Introducing the Amphibious Mudskipper Goby as a Unique Model to Evaluate Neuro/Endocrine Regulation of Behaviors Mediated by Buccal Sensation and Corticosteroids

Some fish have acquired the ability to breathe air, but these fish can no longer flush their gills effectively when out of water. Hence, they have developed characteristic means for defense against external stressors, including thirst (osmolarity/ions) and toxicity. Amphibious fish, extant air-breathing fish emerged from water, may serve as models to examine physiological responses to these stressors. Some of these fish, including mudskipper gobies such asPeriophthalmodon schlosseri,Boleophthalmus boddartiand ourPeriophthalmus modestus, display distinct adaptational behaviors to these factors compared with fully aquatic fish. In this review, we introduce the mudskipper goby as a unique model to study the behaviors and the neuro/endocrine mechanisms of behavioral responses to the stressors. Our studies have shown that a local sensation of thirst in the buccal cavity-this being induced by dipsogenic hormones-motivates these fish to move to water through a forebrain response. The corticosteroid system, which is responsive to various stressors, also stimulates migration, possibly via the receptors in the brain. We suggest that such fish are an important model to deepen insights into the stress-related neuro/endocrine-behavioral effects

Footedness for scratching itchy eyes in rodents

The neural bases of itchy eye transmission remain unclear compared with those involved in body itch. Here, we show in rodents that the gastrin-releasing peptide receptor (GRPR) of the trigeminal sensory system is involved in the transmission of itchy eyes. Interestingly, we further demonstrate a difference in scratching behaviour between the left and right hindfeet in rodents; histamine instillation into the conjunctival sac of both eyes revealed right-foot biased laterality in the scratching movements. Unilateral histamine instillation specifically induced neural activation in the ipsilateral sensory pathway, with no significant difference between the activations following left- and right-eye instillations. Thus, the behavioural laterality is presumably due to right-foot preference in rodents. Genetically modified rats with specific depletion of Grpr-expressing neurons in the trigeminal sensory nucleus caudalis of the medulla oblongata exhibited fewer and shorter histamine-induced scratching movements than controls and eliminated the footedness. These results taken together indicate that the Grp-expressing neurons are required for the transmission of itch sensation from the eyes, but that foot preference is generated centrally. These findings could open up a new field of research on the mechanisms of the laterality in vertebrates and also offer new potential therapeutic approaches to refractory pruritic eye disorders

両生魚トビハゼにおける飲水制御機構の行動生理学的研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 井上 広滋, 東京大学教授 岡 良隆, 東京大学教授 兵頭 晋, 東京大学教授 深津 武馬, 岡山大学教授 坂本 竜哉University of Tokyo(東京大学

The Amphibious Mudskipper: A Unique Model Bridging the Gap of Central Actions of Osmoregulatory Hormones Between Terrestrial and Aquatic Vertebrates

Body fluid regulation, or osmoregulation, continues to be a major topic in comparative physiology, and teleost fishes have been the subject of intensive research. Great progress has been made in understanding the osmoregulatory mechanisms including drinking behavior in teleosts and mammals. Mudskipper gobies can bridge the gap from aquatic to terrestrial habitats by their amphibious behavior, but the studies are yet emerging. In this review, we introduce this unique teleost as a model to study osmoregulatory behaviors, particularly amphibious behaviors regulated by the central action of hormones. Regarding drinking behavior of mammals, a thirst sensation is aroused by angiotensin II (Ang II) through direct actions on the forebrain circumventricular structures, which predominantly motivates them to search for water and take it into the mouth for drinking. By contrast, aquatic teleosts can drink water that is constantly present in their mouth only by reflex swallowing, and Ang II induces swallowing by acting on the hindbrain circumventricular organ without inducing thirst. In mudskippers, however, through the loss of buccal water by swallowing, which appears to induce buccal drying on land, Ang II motivates these fishes to move to water for drinking. Thus, mudskippers revealed a unique thirst regulation by sensory detection in the buccal cavity. In addition, the neurohypophysial hormones, isotocin (IT) and vasotocin (VT), promote migration to water via IT receptors in mudskippers. VT is also dipsogenic and the neurons in the forebrain may mediate their thirst. VT regulates social behaviors as well as osmoregulation. The VT-induced migration appears to be a submissive response of subordinate mudskippers to escape from competitive and dehydrating land. Together with implications of VT in aggression, mudskippers may bridge the multiple functions of neurohypophysial hormones. Interestingly, cortisol, an important hormone for seawater adaptation and stress response in teleosts, also stimulates the migration toward water, mediated possibly via the mineralocorticoid receptor. The corticosteroid system that is responsive to external stressors can accelerate emergence of migration to alternative habitats. In this review, we suggest this unique teleost as an important model to deepen insights into the behavioral roles of these hormones in relation to osmoregulation

The gastrin-releasing peptide/bombesin system revisited by a reverse-evolutionary study considering Xenopus

Bombesin is a putative antibacterial peptide isolated from the skin of the frog, Bombina bombina. Two related (bombesin-like) peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been found in mammals. The history of GRP/bombesin discovery has caused little attention to be paid to the evolutionary relationship of GRP/bombesin and their receptors in vertebrates. We have classified the peptides and their receptors from the phylogenetic viewpoint using a newly established genetic database and bioinformatics. Here we show, by using a clawed frog (Xenopus tropicalis), that GRP is not a mammalian counterpart of bombesin and also that, whereas the GRP system is widely conserved among vertebrates, the NMB/bombesin system has diversified in certain lineages, in particular in frog species. To understand the derivation of GRP system in the ancestor of mammals, we have focused on the GRP system in Xenopus. Gene expression analyses combined with immunohistochemistry and Western blotting experiments demonstrated that GRP peptides and their receptors are distributed in the brain and stomach of Xenopus. We conclude that GRP peptides and their receptors have evolved from ancestral (GRP-like peptide) homologues to play multiple roles in both the gut and the brain as one of the 'gut-brain peptide' systems

Association of glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS): a cross-sectional study

Background While survival of systemic lupus erythematosus (SLE) patients has improved substantially, problems remain in the management of their emotional health. Medium to high-dose glucocorticoid doses are known to worsen emotional health; the effect is unclear among patients receiving relatively low-dose glucocorticoids. This study aims to investigate the association between low glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS). Methods This cross-sectional study drew on data from SLE patients in 10 Japanese institutions. The participants were adult patients with SLE duration of >= 1 year who met LLDAS criteria at the study visit from April 2018 through September 2019. The exposure was the daily glucocorticoid dose (mg oral prednisolone). The outcome was the emotional health score of the lupus patient-reported outcome scale (range: 0 to 100). Multiple linear regression analysis was performed with adjustment for confounders including disease-related damage, activity, and psychotropic drug use. Results Of 192 patients enrolled, 175 were included in the analysis. Their characteristics were as follows: female, 89.7%; median age, 47 years (interquartile range (IQR): 37.0, 61.0). Median glucocorticoid dose was 4.0 mg (IQR 2.0, 5.0), and median emotional health score 79.2 (IQR 58.3, 91.7). Multiple linear regression analysis showed daily glucocorticoid doses to be associated with worse emotional health (beta coefficient = - 2.54 [95% confidence interval - 4.48 to - 0.60], P = 0.01). Conclusions Daily glucocorticoid doses were inversely associated with emotional health among SLE patients in LLDAS. Further studies are needed to determine whether glucocorticoid tapering leads to clinically significant improvements in emotional health

Behavioural osmoregulation during land invasion in fish: Prandial drinking and wetting of the dry skin

Osmoregulatory behaviours should have evolutionarily modified for terrestrialisation of vertebrates. In mammals, sensations of buccal food and drying have immediate effects on postprandial thirst to prevent future systemic dehydration, and is thereby considered to be ‘anticipatory thirst’. However, it remains unclear whether such an anticipatory response has been acquired in the non-tetrapod lineage. Using the mudskipper goby (Periophthalmus modestus) as a semi-terrestrial ray-finned fish, we herein investigated postprandial drinking and other unique features like full-body ‘rolling’ over on the back although these behaviours had not been considered to have osmoregulatory functions. In our observations on tidal flats, mudskippers migrated into water areas within a minute after terrestrial eating, and exhibited rolling behaviour with accompanying pectoral-fin movements. In aquarium experiments, frequency of migration into a water area for drinking increased within a few minutes after eating onset, without systemic dehydration. During their low humidity exposure, frequency of the rolling behaviour and pectoral-fin movements increased by more than five times to moisten the skin before systemic dehydration. These findings suggest anticipatory responses which arise from oral/gastrointestinal and cutaneous sensation in the goby. These sensation and motivation seem to have evolved in distantly related species in order to solve osmoregulatory challenges during terrestrialisation

Behavioural osmoregulation during land invasion in fish: Prandial drinking and wetting of the dry skin

Osmoregulatory behaviours should have evolutionarily modified for terrestrialisation of vertebrates. In mammals, sensations of buccal food and drying have immediate effects on postprandial thirst to prevent future systemic dehydration, and is thereby considered to be 'anticipatory thirst'. However, it remains unclear whether such an anticipatory response has been acquired in the non-tetrapod lineage. Using the mudskipper goby (Periophthalmus modestus) as a semi-terrestrial ray-finned fish, we herein investigated postprandial drinking and other unique features like full-body 'rolling' over on the back although these behaviours had not been considered to have osmoregulatory functions. In our observations on tidal flats, mudskippers migrated into water areas within a minute after terrestrial eating, and exhibited rolling behaviour with accompanying pectoral-fin movements. In aquarium experiments, frequency of migration into a water area for drinking increased within a few minutes after eating onset, without systemic dehydration. During their low humidity exposure, frequency of the rolling behaviour and pectoral-fin movements increased by more than five times to moisten the skin before systemic dehydration. These findings suggest anticipatory responses which arise from oral/gastrointestinal and cutaneous sensation in the goby. These sensation and motivation seem to have evolved in distantly related species in order to solve osmoregulatory challenges during terrestrialisation