It is no exaggeration to say that autonomic neuroscience is the science of stress. There are two types of stress: external and internal environmental stress. Cell membranes of living organisms contain bio-sensors detecting environmental stress. The security gates of the stress center (windows to the brain) are the hypothalamus and periventricular organs. Stress signaling pathways include neural, humoral, and cell signaling control systems. The CREB (cyclic AMP response element binding protein) and CRTC (CREB-regulated transcription coactivator) are the lifeline of the highest command center of stress responses. Disturbance of the hypothalamus, which physiologically protects the body from stress, causes a variety of symptoms, including sleep disorders, autonomic visceral symptoms, emotional and memory disorders, sensory sensitivity, and gait disturbance (hypothalamic syndrome or circumventricular organs dysregulation syndrome). Controlling the stress response leads to prevention of telomere damage, aging, carcinogenesis, and frailty. On the other hand, internal environmental stresses, such as chronic kidney disease, attack the coupon of life, telomeres, inducing shortened life span and carcinogenesis. Let me give you an example. There are approaches to pain and eating disorders from a variety of academic fields; immunology, metabolic endocrinology, psychosomatic medicine (behavioral therapy), neurology, psychiatry, rehabilitation medicine, and imaging neuroscience. However, I can't deny the impression that the blind people are stroking an elephant. I am convinced that autonomic neuroscience is a comprehensive science that can take these approaches from basic and clinical perspectives. We look forward to a renaissance of autonomic neuroscience in the first year of autonomic neuroscience.
Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) is a hereditary systemic amyloidosis caused by mutations in the TTR gene. It is characterized by systemic accumulation of amyloid fibrils in small fiber nerves and autonomic system. Patients with ATTR-FAP frequently experience multiple autonomic dysfunction symptoms, such as orthostatic hypotension, anhidrosis, gastrointestinal motility disorder, and sexual impotence at the early stage. The management of autonomic dysfunction affects prognosis and the quality of life of the patient. Recently, to evaluate small fiber neuropathy, Sudoscan is a useful tool as noninvasive method in addition to skin biopthy. More recently, a novel disease-modifying therapeutic drug for ATTR-FAP, stabilizers of the tetrameric TTR, has been approved and gene silencing therapies are now under clinical trials. These drugs are thought to be more effective in the early stage; hence, effective of those drugs on autonomic dysfunction is expected.
Recent clinical investigations indicated that large blood pressure variability is as powerful as hypertension in predicting cardiovascular events. Although anti-hypertensive drugs can lower blood pressure, they cannot suppress blood pressure variability because the pharmacokinetics of drugs does not have sufficient temporal resolution. To overcome such a limitation of the latest medical treatment, we have been developing intelligent neuromodulation that electrically regulates the autonomic nerve activity. The developed system was capable of suppressing blood pressure variability, just like the native baroreflex system. We believe smart neuromodulation is complementary to medical treatment in the management of refractory cardiovascular diseases.
Recent researches support the longer and adequate working lives contribute the health of aged workers amid policy concerns about the costs of social welfare. Some comprehensive researches showed activity theory that older adults who quit from full-time jobs deteriorated both mental health. In the field of occupational health, proper placement, keep the work ability and employability considering the individual neurophysical status, along with preventive action for workers in workplace. In many cases, working is an effective way of social participation for older people and keep the health status better over in Japan. Neurovegetative researches with a viewpoint of labour science and occupational health can find out the evidence which contribute the good practice for happiness and health of aged workers especially using data science methods.
The mesocortico-limbic system plays critical roles in transforming emotion into behavior and peripheral autonomic responses. In chronic pain states and chronic stress, this system falls into dysfunction and produces various psychosomatic symptoms. However, voluntary exercise can normalize its function and effectively reduce these symptoms. As a possible mechanism, we hypothesized that the amygdala plays an important role in this process. We investigated the effects of voluntary running on the basal amygdala (BA) and the central nuclei of the amygdala (CeA), using partial sciatic nerve ligation (PSL) model mice. The number of activated glutamate (Glu) neurons in the medial BA (medBA) was significantly increased in PSL-Runner mice. A combined immunohistochemical and tracer experiment demonstrated that these activated Glu neurons in the medBA project into the nucleus accumbens lateral shell. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, whereas these numbers were significantly decreased in PSL-Runner mice. Therefore, we conclude that exercise-induced normalization of the mesocortico-limbic system may be induced, at least in part, via plastic changes in the amygdala, and that pursuing an active life-style is essential for the improvement of our QOL. The mesocortico-limbic system plays critical roles in transforming emotion into behavior and peripheral autonomic responses. In chronic pain states and chronic stress, this system falls into dysfunction and produces various psychosomatic symptoms. However, voluntary exercise can normalize its function and effectively reduce these symptoms. As a possible mechanism, we hypothesized that the amygdala plays an important role in this process. We investigated the effects of voluntary running on the basal amygdala (BA) and the central nuclei of the amygdala (CeA), using partial sciatic nerve ligation (PSL) model mice. The number of activated glutamate (Glu) neurons in the medial BA (medBA) was significantly increased in PSL-Runner mice. A combined immunohistochemical and tracer experiment demonstrated that these activated Glu neurons in the medBA project into the nucleus accumbens lateral shell. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, whereas these numbers were significantly decreased in PSL-Runner mice. Therefore, we conclude that exercise-induced normalization of the mesocortico-limbic system may be induced, at least in part, via plastic changes in the amygdala, and that pursuing an active life-style is essential for the improvement of our QOL.
Numerous investigators have reported the use of microneurographic technique in patients with neurological disorders. This technique has been reported to be clinically useful for the pathophysiological analysis of many types of neurological disorders. In patients with peripheral neuropathy, such as diabetic polyneuropathy or demyelinating neuropathy, clinical usefulness was demonstrated by using the microneurographic technique to obtain large amplitudes of nerve action potentials from sensory nerves. In autonomic disorders, characteristic findings were reported in pure autonomic failure and sweating disorders, such as hyperhidrosis and anhidrosis. By using the microneurographic technique, we recorded and evaluated sympathetic neurograms in patients with many neurodegenerative disorders including motor neuron disease, Parkinson’s disease, and spinocerebellar degeneration. In particular, we discovered important findings of autonomic dysfunction by recording muscle sympathetic nerve activity in amyotrophic lateral sclerosis patients. Our findings include identifying the existence of sympathetic hyperfunction at rest with chronological changes, regardless of progressive muscle weakness and exacerbation of respiratory function. These findings were validated by comparing the results to our previously acquired data in patients with amyotrophic lateral sclerosis.
Using confocal laser scanning microscopy, we showed that intraepidermal nerve fibers in skin specimens obtained by skin biopsy were immunohistochemically stained by PGP 9.5 and ran through the epidermal intercellular space. With fixation conditions of 0.08 M phosphate buffer for transmission electron microscopy, we demonstrated the ultrastructure of the epidermis: little shrinkage of keratinocytes, interdigitations of microvilli, and four kinds of processes of keratinocytes, axons, melanocytes, and Langerhans cells in the spaces between keratinocytes. Axons had low electron density and few identifiable organelles without a basement membrane or Schwann cells, and were directly adjacent to the plasma membrane of keratinocytes. Unlike the other processes, axons did not have large intercellular spaces defined as intercellular clefts and the processes had circular or elliptical structures. Recently, skin biopsy for immunostaining with PGP 9.5 has become an indispensable diagnostic tool for small fiber neuropathy, and we discuss the significance based on our cases.
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 nerves control trafficking of lymphocytes through lymph nodes and consequently generate a diurnal rhythm in the adaptive immune response. This review focuses on the mechanism and physiological relevance of adrenergic nerve-mediated control of adaptive immune responses.
Complement-mediated nerve damage induced by antiganglioside antibodies plays a role in pathogenesis of Guillain-Barré syndrome (GBS). Dysautonomia is common in severe cases of GBS and is an important cause of death. Target antigens in autonomic nerves have not been identified. Demyelination with inflammatory cell infiltration is dominant in the vagus nerve in autonomic pathology of GBS, and is confirmed in some experimental neuropathy models sensitized to myelin protein, whereas such pathology has not been confirmed in anti-glycolipid antibody-positive rabbit GBS model. In the management of GBS presenting with dysautonomia, it is necessary to pay attention to external peripheral nervous system complications such as posterior reversible encephalopathy syndrome and Takotsubo cardiomyopathy.
The heart is controlled by the sympathetic and vagal systems. Sympathetic activation increases the heart rate (HR), whereas vagal activation decreases it. The sympathetic and vagal systems also differ in their HR control speeds; the vagal control is faster than the sympathetic control. To quantify the differences in the dynamic characteristics of HR control, we stimulated the cardiac sympathetic nerve and the vagal nerve of anesthetized rabbits using frequency-modulated pulse trains of a white-noise signal. The results show that the sympathetic and vagal systems mutually augment the dynamic gain of the transfer function from nerve stimulation to HR response. The functional aspect of the interaction can be explained by the operating point-dependent sigmoidal nonlinearity of the HR response. A simple neural network structure with only two neurons was able to identify the dynamic characteristics and sigmoidal nonlinearity of the HR response. Refining the neural network structure will contribute to better estimation of the HR response from autonomic nervous activities and enable the reverse estimation of autonomic nervous activities from the HR response in the future.
Multiple system atrophy (MSA) is a sporadic, adult-onset progressive neurodegenerative disease characterized by autonomic dysfunction, parkinsonism, and cerebellar ataxia in various combinations. Sleep-related disorders such as insomnia with sleep fragmentation, sleep-related breathing disorder (SRBD), REM sleep behavior disorder (RBD), and periodic leg movements are common in MSA. SRBD in MSA may manifest as obstructive (e.g., stridor, snoring, obstructive sleep apnea) and central (e.g., central sleep apnea, dysrhythmic breathing) patterns. In particular, stridor reflects upper airway obstruction at the level of the larynx and initially presents during sleep. In later stages, stridor occurs during wakefulness. Stridor should alert the clinician to the risk of sudden death during sleep. Video-polysomnographic recording or laryngeal fiberscopy during wakefulness or sleep are useful to confirm diagnoses of RBD and laryngeal stridor, respectively. In cases of stridor occurring only during sleep, CPAP therapy may be indicated initially. When CPAP is not tolerated or stridor also appears during wakefulness, tracheostomy needs to be considered. Accurate diagnosis or treatment planning for MSA can contribute to an improved prognosis and quality of life of patients and their caregivers.
Autonomic dysfunction in multiple system atrophy (MSA) is mainly caused by the accumulation of α-synuclein, mainly in the central nervous system, and partly in post-sympathetic ganglion fibers. Typical autonomic dysfunctions are urinary dysfunction, impaired orthostatic blood pressure regulation, and sleep-related breathing disorders, which also affect life prognosis. Urinary incontinence and orthostatic decrease of blood pressure are included in the diagnostic criteria for probable MSA, but assessment of residual urine volume and active standing and/or prolonged standing time might improve the sensitivity and specificity of the diagnosis. Since it is difficult to predict sudden death in MSA during sleep, periodical evaluation of respiratory function during natural and drug-induced sleep is warranted.
The renin-angiotensin system (RAS) independently exists in the brain apart from the circulating RAS, and an increase in brain RAS activity causes sympathetic hyperactivity. Renin, the rate-limiting enzyme of RAS, has two distinct isoforms: intracellular renin is the dominant isoform in the brain and transcribed from an alternative promoter-first exon, whereas secreted renin is the classical isoform expressed in the kidney. We generated the intracellular renin knockout mice to investigate the role of brain-specific intracellular renin in cardiovascular and metabolic control. Surprisingly, intracellular renin-deficient mice exhibited hypertension and increased sympathetic nerve activity. Further, intracellular renin-deficient mice gained significantly less weight than control mice when fed high-fat diet. Intracellular renin-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus and an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. Interestingly, despite an ablation of intracellular renin, expression of secreted renin was increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of brain RAS activity by a coordinated regulation of the renin isoforms, with intracellular renin tonically inhibiting expression of secreted renin under baseline conditions. Impairment of this control mechanism may cause hypertension and resistant to obesity through sympathoexcitation.
The vestibular system is a known gravity sensory system. This peripheral sensor, located in the inner ear, consists of two components, namely the semicircular canals and otolith organs, which detect angular and linear accelerations, respectively. Both eye movement (i.e., the vestibulo-ocular reflex) and posture (i.e., the vestibulo-spinal reflex) are contributed by the vestibular system, and these are important for the understanding of the body’s dynamics and kinematics. Interestingly, the stimulation of the peripheral vestibular organs such as gravitational change is also known to induce the sympathetic nervous response, which regulates arterial pressure (vestibulo-cardiovascular reflex). Furthermore, the responsiveness of this reflex is attenuated by the chronic gravitational change; this is due to the plasticity of the vestibular system. This review demonstrates the contribution of the vestibulo-cardiovascular reflex to the orthostatic tolerance. Furthermore, electrical stimulation of the peripheral vestibular organs has a possibility to maintain the vestibular function in elderly people and astronauts, which might prevent the orthostatic hypotension.
Exercise or locomotion is required for survival in mammals, and autonomic cardiovascular adjustments to exercise are necessitated for homeostasis. Brain mechanisms underlying the acute autonomic changes are not fully understood. Central command is defined as a signal that arises in a central area of the brain and causes a parallel activation of skeletal muscle contraction and of autonomic nervous system changes. Our research effort has recently been devoted to exploring central circuitries to generate central command function. This article discusses recent findings and future research direction.
Pancreatic insulin and intestinal glucagon-like peptide-1 (GLP-1) are representative hormones to induce the postprandial actions such as improving postprandial hyperglycemia and inducing satiety. These hormones act on various organs via the classic "humoral pathway" through blood circulation. In addition, we have demonstrated that these hormones, at high concentrations in the vicinity of the secretory tissues, activate the vagal afferents, and thereby control feeding and glucose metabolism. In this review, we describe the direct cooperative action of insulin and GLP-1 on isolated vagal afferent nodose ganglion neurons. We identified rare-sugar D-allulose as a new GLP-1 releaser, and here review the action of D-allulose to regulate feeding and glucose metabolism via GLP-1 release and vagal afferent nerves.
When an animal is exposed to stress, it provokes an autonomic response, such as increased heart rate, respiration, blood pressure, or analgesia, called a stress defense response. Previous studies have shown that these responses are attenuated in orexin knockout mice, suggesting that orexin neurons are an essential factor in stress-induced autonomic responses. However, how orexin is involved in the stress-induced autonomic nervous response, especially whether the orexin nerve is active during stress loading, is still unclear. Therefore, in order to investigate the relationship between orexin neuronal activity and the stress-induced autonomic response, we established a fiber photometry system, which can be used as a neuronal activity recording method for unrestrained/free-moving mice. In this method, a highly sensitive calcium probe (GCaMP6) is expressed only in specific cell types of genetically modified animals and adeno-associated virus (AAV), and a single fiber is placed in the deep brain of consciously free-moving animals. This method is particularly useful for elucidating the neural circuits in the brain that control phenomena such as stress-induced autonomic responses, and physical responses that are observed only when the nervous system of the whole body including peripheral nerves is active. In this study, we generated mice that specifically expressed G-CaMP6 in orexin neurons, and attempted to simultaneously record heart rate variability and orexin neural activity in real-time. In this paper, we introduce the 2ch fiber photometry system we have created and consider the relationship between orexin neuronal activity and autonomic responses using the results obtained by this system.
Ultrasonic vocalizations (USVs) have been used in experimental models of mice and rats, especially in maternal and male-female courtship contexts. In 2005, it was reported that mouse courtship vocalizations have a song-like structure similar to that of birds. Since then, mouse courtship vocalizations have been used as indicators of communication and in various models such as autism-related genetically engineered mice to study sociability, affinity, and language function. In this paper, we provide an overview of these rodent USVs and discuss their association with the autonomic nervous system. Vocalization is closely related to the nervous system that controls the respiratory system. Therefore, vocal communication research may have useful implications for future studies of autonomic nerves and the diseases they are associated with.
The vagus nerve is a part of the autonomic nervous system, serving as a central pathway to communicate between the central and peripheral organs. Recently, optogenetic tools have been widely used to monitor and manipulate specific classes of cell populations. These tools are now applicable to the study of the vagus nerve, which can selectively examine the physiological significance of individual vagus nerve subclasses such as afferent/efferent vagal neurons and specific organ-innervating vagal neurons. Here, I summarize recent optogenetic approaches and electrophysiological recording methods to study vagus nerve physiology in the cardiac system, respiratory system, and gastrointestinal system. Further studies with these optogenetic tools will facilitate our understanding of the fundamental characteristics of vagus nerve signals.
Psychological stress causes a variety of physiological responses in mammals, such as sympathetic thermogenesis, hyperthermia, tachycardia and avoidance behavior from stressors. These responses are all for coping with stressors. In the brain, psychological stress and emotions are processed in the corticolimbic system, while the hypothalamus and brainstem are responsible for maintaining homeostasis. However, the psychosomatic neural pathway that connects the corticolimbic system and the hypothalamus has not been determined. We have previously reported that psychological stress induces thermogenesis in brown adipose tissue, hyperthermia and tachycardia by activating a monosynaptic neural pathway from the dorsomedial hypothalamus (DMH) to the rostral medullary raphe region. Recently, we further discovered that the DMH receives glutamatergic excitatory stress inputs from the dorsal peduncular cortex and dorsal tenia tecta, unexplored areas located at the ventral limit of the medial prefrontal cortex. This cortico-hypothalamic psychosomatic pathway mediates master signaling that drives a variety of sympathetic and behavioral responses to psychological stress.
The gastrointestinal tract is connected with the central nervous system by autonomic nerves, which transmit information from digested substances at the luminal side. Afferent fibers constitute between 80% and 90% of the vagus nerve and play an important role in conveying sensory information evoked by the gastrointestinal luminal substances to the central nervous system. The luminal substances consist of digested food, bacterial metabolites, and endogenous digestive juice, which can modulate the function of the afferent vagal nerve with the epithelial cells acting as intermediaries. In this process, epithelial cells receive luminal substances and promptly release a series of peptide hormones, so-called food-related hormones, which act directly on the receptors of the afferent vagal nerve, thereby controlling signals to the central nervous system. Recently, the gastrointestinal nutrient sensing exerted by food-related hormones and the afferent vagal nerve have been recognized as regulators of hypothalamic autonomic functions. In this session, current knowledge about gastrointestinal nutrient sensing and the function of the afferent vagal nerve is summarized from the clinical perspective, and their clinical relevance to the symptoms of autonomic disorders including Parkinson’s disease is discussed.
GABAB receptors (GABABR) are dimerized receptors composed of GABAB1 and GABAB2 subunits. There are many functional proteins that bind to GABABR, and they are among the candidate targets in developments for drug discovery. Baclofen, a central muscle relaxant, acts on GABABR in the spinal cord and reduces spasticity. However, the blood-brain barrier is largely impermeable to baclofen, so intrathecal baclofen therapy (ITB) has been developed to increase the baclofen concentration in the spinal cord. Baclofen resistance, the state in which baclofen does not act very well, may develop during ITB therapy, and it is thought to be due to desensitization of GABABR. It is thus important to support patients who develop baclofen resistance, and research on the prevention of baclofen resistance, through elucidation of its mechanisms, is an important issue
Intrathecal baclofen (ITB) therapy is effective for the treatment of patients with subacute or chronic severe spasticity due to, for example, stroke, cerebral palsy, and severe traumatic brain- and spinal cord injury. The anti-spasticity effect of baclofen has been attributed to its binding to GABAB receptors at the dorsal column of the spinal cord. GABAB receptors are members of the G protein-coupled receptor family; tolerance must be considered during ITB therapy. One of the activation mechanisms is their desensitization in the presence of G protein-coupled receptor kinase (GRK) subtypes (GRK4 and GRK5); their degradation in cells (their downregulation) with prolonged administration of baclofen is another. Therefore, the prolonged administration of ITB and/or overstimulation of receptors should be avoided. The prescribed dose should be as low as possible if spasticity does not become worse. Interestingly, ITB therapy is effective not only in patients with spasticity, but also in patients with paroxysmal sympathetic hyperactivity due to severe traumatic brain injuries. We reviewed the effectiveness and problems with ITB therapy in 57 patients (59 pumps implanted).
Neuropathic pain (NP) is an intractable pain caused by a lesion or disease of the somatosensory nervous system. Some causes of NP are well-known, but in many cases it is difficult to identify the cause of NP. Therefore, it is challenging to treat it appropriately. Recently, autoantibody-mediated pain disorders have been recognized as novel NP causes in the field of autoimmune neurology. We recently discovered Plexin D1-IgG that binds to pain-conducting small dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons in patients with NP. Plexin D1-IgG bound to isolectin B4-positive unmyelinated C-fiber type small DRG and TG neurons and vasoactive intestinal peptide-positive postganglionic parasympathetic nerve fibers in the skin. NP patients with Plexin D1-IgG developed burning pain, tingling, and peripheral vascular dysfunction symptoms in their face, limb, and/or trunk. The coexisting disorders in patients with Plexin D1-IgG were allergic diseases, collagen diseases, and malignant neoplasms. Immunotherapies, including plasma exchange and intravenous methylprednisolone pulse therapy, are effective for NP in patients with Plexin D1-IgG, indicating Plexin D1-IgG might be pathogenic in NeP. In this review, we describe the concept of autoantibody-mediated NP and the clinical features of Plexin D1-IgG-mediated NP.
Although inter-individual variation is seen in the pressor response of the cold pressor test (CPT), it is not clear whether or not the differences are related to autonomic nerve activity. The present study employed heart rate variability and pupil diameter as indicators of autonomic nerve activity to investigate this. Sixteen normotensive healthy young subjects (22 ± 1 years) were divided into two groups, responders (≥ 10 mmHg) and hyporesponders (＜10 mmHg), according to their degree of diastolic blood pressure changes during CPT. Data were analyzed using two-way ANOVA for repeated measures followed by a multiple range post hoc test. Responders showed higher resting values of LF/HF, LF normalized unit (LFnu) and coefficient of variation of R-R intervals, and lower resting values of HF normalized unit (HFnu). Furthermore, responders showed significant decreases in LF/HF and LFnu, and increases in HFnu during CPT. Hyporesponders showed no significant changes in any parameter of HRV during CPT. There were no differences in the pupil response to CPT between responders and hyporesponders. Our data suggest that differences in the pressor responses to CPT between responders and hyporesponders are partly due to differences in their basal levels and the responsiveness of the cardiac autonomic nerve activities.