The hypothalamus regulates various kinds of physiological functions to maintain homeostasis in the whole body. The hypothalamus also has many neuronal nuclei that each have a different physiological function. In particular, the paraventricular nucleus (PVN) of the hypothalamus is known to be one of the most important nuclei that integrate the autonomic nervous system and neuroendocrine system. When I was a PhD student, I revealed that synaptic inputs from the gastric branch of the vagal nerves to the PVN magnocellular neurosecretory neurons, that produce vasopressin and oxytocin, modulate the neuronal activities of these neurons and the secretion of vasopressin and oxytocin via central noradrenergic pathway in rats, using electrophysiology and a microdialysis system. Since then, we have continued to conduct basic studies on the hypothalamus as an integrative site of the autonomic nervous system and neuroendocrine system. In this paper, I introduce some of our recent research related to the autonomic nervous and neuroendocrine systems in the hypothalamus, using electrophysiology and genetically modified animals.

Toyokura’s remark on the “negative tetrads of ALS” made Mannen to begin the pathological investigations of the sacral anterior horn of the autopsied materials. He found the sparing of the Onuf ’s nucleus among the markedly depopulated anterior horn of the second sacral cord in ALS cases. He also found that the Onuf ’s nucleus is markedly depopulated in Shy-Drager syndrome with incontinence of urine and feces. Mannen’s discovery of the pathology of Onuf ’s nucleus in ALS and Shy-Drager syndrome was followed by numerous animal experiments using retrograde tracers injected in pelvic sphincter muscles and these experiments revealed unanimously that the neurons of the Onuf ’s nucleus are really innervating pelvic sphincter muscles. Our further investigations on the sacral cord in a case of rectal amputation showed the somatotopic localization of the somatic and autonomic efferent neurons innervating the external and internal anal sphincter muscles. Onuf ’s nucleus was described anatomically by Onuf but the functional significance of that nucleus was elucidated by Mannen, as a consequence this nucleus should be named Onuf-Mannen’s nucleus.

We found that defecation was significantly promoted when an agonist of ghrelin was administered to rats. This unexpected finding motivated novel research focusing on the regulatory mechanism of colonic motility by the central nervous system, because the action site of the ghrelin agonist was the lumbosacral defecation center. In addition to the ghrelin agonist, noradrenalin, dopamine and serotonin were found to act on the spinal defecation center to enhance colonic motility. All of the monoamines were transmitters of the descending pain inhibitory pathways. Accordingly, we have proposed a novel concept that “the regulatory system of pain transmission and the regulatory system of colorectal motility are linked at the spinal cord”. In this review article, we summarize our recent findings on the central regulatory mechanism of colonic motility.

Neurological diseases often cause bladder and bowel dysfunction. Bladder dysfunction depends on the site of neural lesion, i.e., overactive bladder (brain and suprasacral), underactive bladder/urinary retention (sacral and peripheral nerve) and their combination (suprasacral spinal and multiple system atrophy, etc.). Bowel dysfunction mostly is constipation irrespective of the site of neural lesion. Many disorders should be excluded before reaching neurogenic bladder and bowel dysfunction and proper management.

Since olfactory impairment occurs in the very early stage of dementia, it is expected to have an application in the early detection and prevention of dementia. Animal experiments at our laboratory have shown that basal forebrain cholinergic nerves, which degenerate in Alzheimer’s disease, play a role of autonomic-like vasodilators that increase regional blood flow in the neocortex and hippocampus. The cholinergic nerve also projects to the olfactory bulb, the primary olfactory center. Recently, we reported that intravenously injecting anesthetized rats with nicotine, a nicotinic cholinergic agonist, increases the olfactory-evoked blood flow response in the olfactory bulb, suggesting a role in enhancing olfactory sensitivity. Also, in a clinical study, we found a relationship between olfaction and cognitive function, especially attention, in the elderly. In this paper, we present basic and clinical research on olfaction and cognitive function, focusing on the cholinergic system.

Both the James-Lange theory (1884, 85) and the Cannon-Bard theory (1927, 28) were proposed in regard to the causal relationship between emotion and autonomic activity; the former insisted that emotion was formed by the change in visceral conditions, while the latter argued that emotion influenced autonomic activity and not vice versa. The conflict between the both theories was derived from the definition of the autonomic nervous system by Langley (1898), who asserted that the autonomic nervous system did not include central and afferent fibers. Being free from “Langley’s curse”, I herein describe the real history of autonomic science concerning the central autonomic network (CAN) and the autonomic afferents as well as the causal relationship between emotion and autonomic activity. Supporting the James-Lange theory, Bechterew (1887) first clarified that emotion was evoked in the thalamus, which was a common channel of afferent inputs into the brain. L. R. Müller, an academic opponent of Langley, maintained that the causal relationship between emotion and autonomic activity was bidirectional (1906), and that the both were originated in the neural network within the diencephalon (1929). More recently, Prechtl and Powley (1990) stated that afferent impulses from the visceral organs (interoception) passed through the spino-thamamic tract, which was considered as the autonomic afferents. Craig (2002) confirmed that the afferent fibers from the visceral organs and the sympathetic fibers constituted the CAN in the brain, and suggested that both emotion and autonomic activity were concurrently generated within the CAN.

The autonomic nervous system dynamically controls homeostasis in the circulatory system. Recently, it has become clear that the autonomic nervous system not only regulates circulatory function, but also contributes to the maintenance of homeostasis through organ crosstalk. Moreover, it may also promote organ dysfunction by affecting chronic inflammation. In addition, autonomic regulation of multiple organs may lead to multimorbidity. This review outlines the interaction between autonomic nerves and macrophages in cardiorenal syndrome and myocardial infarction.

The liver-brain-gut axis has been focused on its effect on the several liver diseases. Among the various factors involved in the axis, we have focused on the effect of autonomic neural axis and reported its effect on NAFLD. In this review, we will talk about our recent progress with the basic information in this field.

Vagal nerve stimulation (VNS) is an established palliative treatment for medically intractable epilepsy. It has also received FDA approval for treatment-resistant depression, headache, and stroke rehabilitation. Studies to determine whether VNS could be the next treatment of choice for other pathologies such as heart failure, Parkinson’s disease, Alzheimer’s disease and inflammatory disease are actively being conducted. The cumulative results of clinical and experimental studies suggest that VNS achieves its anti-epileptic effect by stabilizing activity in the cerebral cortices, inhibiting abnormal excitability via multiple afferent pathways such as the cholinergic, noradrenergic and serotonergic pathways, originating from the nucleus tractus solitarius. Non-invasive transcutaneous stimulation, which has been proved to be safe and effective for clinical conditions such as episodic headaches, is also actively being studied to investigate its therapeutic indications for other pathologies. Non-invasive VNS would increase the opportunity to investigate the physiological effect of VNS with higher precision, through the recruitment of healthy subjects, and could expand the frontiers of basic neuroscience research into neuromodulation.

It has long been suggested that various aspects of the immune system are controlled by the nervous system. However, how the inputs from the nervous system are converted into the outputs from the immune system had been largely unclear. Studies in the last decade revealed the cellular and molecular basis by which inputs from the autonomic nervous system control the functions of immune cells. We recently discovered that adrenergic neurons control trafficking of lymphocytes through lymph nodes. This mechanism was found to generate a diurnal rhythm in adaptive immune responses and regulate inflammatory responses in peripheral tissues. In this review, I discuss the molecular mechanism, physiological significance, and clinical relevance of adrenergic neuron-mediated control of lymphocyte trafficking.

Glucagon-like peptide-1 (GLP-1) is secreted by enteroendocrine L cells and promotes insulin secretion and suppresses appetite. GLP-1 secretion is regulated by various substances in the lumen of the gastrointestinal tract, neurotransmitters and hormones in the blood, and various metabolites produced by the intestinal microflora, but the detailed regulation mechanism is unknown. In the present review, we will introduce the effects of amino acids and intestinal bacterial metabolites on GLP-1 secretion.

The intracerebral cholinergic system is important not only for cognitive function, but also for cerebral blood flow control. In patients with dementia, neuron loss is observed in the intracerebral cholinergic system, and cerebral cortical blood flow decreases. It has been reported that a Japanese medicine, ninjin’yoeito, improves cognitive decline in patients with Alzheimer’s disease, and activation of the intracerebral cholinergic system has been suggested as the mechanism. In this mini-review, we summarize current knowledge regarding cerebral blood flow control by the intracerebral cholinergic system and introduce our recent study on the effect of ninjin’yoeito on the resting cerebral cortical blood flow and the cerebral blood flow response to somatosensory stimulation.

Emotion is closely related to autonomic responses. However, the causal relationship between the two has not yet been fully elucidated. In order to better understanding the relationship, we investigate the effects of emotional changes on autonomic responses and the effects of autonomic responses on emotion. Therefore, we developed two experimental systems for freely-moving mice using by optogenetical methods. In this study, we found that aversive emotion-induced orexin neuron activity resulted in increased heart rate.

Measuring discomfort during a virtual reality (VR) experience (VR sickness) is important to prevent health hazards and to encourage people to utilize VR technology safely. Using simultaneous measurements of subjective discomfort intensity and electrocardiogram (ECG), we investigated changes in the autonomic nervous activity related to the discomfort caused during a VR experience. In this study, the ECGs of sixteen healthy adults were monitored while they watched a 5-minute VR roller coaster video, which included various rotational and reciprocating motions, using a head-mounted display. The participants were instructed to continuously report their momentary intensity of discomfort using a slider device. Their heart rate variability was analyzed using the R-R interval data of ECGs to calculate the heart rate, the sympathetic nervous activity, and the parasympathetic nervous activity. The values obtained during the time periods of moderate to severe discomfort were compared with those during control periods, in which the roller coaster was at the station and motionless. The results indicate that participants' perceived discomfort was associated with increases in heart rate and sympathetic nervous activity, and a decrease in parasympathetic nervous activity. These results suggest that there is a significant association between autonomic activity and subjective discomfort during VR experiences. This kind of cardiac autonomic nervous activity could be used as a useful biological index for the objective evaluation of VR sickness.