David W. Adelson

The dominant narrative of autonomic nervous function remains essentially that proposed by Walter B. Cannon over a hundred years ago. It emphasizes sympathetic mediation of “fight-or-flight” responses and catabolism and associates the parasympathetic system with “rest-and-digest” functions and anabolism. Dual innervation of tissues and an antagonistic relationship between the divisions is presented as the rule, with minor exceptions. Extensive evidence accumulated over the past century renders these generalizations untenable, as autonomic neuroscientists have been pointing out for decades. Yet such critiques have not changed how the system is taught or understood. To remedy this situation, it is proposed that an alternative framework is needed that aptly summarizes sympathetic and parasympathetic functions, respectively. Here, following a systematic critique of the traditional approach, such an alternative is developed based on a consideration, first, of functions in tissues innervated by only one branch, such as the kidneys, and then, of specific functions in tissues receiving dual innervation where distinct regulatory responsibilities of one or the other branch is clear, e.g. respiratory sinus arrhythmia and the pupillary light reflex. The proposed schema describes the sympathetic division as the body’s “quartermaster,” responsible for regulating physico-chemical conditions and distributing metabolic resources to meet, and where necessary adjust, current and anticipated demand, under all circumstances. In contrast, the parasympathetic division is described as the body’s “coordinator,” regulating secretory and smooth muscle function involved in interactions and exchanges with the outside world—eating, breathing, speaking, voiding, looking, mating, moving, etc—often closely articulated with specific patterns of associated somatic motor activity. The schema emphasizes that the actions of the respective branches in each tissue relates to their respective regulatory responsibilities, and not to a generically counterbalancing relationship to the other. The proposed alternative leads to novel hypotheses regarding the function of autonomic innervation in cases where its physiological importance remains obscure, such as the parasympathetic supplies to airway smooth muscle and the pulmonary and cerebral vasculature. It is offered to stimulate debate directed toward the creation of a consensus alternative narrative that can displace the misleading traditional narrative and advance a more realistic view of autonomic function.

Pavlov’s seminal findings in the early twentieth century showed that the sight, smell or taste of food in dogs with chronic esophagostomy induces a vagal-dependent gastric acid secretion. These observations established the concept of the cephalic phase of digestion. Compelling experimental evidence in rats indicates that the three amino acid peptide thyrotropin-releasing hormone (TRH) expressed in the brainstem plays a key role in the vagal stimulation of gastric function. Neurons in the dorsal motor nucleus of the vagus (DMN) expressed TRH receptor subtype (TRH-R1) and received efferent input from TRH containing fibers arising from TRH synthesizing neurons in the raphe pallidus, raphe obscurus, and the parapyramidal regions. TRH microinjected into the DMN or intracisternally excites the firing of DMN neurons and stimulates efferent activity in the gastric branch of the vagus nerve and gastric myenteric cholinergic neurons. At the functional level, this results in a vagally-mediated and atropine-sensitive stimulation of gastric epithelial and endocrine cells secreting acid, pepsin, serotonin, histamine and ghrelin, and enteric neurons leading to increased gastric motility and emptying. Importantly, the blockade of TRH or TRH-R1 in the brainstem by pretreatment into the cisterna magna or the DMN with TRH antibody or TRH-R1 oligodeoxynucleotide antisense respectively abolishes the stimulation of gastric acid induced by sham-feeding. The gastric response to TRH injected into the DMN is potentiated by serotonin and the proTRH flanking peptide, Ps4 and suppressed by a number of brainstem peptides and cytokines activated during stress or immune response and inhibiting food intake and gastric acid secretion. These convergent data strongly support a physiological involvement of TRH signaling pathway in the brainstem to stimulate vagal activity and identified TRH-TRH-R1 system as a major effector in the dorsal vagal complex to drive the vagally mediated gut response triggered by the cephalic phase.

Sympathetic hyperactivity has an important role in cardiovascular mortality in patients with type 2 diabetes (T2D). Thyrotropin-releasing hormone (TRH)-containing fibers innervate autonomic motor and premotor nuclei of the brainstem and spinal cord that regulate cardiovascular functions. We compared cardiovascular responses to application of TRH-analog in the brainstem of Wistar and T2D Goto-Kakizaki (GK) rats. GK rats exhibited basal systolic hypertension (152±2 mm Hg) and had a significantly potentiated, dose-related hypertensive response to intracisternal (i.c.) injection of the TRH-analog RX77368 (10-60 ng). In GK rats only, i.c. RX77368 (30-60 ng) markedly increased heart rate (HR; +88 b.p.m.) and induced acute cardiac mortality (100%), concurrent with extreme hyperglycemia (>26 mmol l(-1)), increased plasma H(2)O(2) and 8-isoprostane, and enhanced heart expression of NADPH oxidase 4 and vascular cell adhesion molecule-1 mRNAs. GK rats also had elevated basal plasma epinephrine, higher adrenal gene expression of tyrosine hydroxylase and dopamine β-hydroxylase (DβH), and greater plasma catecholamine and adrenal DβH responses to i.c. TRH-analog, compared with Wistar rats. In GK rats, hexamethonium blocked i.c. RX77368-induced hypertensive and tachycardic responses, and reduced mortality by 86%, whereas phentolamine abolished the hypertensive response but enhanced tachycardia (+160 b.p.m.), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented i.c. RX77368-induced increases in blood pressure, HR and mortality. In conclusion, sympathetic overactivation triggered by brainstem TRH contributes to the mechanism of cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to sympathetic drive, and a mediating role of the renin-angiotensin system.

Non‐technical summary: Gut activity is controlled by the vagus nerves. In anaesthetized rats, both sensory and motor nerve activity evoked by intravenous injection of the gut hormone cholecystokinin were recorded in separate sub‐branches of the gastric vagus nerve that supply the forestomach and hindstomach, respectively. Activity in the forestomach branch has not been studied before. Motor nerve activity in response to cholecystokinin differed between the two branches, in both timing and direction. Motor output to the forestomach paralleled sensory input from the hindstomach, while motor output to the hindstomach paralleled sensory input from the intestines. The data suggest that cholecystokinin released in the intestines after a meal immediately influences churning and propulsion of food by the hindstomach, via reflexes initiated by nearby intestinal sensory nerve terminals, but may influence gastric capacity only later, once circulating levels of cholecystokinin rise to levels capable of activating sensors in the hindstomach.

Visceral pain modulation by chronic stress in mice has been little studied. Electromyography (EMG) recording of abdominal muscle contractions, as a proxy to the visceromotor response (VMR), requires electrode implantation and post-surgical single housing (SH) which could affect the VMR to stress. To test this hypothesis, male mice had electrode implantation surgery (S) plus SH, or no surgery and were group housed (NS-GH) or single housed (NS-SH) and exposed to either water avoidance stress (WAS, 1 h/day) or left undisturbed in their home cages for 10 days. The VMR to phasic ascending colorectal distension (CRD) was assessed before (basal) and 24 h after 10 days of WAS or no stress using a surgery-free method of intraluminal colonic pressure (ICP) recording (solid-state manometry). WAS heightened significantly the VMR to CRD at 30, 45, and 60 mmHg in S-SH vs. NS-GH, but not compared to NS-SH conscious mice. Compared to basal CRD, WAS increased VMR at 60 mmHg in the S-SH group and decreased it at 30–60 mmHg in NS-GH mice, while having no effect in NS-SH mice. The average defecation during the hour of repeated WAS over 10 days was 1.9 and 2.4 fold greater in S-SH vs. NS-GH and NS-SH mice, respectively. These data indicate that the combination of S-SH required for VMR monitoring with EMG is an important component of repeated WAS-induced post-stress visceral hypersensitivity and defecation in mice.

Corticotropin-releasing factor (CRF) 1 receptor (CRF₁) activation in the brain is a core pathway orchestrating the stress response. Anatomical data also support the existence of CRF signaling components within the colon. We investigated the colonic response to intraperitoneal (ip) injection of cortagine, a newly developed selective CRF₁peptide agonist. Colonic motor function and visceral motor response (VMR) were monitored by using a modified miniaturized pressure transducer catheter in adult conscious male Sprague-Dawley rats and C57Bl/6 mice. Colonic permeability was monitored by the Evans blue method and myenteric neurons activation by Fos immunohistochemistry. Compared with vehicle, cortagine (10 μg/kg ip) significantly decreased the distal colonic transit time by 45% without affecting gastric transit, increased distal and transverse colonic contractility by 35.6 and 66.2%, respectively, and induced a 7.1-fold increase in defecation and watery diarrhea in 50% of rats during the first hour postinjection whereas intracerebroventricular (icv) cortagine (3 μg/rat) had lesser effects. Intraperitoneal (ip) cortagine also increased colonic permeability, activated proximal and distal colonic myenteric neurons, and induced visceral hypersensitivity to a second set of phasic colorectal distention (CRD). The CRF antagonist astressin (10 μg/kg ip) abolished ip cortagine-induced hyperalgesia whereas injected icv it had no effect. In mice, cortagine (30 μg/kg ip) stimulated defecation by 7.8-fold, induced 60% incidence of diarrhea, and increased VMR to CRD. Stresslike colonic alterations induced by ip cortagine in rats and mice through restricted activation of peripheral CRF₁receptors support a role for peripheral CRF₁signaling as the local arm of the colonic response to stress.