps with the caudal half
VLM and central cardiorespiratory coupling
CO2 excretion by the lungs usually equals the metabolic production of this gas and, as a result, arterial PCO2 and PO2 remain constant. This regulation relies on feedforward processes (central command) and sensory afferent feedback (chemoreceptors, metaboreceptors) (Forster et al., 2012; Smith et al., 2010). O2 delivery and CO2 removal to and from tissues require continual adjustments of the cardiac output and re-apportionment of this output to various organs according to their metabolic needs.
Respiratory chemoreceptors: the RTN
Interoceptors (mechanoreceptors, nociceptors, chemoreceptors) are sensory afferent neurons that inform the CNS about the internal state of the body. The brain has its own interoceptors that monitor variables such as PCO2, PO2, intracerebral pressure, temperature, glucose, [Na+], etc. and elicit homeostatic responses. PCO2, PO2 and intracerebral pressure are detected in the RVLMRP region and initiate neural responses of great importance to cardiovascular and respiratory homeostasis. Central
Brainstem oxygen sensors and cardiorespiratory homeostasis
Carotid body stimulation is primarily responsible for the stimulatory effect of hypoxia on breathing and the sympathetic system (hypoxic ventilatory reflex, HVR)(Kumar and Prabhakar, 2012; Ortega-Saenz and Lopez-Barneo, 2019). The contribution of brain oxygen sensors to these responses has long been debated and remains controversial (Golanov and Reis, 1996; Gourine and Funk, 2017; Reis et al., 1994; Roux et al., 2000b). Indeed, systemic hypoxia was repeatedly showed to depress breathing in
Brainstem mechanoreceptors and autonomic regulation: the Cushing response revisited
Finally, the caudal brainstem also responds to changes in intracerebral pressure by increasing sympathetic tone and blood pressure, the Cushing response (Cushing, 1901). This reflex has now been observed in rats, sheep and humans in the absence of anesthesia (Guild et al., 2018; McBryde et al., 2017; Schmidt et al., 2018). The blood pressure increase triggered by elevating intracranial pressure also requires the exocytotic release of transmitters by brainstem astrocytes (Marina et al., 2020).
RVLMRP and cardiorespiratory correlates of psychological stress
Agonistic behavior, isolation, interspecies aggression and all other forms of stress deemed psychological have autonomic and respiratory correlates that reflect the level of arousal, the emotional state and the metabolic needs associated with the behavior (Keay and Bandler, 2001; Sieminski et al., 2018). What follows addresses a simple question: whether the changes in sympathetic outflow and breathing associated with acute stress are mediated by changes in the activity of the RVLM pre-autonomic
Summary and conclusions
The RVLM and immediately adjacent RTN are critical to cardiorespiratory regulation, probably under most circumstances with the possible exception of a pure psychological stress. RVLM also regulates blood glucose, immune responses and as yet poorly defined subsets of vagal parasympathetic outflows. This region controls autonomic efferent pathways via monosynaptic projections to sympathetic and parasympathetic preganglionic neurons as well as indirectly, via axonal projections to dorsolateral
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