Circumventricular organs dysregulation syndrome (CODS)

● 第 70 回日本自律神経学会総会 / 理事長講演 司会：髙橋 昭 Circumventricular organs dysregulation syndrome (CODS)

Yoshiyuki Kuroiwaa,b

Kew words: aquaporin, , circadian rhythm, guanine nucleotide coupling protein, transient receptor potential

Abstract: The biological origin of circumventricular organs (CVOs) evolutionally goes back to the inverte- brates and even further to plants. The CVOs are classified into sensory CVOs (subfornical organ, organum vasculosum of lamina terminalis, and area postrema) and secretory CVOs (neurohypophysis, , subcommissural organ, and ). Physiological mechanisms of life-saving arising from CVOs consist of at least the following eight axes; neuroendocrine regulation axis, circadian rhythm regulation axis, innate immune regulation axis, nociceptive response regulation axis, body fluid regulation axis, cognitive regulation axis, locomotive driving regulation axis, and inhibitory regulation axis. Summarizing the above, the CVO physiologically contributes to a wide spectrum of autonomic, endocrine, cognitive, sensory gating, and motor regulations, whose impairments potentially result in the complex symptoms being composed of sleep- related, cardiovascular, gastrointestinal, menstrual, emotional, cognitive, sensory, and motor symptoms. I pro- pose the new clinical concept, “circumventricular organs dysregulation syndrome (CODS)” that is known to be seen in human papilloma virus vaccination-associated neuro-immunopathic syndrome (HANS), von Economo’s encephalitis lethargica, craniopharyngioma, interferon encephalopathy, metronidazole induced encephalopathy, Wernicke encephalopathy, schizohrenia with water intoxication, Alzheimer’s disease with overeating, neuromy- elitis optica, stiff-person syndrome, cerebrospinal fluid hypovolemia, heat stroke, fibromyalgia, chronic fatigue syndrome / myalgic encephalomyelitis, menopausal syndrome, and frailty syndrome (sarcopenia syndrome). （The , 56: 1 ～ 5, 2019）

1. Introduction 2. Anatomical Structures of the CVOs / Complex Circumventricular organs (CVOs) are organs which regulate life-saving homeostasis of the . The CVOs are structurally and functionally designed The biological origin of CVOs evolutionally goes back as specialized organs which defend the vertebrates to the invertebrates and even further to the plants. I against environmental stress. The autonomic and neu- referred clinical disorders occurring after their dys- roendocrine centers exist in the CVOs, and contribute regulation as to circumventricular organs dysregulation to homeostatic regulation of the vertebrates. The CVOs syndrome (CODS). The first half of this paper explains are located in the and the medulla of the anatomical and physiological knowledges of CVOs, while vertebrates, and are characterized as symmetrical mid- the second half describes clinical spectrum of CODS. line organs around the third and the fourth ventricles. The CVOs around the are adjacent to the (paraventricular organ) and the hypothalamus. The retina and the choroid plexus (CP) are not usually classified into the CVOs, but embryologically belong to a Medical Office, Ministry of Finance, 3-1-1 Kasumigaseki, the CVOs. The CP is adjacent to the lateral, the third Chiyoda-ku, Tokyo 100-8940, Japan b and the fourth ventricles. The CP not only secretes Department of Neurology and Stroke Center, Mizonokuchi Hospital, Teikyo University School of Medicine, 5-1-1 Futako, cerebrospinal fluid (CSF), but also regulates circadian Takatsu-ku, Kawasaki, Kanagawa 213-8507, Japan rhythm along with (SCN) of

（1） 自律神経 56 巻 1 号 2019 年 the hypothalamus. Among the hypothalamus, only the as a neuro-glandular organ, to secrete and median eminence (ME) is usually classified into the . CVOs. However, the CVOs and the hypothalamus are The CVOs / hypothalamus complex has vital neuro- anatomically connected, and are closely related with immuno-endocrine network, and is essential for homeo- each other. The CVOs are classified into sensory and static activity of the vertebrates. Guanine nucleotide secretory organs. coupling protein (G protein) subfamilies in the CVOs / The subfornical organ (SFO), the organum vasculosum hypothalamus complex act as biological timer switches of the lamina terminalis (OVLT), and the area postrema which maintain and regulate neuro-immuno-endocrine (AP) are referred to as sensory CVOs, because they are homeostasis of the vertebrates. Summarizing the neuronal organs and are able to detect environmental above, life-saving homeostasis arises from the CVOs / stress. The SFO exists around the lateral and the third hypothalamus complex, which physiologically contributes ventricles, while the OVLT is adjacent to the ventral to a wide spectrum of autonomic, endocrine, cognitive, wall of the third ventricle. The AP in the lower medulla sensory gating, and motor regulations. The CVOs / is adjacent to the dorsal wall of the fourth ventricle. The hypothalamus complex has its regulatory mechanisms sensory CVOs have neural networks connecting with consisting of eight physiological axes, as described in the (POA) and paraventricular nucleus (PVN) next paragraph. in the hypothalamus. 3. Physiological Axes of the CVOs / Hypothalamus The neurohypophysis, the pineal gland, the subcom- Complex missural organ (SCO), and the ME have glandular structures with secretory functions, and are referred 3.1. Neuroendocrine regulation axis to as secretory CVOs. The neurohypophysis (posterior Hypothalamic-pituitary-neuroendocrine pathways ) is adjacent to the ventral wall of the consist of hypothalamic-pituitary-adrenal axis (HPA third ventricle, and secretes vasopressin and oxytocin, axis), hypothalamic-pituitary-gonadal axis (HPG axis), and while the pineal gland secretes melatonin. The SCO is hypothalamic-pituitary- thyroid axis (HPT axis). located in the dorsocaudal region of the third ventricle, The HPA axis plays an important role to protect the and at the entrance of the . The life of the vertebrates from emergency stress, and is ependymal cells of the SCO secrete high molecular mass essential to their survival4). The HPA axis is our central glycoproteins (spondin in Reissner’s fiber) and brain stress response system, which contributes to regulation . The ME is rich in mast cells, and secretes of homeostasis against environmental stress. The neuro- inflammation mediating substances. endocrine activation of the HPA axis triggers stress The window of the brain (CVOs) lacks blood brain response (Fight-or-flight response), such as elevation of barriers. The subependymal ventricular zone in CVOs blood pressure and blood sugar, and suppression of pain. and the hypothalamus are exceptional brain structures, This stress response system is characterized by hypo- where neurogenesis occurs even in adult brain. It is thalamic release of corticotropin-releasing factor (CRF). important to recognize the view point of the CVOs / hy- When CRF binds to CRF receptors on the anterior pothalamus complex from the perspective of functional pituitary gland, adrenocorticotropic hormone (ACTH) is differentiation; 1) OVLT, neurohypophysis, and saccus released. When ACTH binds to receptors on the adrenal vasculosus were differentiated as organs having blood cortex, it stimulates adrenal release of cortisol lasting for vessels in abundance, 2) SFO, OVLT, and AP were dif- several hours after encountering the stressor. ferentiated as neuro-sensory organs, 3) neurohypophysis, The HPG axis plays a critical part in the development pineal gland, SCO, and ME were differentiated as neuro- and regulation of the reproductive and immune systems. glandular organs, 4) SFO was differentiated as an organ Gonadotropin-releasing hormone (GnRH) expressing to regulate instinctive drinking behavior via angiotensin neurons in the hypothalamus secretes GnRH. Leptin II receptor, 5) POA was differentiated as a window of and insulin have stimulatory effects and ghrelin has the brain to detect harmful changes in external environ- inhibitory effects on GnRH secretion. In response to ment, such as hypoxia, toxic gas, chemical toxins, high GnRH stimulation, the anterior portion of the pituitary or low temperature, strong ultraviolet rays, and nuclear gland produces follicle-stimulating hormone (FSH) and radiation exposure, etc, and 6) PVN was differentiated luteinizing hormone (LH), which travel into the blood

（2） Circumventricular organs dysregulation syndrome (CODS) stream. The gonads produce estrogen and testosterone, rich in perivascular mast cells19). As the front line of the which significantly influence the neurovascular coupling brain, the hypothalamic mast cells regulate innate im- system. Besides cortisol and estrogen, vitamin D is mune system via pattern-recognition receptors (PRRs)10) another steroid hormone, whose activating enzymes and via HPA axis. After bactrial infection or traumatic exist in the hypothalamus, and contributes to generation injury, hypothalamic PRRs recognize pathogen-associated of stress response. molecular patterns (PAMPs) and/or damage-associated The HPT axis contributes to thyrotropic feedback con- molecular patterns (DAMPs), and activate the innate trol as a part of the neuroendocrine system responsible immune system. Then, the hypothamic PRRs interact for metabolic regulation. The sensory CVOs sense low with non-selective cation-permeable transient receptor circulating levels of thyroid hormone (triiodothyronine, potential channels (TRP channels), which are polymodal T3 and thyroxine, T4). Then, the HPT axis responds cellular sensors10). Then, the innate immune response by releasing thyrotropin-releasing hormone (TRH), after activation of PRRs is converted to an ion channel which stimulates the gland to produce expression of immunological and inflammatory responses. thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce thyroid hormone 3.4. Nociceptive response regulation axis until levels in the blood return to normal. The HPT axis Nociceptive pain is modulated by the posterior and supports thyroid homeostasis, which is vital for growth, , which is engaged in pain reduc- differentiation, reproduction, and intelligence. tion7)13). The hypothalamus also prevents the occurrence of photpophobia14)21)24) and headache24). The hypothalamus 3.2. Circadian rhythm regulation axis regulates perceptive stress responses evoked by Circadian rhythms are physical, mental, and behavioral nociceptive stimuli (pain, light, sound, smell, heat, etc), changes that follow a daily cycle. Circadian rhythms via polymodal cellular sensors and TRP channels in the can influence sleep-wake cycles, hormone release, eating sensory CVOs10). habits and digestion, and body temperature. They respond primarily to light and darkness, and contribute 3.5. Body fluid regulation axis to circadian control of the autonomic, metabolic, and The CVOs and the CP regulate circadian rhythm of endocrine homeostasis. Circadian rhythms are found in the glymphatic system (GS), via both astrocytic aqua- both animals and plants, and even in microbes. porin 4 (AQP4) water channnels and TRPV4 polymodal Circadian rhythms are produced and regulated by cir- sensor channnels. The GS is a functional waste clearance cadian clocks, which are composed of specific molecules pathway for the brain3). The GS pathway (proteins), existing in nearly every tissue and organ, and consists of a para-arterial influx route for CSF to enter interacting in cells throughout the body. The main cue the brain parenchyma, coupled to a clearance mechanism influencing circadian rhythms is daylight. The light can for the removal of interstitial fluid (ISF) and extracellular turn on or off genes which control the molecular struc- solutes from the interstitial compartments of the brain ture of circadian clocks. Changing the light-dark cycles and spinal cord. The CP not only secretes CSF, but also can speed up, slow down, or reset circadian clocks. Circa- controls via its master clock20) circadian rhythm of the dian clocks have a hierarchical organization, governed by GS. Exchanges of solutes between CSF and ISF are the master clock in the brain which coordinates all the enhanced during sleep by the expansion and contraction circadian clocks, and keeps the clocks in synchronization. of brain extracellular space. The master clock in the vertebrates is a group of about SFO and OVLT were differentiated as neuro-sensory 20,000 neurons in the SCN of the hypothalamus, which organs and have vital roles to detect sodium level in the receives direct input from the eyes. The master clock body fluid, and to regulate instinctive drinking behavior in the CP adjusts the SCN clock likely via circulation of via angiotensin II receptor. The SFO also modulates CSF, thus finely tuning behavioral circadian rhythms20). sympathetic and hemodynamic homeostasis, mediating responses to pro-inflammatory cytokines28). 3.3. Innate immune regulation axis Life-saving host defense reactions are modulated by 3.6. Cognitive regulation axis pars tuberalis and ME of the hypothalamus, which are Clearance of soluble proteins, waste products, and

（3） 自律神経 56 巻 1 号 2019 年 excess extracellular fluid is accomplished through con- hypothalamus complex therefore causes CODS, which is vective bulk flow of ISF, facilitated by astrocytic AQP4 usually characterized by the following four categories: water channnels. The AQP4 water channnels at the (1) autonomic, endocrine and inflammatory symptoms perivascular astrocytic end feet are known to maintein (insomnia, hypersomnia, orthostatic intolerance, syncope, congnitive performance30). The thalamic paraventricular menstrual irregularity, hyperthermia, hypothermia, and nucleus projects to the amygdala, and modulates diarrhea), (2) cognitive and emotional symptoms (fatigue, retrieval and maintenance of long-term emotional dyscalculia, disorientation, memory impairment, anxiety, memories22). and panic reaction), (3) environmental hypersensitiv- ity and pain symptoms (photophobia, phonophobia, 3.7. Locomotive driving regulation axis hyperosmia, hypergeusia, headache, and joint pain), and Several lines of evidence indicate that hypothalamic (4) locomotion and motor symptoms (locomotion step command signals are primarily responsible for the disorder, muscle weakness, involuntary movement, and driving of locomotion and that locomotor stepping is muscle spasm). The followings are various diseases or mediated by the perifornical and lateral hypothala- syndromes, potentially manifesting CODS. mus8)11)26). Flight-directed locomotion and escaped jumps 5. Clinical Spectrum of CODS are mediated by medial hypothalamus18). The PVN of the hypothalamus may also contribute to locomotive driving 5.1. Encephalopathy after vaccination regulation, via its neural connections to the cerebellum. HANS (human papilloma virus vaccination associated neuro-immunopathic syndrome)1)2)16)17)22)29), and narcolepsy 3.8. Inhibitory regulation axis after influenza vaccination. Autonomic, endocrine, pain, and motor functions are 5.2. Encephalitis strongly modulated by inhibitory transmitter receptors Influenza virus encephalitis, tetanus encephalitis, and in the CVOs / hypothalamus complex. About 30% of von Economo’s encephalitis lethargica6)23). the brain neurons is gamma amino butyric acid (GABA) 5.3. Brain tumor neurons. The hypothalamus is especially rich in GABA Craniopharyngioma and pituitary adenoma. and glycine receptors, and receives modulatory controls 5.4. Metabolic/ toxic encephalopathy by these inhibitory transmitter receptors. Recent scien- Interferon encephalopathy, metronidazol induced tific studies highlighted important functions of GABA encephalopathy9)15)25), and Wernicke encephalopathy. neurons. The GABA neurons contribute to regulation of 5.5. Neurodegenerative disorders hypothalamic hormones, and to detection of sodium level Water intoxication in schizophrenia, overeating in in the body fluid. The stressor causes plasticity of GABA Alzheimer’s disease, and multiple system atrophy. neurons affecting retrieval of long-term emotional memo- 5.6. Paroxysmal disorders ries. GABAnergic inputs to the hypothalamus affect Migraine and medial thalamic lesions after status parvocellular neuroendocrine cells in the PVN secreting epilepticus. CRF, and induce plasticity of neurons to chronic stressor. 5.7. Autoimmune disorders Anti-NMDA receptor encephalitis, anti-VGKC complex 4. Symptomatic Features of CODS receptor encephalitis, anti-GluR encephalitis, neuromyeli- The CVOs have vitally important sensor proteins, such tis optica27), and stiff-person syndrome (anti-GABA recep- as sodium sensor, calcium sensor, osmotic sensor (TRPV4 tor encephalitis and anti-glycine receptor encephalitis)5). channel), and AQP-4 channel, as well as other receptors 5.8. Other CODS for angiotensin II, amylin, calcitonin, natriuretic peptide, Cerebrospinal fluid hypovolemia, heat stroke, estrogen, mineral corticoid, endothelin, adiponectin, fibromyalgia, chronic fatigue syndrome / myalgic apelin, endocannabinoids, leptin, prolactin, and thyroid encephalomyelitis (CFS / ME), anorexia nervosa, chemi- hormone. cal hypersensitivity, menopausal syndrome, and frailty As described before, the CVOs / hypothalamus syndrome (or sarcopenia syndrome). complex is neurally linked with the limbic system, and integrally controls autonomic, endocrine, mental and sen- Conflict of Interest: The author declares no conflict of sory-motor regulations. The impairment of the CVOs / interest in the preparation of this article.

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