The biological origin of circumventricular organs (CVOs) and the hypothalamus evolutionally goes back to invertebrates and even to plants. There are resting and action types of behavior of the hypothalamus. The resting hypothalamus (ventromedial hypothalamus and arcuate nucleus inhibiting eating behavior) facilitates vagal, pelvic and oculomotor parasympathetic nerves, and sympathetic nerves innervating the liver and spleen. The action hypothalamus (lateral hypothalamus and arcuate nucleus facilitating eating behavior) facilitates the cardiac sympathetic nerves and the hypothalamic-pituitary-adrenal axis. There are sensory CVOs (subfornical organ, organum vasculosum of lamina terminalis, and area postrema) and secretory CVOs (neurohypophysis, pineal gland, subcommissural organ, and median eminence). Physiological mechanisms of life-saving homeostasis arising from the hypothalamus and CVOs consist of seven axes: the autonomic nervous system axis, the circadian rhythm axis, the neuroendocrine axis, the emotion and memory axis, the pain and sensation axis, the gait and motion axis, and the neurometabolism and neuroimmunity axis (eating and drinking behavior, heat energy metabolism, waste clearance, innate immunity). Thus, CVOs and the hypothalamus contribute to a wide spectrum of regulation axes, whose impairments result in complex symptoms composed of sleep-related, cardiovascular, gastrointestinal, menstrual, emotional, cognitive, sensory, and motor symptoms. We propose a new clinical concept “hypothalamic syndrome,” or “circumventricular organ dysregulation syndrome,” to describe a range of known disorders including human papilloma virus vaccination-associated neuro-immunopathic syndrome (HANS), von Economo’s encephalitis lethargica, craniopharyngioma, interferon encephalopathy, metronidazole-induced encephalopathy, Wernicke’s encephalopathy, schizophrenia with water intoxication, Alzheimer’s disease with overeating, neuromyelitis optica, stiff-person syndrome, cerebrospinal fluid hypovolemia, heat stroke, fibromyalgia, chronic fatigue syndrome / myalgic encephalomyelitis, menopausal syndrome, frailty syndrome (sarcopenia syndrome), and environmental hypersensitivity.

The neuroendocrine system, in particular the hypothalamic pituitary system, plays important roles in maintaining homeostasis with the autonomic nervous system in the whole body. The neurohypophysial system has been studied for a long time as a typical neuroendocrine model. Classical studies revealed the pressor effects of pituitary extract on the whole body. In the middle of the twentieth century the neurohypophysial hormones named vasopressin and oxytocin were purified, identified and synthesized by biochemical methods. Subsequently, much knowledge has been accumulated through molecular biological approaches and modern techniques in life sciences. Recently, newly developed tools, optogenetics and chemogenetics, have been intensively used to reveal neuronal circuits related to brain/whole body functions including the autonomic nervous system. In this paper, recent progress in this field is reviewed together with our data obtained from optogenetic and chemogenetic approaches.

Autonomic neuropathies are a group of disorders in which small, lightly myelinated and unmyelinated autonomic nerve fibres are selectively targeted. They include autonomic neuropathies associated with diabetes, amyloid and immune-mediated autonomic neuropathies. Predominant symptoms of autonomic neuropathy are orthostatic hypotension, gastro-intestinal problems, urogenital dysfunction, and cardiac arrhythmia, all of which can severely impair the quality of life in affected patients. Peripheral autoimmune autonomic disorders include autoimmune autonomic ganglionopathy (AAG) and acute autonomic and sensory neuropathy. An antibody targeting the ganglionic nicotinic acetylcholine receptor (gAChR) is detected in approximately 50% of AAG patients. Treatment aims to control the specific cause of the autonomic neuropathy and the symptoms of autonomic dysfunction.

Heart failure is a disruption of the circulatory homeostasis regulated by brain interaction with multiple organs. The brain understands the circulatory homeostasis from neural and hormonal inputs, and determines efferent sympathetic output. In this system, the brain works as a central processing unit integrating neural information and hormonal factors. We have demonstrated the mechanisms of the brain in heart failure. Angiotensin II receptor type 1 (AT1R)-induced oxidative stress and inflammation in the vasomotor center cause heart failure via sympathoexcitation. Targeted deletion of AT1R in astrocytes, which are more abundant than neurons and are connected with neurons and the vascular system, remarkably improved survival with prevention of left ventricular (LV) remodeling and sympathoinhibition. In addition, the central arc of the baroreflex (from the carotid sinus pressure to the sympathetic output) fails in heart failure, and baroreflex failure induces marked volume intolerance independent of LV dysfunction worsening the renal pressure-diuresis relationship. On the basis of these results, we consider that the brain is a novel therapeutic target in heart failure via sympathoinhibition.

There are close relationships between sleep-disordered breathing (SDB) and cardiovascular disease. Mechanisms linking between SDB and cardiovascular disease include a reduction in cardiac output induced by negative inspiratory intrathoracic pressure during obstructive sleep apnea, oxidative stress, enhanced inflammatory reaction caused by repeated intermittent hypoxia, and augmented sympathetic nerve activity. Hypoxia and hypercapnia induced by apnea, reduced cardiac output, diminished stimulations of lung stretch receptor, and arousals enhance sympathetic nerve activity in SDB patients. In addition, such enhanced sympathetic nerve activity is not only observed during sleeping but also during awakening and contribute to pathogenesis of cardiovascular disease through elevated blood pressure, heart rate, and provocation of cardiac arrhythmias.

The autonomic nervous system is involved in the trigger of arrhythmias that are due to an arrhythmogenic substrate and in the maintenance of these arrhythmias. Pulmonary vein isolation (PVI) is the main therapeutic strategy for paroxysmal atrial fibrillation. The intrinsic autonomic nervous system located around the heart (which is also known as the ‘ganglionated plexi [GP]’) is suspected to be related to both the onset and maintenance of atrial fibrillation. The vagal response can be provoked by frequent stimulation of the GP, and GP ablation has been reported to be effective for suppressing paroxysmal atrial fibrillation. It is thus possible that PVI could become a therapeutic strategy for both tachyarrhythmia (i.e., atrial fibrillation) and bradyarrhythmia (i.e., sick sinus syndrome). According to studies of catheter ablation for paroxysmal atrial fibrillation that is associated with sick sinus syndrome, in some patients the presence of sinus node dysfunction is accompanied by a higher recurrence of atrial fibrillation and will require the implantation of a pacemaker for sinus node dysfunction. It was also suggested that the GP may be involved in the development of atrial fibrillation. However, our knowledge about selective autonomic modification and therapeutic endpoints is limited. As a therapeutic strategy for both tachyarrhythmia and bradyarrhythmia, neuromodulation therapy has shown promise but remains controversial. Further investigations of the long-term effects of neuromodulation therapy for arrhythmias are necessary.

The present study was designed to clarify the characteristics of hepatic and pulmonary MALT lymphoma and substance P by investigating the participation of the autonomic nervous system and neuropeptides in hepatic and pulmonary tumors. We detected hepatic and pulmonary MALT lymphomas after long term Helicobacter infection. In situ hybridization study revealed the positive reaction of Helicobacter heilmannii in the hepatic and pulmonary MALT lymphomas. Substance P immunoreactivity was clearly shown in the lymphoma cells in the liver and lung, and intraperitoneal administration of spantide II, a substance P analogue, induced a marked decrease in the size of the tumors.

Orexins are neuropeptides that are localized in neurons within the lateral hypothalamic area and regulate feeding behavior. Accumulating evidence have shown that orexins acts centrally to regulate a wide variety of body functions including gastrointestinal functions. The aim of this review is to summarize relevant findings on brain orexins and a digestive system, and discuss the pathophysiological roles of the peptides with special reference to functional gastrointestinal disorders. Exogenously administered orexin or endogenously released orexin in the brain potently stimulates gastric acid secretion, and gastric and colonic motility in conscious rats. In addition, central orexin induces an antinociceptive action against colonic distension. Pretreatment with either dopamine, adenosine A1 or cannabinoid antagonist potently blocked the centrally injected orexin-A-induced antinociceptive action. These results suggest that dopaminergic, adenosinergic or cannabinoid signaling may be involved in the central orexin-induced antinociceptive action against colonic distension. From these evidence, we would like to make a hypothesis that decreased orexin signaling in the brain may play a role in the pathophysiology in a part of patients with functional gastrointestinal disorders such as irritable bowel syndrome (IBS) who are frequently accompanied with the inhibition of gut function such as GI motility and visceral hypersensitivity.

Corticotropin releasing factor (CRF) is released not only in the anterior pituitary but also in the amygdala, the locus ceruleus and the lateral nucleus of the medulla oblongata, and has various physiological actions such as the endocrine system of stress response and autonomic nerve regulation. We found that restraint-induced elevation of corticosterone levels in the blood were elongated in low birth weight rats from dams fed a low sugar and calorie restricted diet during pregnancy, and that blood Methionine has decreased in low birth weight rats compared to control rats. Feeding the methyl modulator diet to lactating dams normalized the restraint-induced elevation of blood corticosterone concentration. Therefore, in this mini-review, the effect of early intervention by methyl modulator will be outlined.

This mini-review article introduces our recent studies of the interactions between estradiol and the autonomic nervous system. Ovarian estradiol secretion is hormonally controlled in a cyclic manner by a hierarchical feedback mechanism consisting of the hypothalamic-pituitary-ovarian axis after puberty. In addition to this hormonal regulation of the ovary, ovarian autonomic innervation, particularly that of the sympathetic nerve, regulates ovarian hormonal secretion. We examined the effects of long-term estradiol treatment on the sympathetic regulation of ovarian estradiol secretion. The ovarian estradiol secretion rate was not significantly changed by sympathetic nerve stimulation in saline-treated rats; however, it was markedly decreased by sympathetic nerve stimulation in estradiol-treated rats. This suggests that chronic estradiol treatment augments sympathetic inhibition of ovarian estradiol secretion, perhaps by inhibiting the hypothalamic-pituitary-ovarian axis.

It is well known that stress not only activates the hypothalamic-pituitary-adrenal axis, but also sympatho-adrenomedullary outflow. Activation of these systems leads to secretion of cortisol (corticosterone) or release/secretion of catecholamines. However, the precise mechanisms underlying these phenomena are still unresolved. We previously investigated the mechanisms of central activation of sympatho-adrenomedullary outflow with regard to prostanoid (prostaglandin E₂ and thromboxane A₂) and adrenoceptor (α-and β-adrenoceptors) in the brain using anesthetized rats. In this paper, we outline the regulatory mechanisms of plasma catecholamine levels in the paraventricular nucleus of the hypothalamus, the major center for regulation of sympathetic function and stress responses, based on our previous reports.

In Japan’s guidelines for chronic headache 2013, acupuncture for effective treatment and prevention of primary headache is considered effective. In the Cochrane Review, acupuncture for migraine headaches showed no difference compared to placebo acupuncture. However, when limited to episodic migraine, the difference in effect between placebo acupuncture and true acupuncture has been recognized. In Japan, it has been reported that acupuncture treatment for episodic migraine is more effective than chronic migraine. It has also been shown that brain imaging can be used with acupuncture to treat the pain-related areas of the brain for preventive effects and seizure phases in migraine headache patients.

Energy homeostasis is balanced by regulating energy intake (food intake) and energy expenditure. Mammals including humans consume a large amount of energy to maintain body temperature. In starved conditions, neuropeptide Y (NPY) is secreted in the hypothalamus, resulting in lowered energy expenditure and increased appetite. However the central neural mechanism by which NPY lowers metabolism and stimulates appetite was unknown. We revealed that NPY action in the hypothalamus leads to activation of GABAergic neurons in the intermediate and parvicellular reticular nuclei (IRt/PCRt) in the medulla oblongata, which then inhibit brown adipose tissue thermogenesis and promote food intake. The NPY-elicited reduction of energy expenditure and promotion of food intake are representative hunger responses for animals to effectively survive starvation.

Transthyretin-type familial amyloid polyneuropathy (ATTR-FAP) is an autosomal dominant disorder caused by mutations in TTR, characterized by systemic accumulation of amyloid fibrils in various organs. ATTR-FAP patients usually show small fiber neuropathy (SFN). Novel disease-modifying therapies are most effective when started early in the disease process. Therefore, early diagnosis is becoming more important. Moreover, accurate and reliable methods for monitoring efficacy of these new treatments are also needed. In our study, we found early skin denervation in ATTR-FAP, even in the presymptomatic stage of the disease. Skin denervation may be a useful marker for early diagnosis and may aid quantitative evaluation for evaluating SFN in ATTR-FAP.

The purpose of our study was to simultaneously measure and compare accommodation and pupillary constriction during the near response among hyperopia, emmetropia, and myopia (refractive errors). We examined 60 normal eyes of 30 subjects (10 males, 20 females) without signs of disease, aged 20–26 years (mean 21.2 years). The refractive error ranged from +5.50 diopters (D) to −8.50 D and was used to divide subjects into five groups of 12 eyes each: hyperopia, emmetropia, low myopia, moderate myopia, and high myopia groups. The gain of accommodation (%) and pupillary size (mm²) to step stimulus of +5 D were measured under adequate correction of refractive errors using a refraction/accommodation measurement device. The high-myopia group exhibited low gain of accommodation (76.7%) and maximum change in pupillary size (13.03 mm²). In contrast, the hyperopia group exhibited low gain of accommodation (72.5%) and minimum change in pupillary size (5.50 mm²). We observed differences in accommodation and pupillary responses in the context of different refractive errors. In high myopia, the large pupillary constriction in the near response compensated for weak accommodation, even at young ages. In hyperopia, small pupillary size daily compensates for accommodation by increasing the depth of focus; therefore, subjects could clearly view near objects despite the weak accommodation and small pupillary constriction.