The nature of sympathetic rhythmicity

The adequate supply of nutrients and oxygen to all cells in our body and the removal of the metabolism products is a sine qua non for life. This condition results from an integrated work of multiple physiological systems. The sympathetic nervous system regulates the blood flow to all tissues through the continuous control of the heart activity and vascular resistance. At the blood vessel level, the sympathetic nerves determine the vasoconstrictor tone through the release of noradrenaline (and other co-transmitters) and the activation of adrenoreceptors expressed on vascular smooth muscle cells. Although persistent, the activity of the sympathetic discharge to blood vessels fluctuates in response to internal and external disturbances causing reflex modifications in the blood vessel diameter to adjust blood flow according to the metabolic demand (Guyenet, 2006). The control of cardiovascular function by the brain is the topic of investigation of several studies exploring its physiological relevance and involvement in the development of life-threatening cardiovascular dysfunctions. Since the original observations of the circulatory system in the 17th century, our understanding of how the sympathetic nervous system controls blood pressure in health and disease states has advanced significantly. In almost 145 years, the Journal of Physiology has published fundamental studies about the organization and functioning of the sympathetic nervous system, which laid the foundation for subsequent investigations. To celebrate the 600th volume of the journal, I would like to draw attention to an impactful study published 90 years ago by Adrian, Bronk and Phillips, describing, for the first time, the pattern of sympathetic discharge in mammals (Adrian et al., 1932). Edgar Douglas Adrian was awarded the 1932 Nobel Prize in Physiology and Medicine, jointly with Sir Charles Sherrington, for his discoveries on the basic principles of neuron function. His studies published in the Journal of Physiology in the 1920s and 1930s covered fundamental aspects in neurophysiology as the nature of the electrical signal transmission in nerves and their reception in the brain. In 1932, Adrian and colleagues employed a new technical arrangement to record from cervical and abdominal sympathetic nerves in rabbits and cats, reporting that their activity occurs in bursts as a ‘background of waxing and waning excitation’ larger than in the sensory and motor nerves. The authors also performed manipulations like asphyxia or vasoactive drug injections to demonstrate an association between fluctuations in the sympathetic activity amplitude and changes in blood pressure levels. It was then proposed that the sympathetic vasoconstrictor activity would be persistent but never show a regular discharge pattern compared with other nerves during a steady state. The pioneering descriptions about the mammalian sympathetic discharge by Adrian et al. (1932) fostered cardiovascular and neurophysiology researchers to investigate the mechanisms underlying the regulation of blood pressure levels by the sympathetic nervous system under different conditions. Currently, evidence indicates that a group of spinally projecting neurons located in the rostral ventrolateral surface of the medulla oblongata (a.k.a. RVLM) mainly defines the baseline vasoconstrictor activity (Guertzenstein & Silver, 1974; Ross et al., 1984). The activity of the RVLM pre-sympathetic neurons is determined by a balance of excitatory and inhibitory synaptic drives (Lipski et al., 1996; Moraes et al., 2013), although some RVLM neurons may also be capable of intrinsic firing based on pacemaker properties (Sun et al., 1988). The RVLM is interconnected with several brain regions, and its activity is also modulated by peripheral afferent information (such as from baro- and chemoreceptors), indicating that this region also acts as an integrative site. The RVLM houses two groups of sympatho-excitatory neurons: (i) the C1 group, composed of glutamatergic cells (containing the vesicular glutamate transporter-2, VGLUT2) that also express the phenyl-ethanolamine N-methyl transferase (PNMT), hence synthesize adrenaline; and (ii) the non-C1 group, consisting of glutamatergic cells (VGLUT2-positive) that do not contain PNMT (Guyenet et al., 2013). These neurons may form subgroups in the RVLM and promote a regional control of sympathetic activity to different territories (Guyenet, 2006). The activation of these RVLM populations increases the sympathetic discharge and blood pressure levels, and plasticity in the RVLM (and other regions that communicate with the RVLM) is associated with the development of baseline sympathetic overactivity (Guyenet, 2006). In addition to the role of sympathetic nerves, the study by Adrian et al. (1932) also provided information about the pattern of sympathetic discharge. The authors observed that the voltage waves in the sympathetic nerves, although irregular, were in synchrony with respiration and heartbeats. The authors also identified that the respiratory rhythmicity in the sympathetic activity resulted from direct actions of the respiratory centre on the vasomotor centre (as it persisted after procedures that isolated the brainstem from sensory feedback) while the cardiac modulation disappeared after sectioning the aortic depressor nerve. With the development of newer amplifiers and computer-assisted analyses, studies confirmed that respiratory and cardiac-related oscillations are hallmarks of mammalian sympathetic discharge. Other rhythms were also identified at frequencies lower than respiration and higher than the heart rate (≥10 Hz), whose amplitude might vary depending on the animal species and experimental conditions (Barman & Gebber, 2000). Therefore, rhythmicity is an innate feature of the sympathetic nervous system, which was firstly described by Adrian et al. (1932). However, the physiological relevance of the sympathetic rhythms received less attention than the mechanisms regulating the absolute levels. But why would it be relevant to study the rhythmicity of sympathetic discharge? From my perspective, there are reasons to look at this feature with more attention. Within the RVLM, the C1 and non-C1 pre-sympathetic populations exhibit distinct firing patterns that collectively account for the overall oscillations in the sympathetic discharge. Some patterns are suggested to be produced intrinsically, while other rhythms require external oscillators’ input (Barman & Gebber, 1981; Moraes et al., 2013). Therefore, identifying the rhythmic components can reveal how the sympathetic nervous system is wired with other complex networks. This strategy has helped to understand the interactions between the sympathetic nervous system and the respiratory network. Under baseline conditions, sympathetic vasoconstrictor activity shows bursts synchronized with respiration that peaks at the transition from inspiration to expiration. During challenges such as low oxygen availability (hypoxia) or excess of carbon dioxide (hypercapnia), this respiratory-related modulation shifts phase, and the sympathetic discharge reaches its maximum during mid to late expiration (Moraes et al., 2014). The sources of synaptic inputs driving these respiratory-related patterns in sympathetic outflow are still not well defined, in part due to the complexity of the respiratory network. Single-unit examination of RVLM activity revealed that groups of C1 neurons exhibit regular cycles of firing synchronization during inspiration (Moraes et al., 2013) driven, at least in part, by excitatory inputs from inspiratory neurons of the pre-Bötzinger complex (a region required for respiratory rhythmogenesis) (Menuet et al., 2020). The selective inhibition of either the C1 population or the inspiratory preBötC neurons suppresses baseline respiratory-related bursts in sympathetic discharge (Menuet et al., 2020; Moraes et al., 2017), indicating the existence of interactions between two critical regions for the cardiorespiratory control. In contrast, the generation of expiratory-related oscillations in the sympathetic discharge during blood gas challenges (e.g. hypoxia and hypercapnia) appears to rely on synaptic inputs from expiratory centres to non-C1 neurons (Molkov et al., 2011; Moraes et al., 2017). Therefore, the respiratory modulation of sympathetic discharge occurs through interactions between specific respiratory and pre-sympathetic neurons rather than a general excitation of the RVLM. This might also be the scenario of hypothalamic and midbrain circuitries that interact with medullary networks to generate coordinated sympathetic and respiratory responses to psychological stressors (Dampney, 2015). Therefore, understanding the rhythms and activity patterns in sympathetic outflow can provide information on how circuitries are connected to generate a spatiotemporal synchronization in networks to entrain behaviours that also cause an increase in blood pressure. Regarding the physiological relevance, the rhythmic activity within a network can promote a more robust neuronal activation than a stochastic occurring activity, improving signal transmission. In the context of the sympathetic nervous system, the firing synchronization at the level of pre-sympathetic, pre- and post-ganglionic neurons can improve the vasoconstrictor response by increasing neurotransmitter release or promoting the summation of multiple weak impulses. Consequently, an increase in the power of a frequency component can be as effective in promoting a physiological response as an increase in absolute levels. In agreement with this observation, evidence shows that the rhythmical sympathetic discharge occurring every respiratory cycle causes vasoconstriction and contributes to the respiratory-related variability in arterial pressure. The attenuation of the respiratory-related bursts in sympathetic activity reduces the magnitude of oscillations and level of blood pressure, while the amplification of the respiratory modulation in sympathetic activity, as seen during the exposure to hypoxia, is associated with an increase in vascular resistance (Moraes et al., 2014). In animal models of arterial hypertension (such as spontaneously hypertensive and chronic intermittent hypoxia-treated rats), the higher levels of sympathetic discharge and high blood pressure correlates with changes in the strength and timing of respiratory-sympathetic synchronization (Simms et al., 2009; Zoccal et al., 2008), suggesting a possible pathological consequence of respiratory-sympathetic coupling dysregulation. Changes in the frequency domain of sympathetic oscillations can also produce pressor responses. For example, a drop in blood pressure can evoke an increase in the 10 Hz rhythmic discharge in the sympathetic activity to cause a vasoconstrictor response (Barman & Gebber, 2000). Therefore, understanding the nature of the sympathetic activity's rhythmic components can help us comprehend the development of cardiovascular responses under different conditions. The studies by Adrian et al. (1932) were critical to boosting the interest in the functioning of the sympathetic nervous system. In addition to demonstrating the vasoconstrictor actions, the authors provided information about the sympathetic activity synchronization and integration of the sympathetic nervous system with other networks. The rhythmic control of sympathetic activity has physiological relevance and should be considered while investigating blood pressure control associated with other behaviours. Besides, the sympathetic nervous system participates in the regulation of other functions, such as thermoregulation, metabolism, and breathing (Guyenet et al., 2013). Sympathetic neurons also connect with waking-promoting areas and stimulate arousal in a state-dependent manner (Burke et al., 2014). Therefore, it might be worth considering investigating how the synchronization of the sympathetic nervous system also influences other autonomic functions and behaviours that affect body homeostasis. Understanding these rhythmic patterns can reveal the mechanisms coordinating system activity, network dynamics, and the control of biological processes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. Sole author. I thank the financial support from the São Paulo State Research Foundation (FAPESP, grant 2018/21000-2), National Council for Scientific and Technological Development (CNPq, grants 310331/2017-0 and 408950/2018-8), and Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES, grant 88887.310463/2018-00).