Orbital Evolution of a Circumbinary Planet in a Gaseous Disk

Sub-Jupiter classed circumbinary planets discovered in close-in binary systems have orbits just beyond the dynamically unstable region, which is determined by the eccentricity and mass ratio of the host binary stars. These planets are assumed to have formed beyond the snow line and migrated to the current orbits rather than forming in situ. We propose a scenario in which a planet formed beyond the snow line and migrated to the inner edge of the circumbinary disk, which was within the unstable area, and then moved to the current orbit through outward transportation. This outward transportation is driven by the balance of orbital excitation of the central stars inside the gravitationally unstable region and damping by the gas-drag force. We carried out N-body simulations with a dissipating circumbinary protoplanetary disk for binary systems with different eccentricities and mass ratios. Planets are more likely to achieve a stable orbit just beyond the unstable region in less eccentric binary systems. This result is not as sensitive to mass ratio as it is to eccentricity. These dependencies are consistent with the data from observed binary systems hosting circumbinary planets. We find CBPs' orbits close to the instability boundaries are explained by our orbital evolution scenario.Comment: 26 pages, 8 figures, accepted for publication in Earth, Planets and Spac

The regulation of sleep and wakefulness by the hypothalamic neuropeptide orexin/hypocretin

ABSTRACT Orexins, also known as hypocretins, are neuropeptides that are exclusively expressed by neurons in the lateral hypothalamic area. Although originally recognized as regulators of feeding behavior, orexins are now mainly regarded as key modulators of the sleep/wakefulness cycle. In addition, anatomical studies of neural networks and analyses of transgenic mice have revealed integrated roles for orexin neurons in the coordination of emotion, energy homeostasis, and the reward system. A functional link between the limbic system and orexin neurons may be important for increasing vigilance in response to emotional stimuli. These findings suggest that orexin neurons relay information about an organism's environment to maintain the proper amount of sleep and wakefulness in animals

Acute optogenetic silencing of orexin/hypocretin neurons induces slow wave sleep in mice

Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. To help determine how these neurons promote wakefulness, we generated transgenic mice in which orexin neurons expressed halorhodopsin (orexin/Halo mice), an orange light-activated neuronal silencer. Slice patch-clamp recordings of orexin neurons that expressed halorhodopsin demonstrated that orange light photic illumination immediately hyperpolarized membrane potential and inhibited orexin neuron discharge in proportion to illumination intensity. Acute silencing of orexin neurons in vivo during the day (the inactive period) induced synchronization of the electroencephalogram and a reduction in amplitude of the electromyogram that is characteristic of slow-wave sleep (SWS). In contrast, orexin neuron photoinhibition was ineffective during the night (active period). Acute photoinhibition of orexin neurons during the day in orexin/Halo mice also reduced discharge of neurons in an orexin terminal field, the dorsal raphe (DR) nucleus. However, serotonergic DR neurons exhibited normal discharge rates in mice lacking orexin neurons. Thus, although usually highly dependent on orexin neuronal activity, serotonergic DR neuronal activity can be regulated appropriately in the chronic absence of orexin input. Together, these results demonstrate that acute inhibition of orexin neurons results in time-of-day-dependent induction of SWS and in reduced firing rate of neurons in an efferent projection site thought to be involved in arousal state regulation. The results presented here advance our understanding of the role of orexin neurons in the regulation of sleep/wakefulness and may be relevant to the mechanisms that underlie symptom progression in narcolepsy.National Institutes of Health (U.S.) (Grant R01NS057464

Light-induced silencing of neural activity in Rosa26 knock-in and BAC transgenic mice conditionally expressing the microbial halorhodopsin eNpHR3

An engineered light-inducible chloride pump, Natronomonas pharaonis halorhodopsin 3 (eNpHR3) enables temporally and spatially precise inhibition of genetically defined cell populations in the intact nervous tissues. In this report, we show the generation of new mouse strains that express eNpHR3-EYFP fusion proteins after Cre- and/or Flp-mediated recombination to optically inhibit neuronal activity. In these mouse strains, Cre/Flp recombination induced high levels of opsin expression. We confirmed their light-induced activities by brain slice whole-cell patch clamp experiments. eNpHR3-expressing neurons were optically hyperpolarized and silenced from firing action potentials. In prolonged silencing of action potentials, eNpHR3 was superior to eNpHR2, a former version of the engineered pump. Thus, these eNpHR3 mouse strains offer reliable genetic tools for light-induced inhibiting of neuronal activity in defined sets of neurons

Mammalian Lgl Forms a Protein Complex with PAR-6 and aPKC Independently of PAR-3 to Regulate Epithelial Cell Polarity

AbstractBackground: Epithelial cells have apicobasal polarity and an asymmetric junctional complex that provides the bases for development and tissue maintenance. In both vertebrates and invertebrates, the evolutionarily conserved protein complex, PAR-6/aPKC/PAR-3, localizes to the subapical region and plays critical roles in the establishment of a junctional complex and cell polarity. In Drosophila, another set of proteins called tumor suppressors, such as Lgl, which localize separately to the basolateral membrane domain but genetically interact with the subapical proteins, also contribute to the establishment of cell polarity. However, how physically separated proteins interact remains to be clarified.Results: We show that mammalian Lgl competes for PAR-3 in forming an independent complex with PAR-6/aPKC. During cell polarization, mLgl initially colocalizes with PAR-6/aPKC at the cell-cell contact region and is phosphorylated by aPKC, followed by segregation from apical PAR-6/aPKC to the basolateral membrane after cells are polarized. Overexpression studies establish that increased amounts of the mLgl/PAR-6/aPKC complex suppress the formation of epithelial junctions; this contrasts with the previous observation that the complex containing PAR-3 promotes it.Conclusions: These results indicate that PAR-6/aPKC selectively interacts with either mLgl or PAR-3 under the control of aPKC activity to regulate epithelial cell polarity

A study on ensuring the quality and safety of pharmaceuticals and medical devices derived from processing of autologous human induced pluripotent stem(-like) cells

As a series of endeavors to establish suitable measures for the sound development of regenerative medicine using human stem cell-based products, we studied scientific principles, concepts, and basic technical elements to ensure the quality and safety of therapeutic products derived from autologous human iPS cells or iPS cell-like cells, taking into consideration scientific and technological advances, ethics, regulatory rationale, and international trends in human stem cell-derived products. This led to the development of the Japanese official Notification No. 0907-4, “Guideline on Ensuring the Quality and Safety of Pharmaceuticals and Medical Devices Derived from the Processing of Autologous Human Induced Pluripotent Stem(-Like) Cells, ” issued by Pharmaceuticals and Food Safety Bureau, Ministry of Health, Labour and Welfare of Japan, on September 7, 2012. The present paper addresses various aspects of products derived from autologous human iPS cells (or iPS cell-like cells), in addition to similar points to consider that are described previously for autologous human stem cell-based products. Major additional points include (1) possible existence of autologous human iPS cell-like cells that are different from iPS cells in terms of specific biological features; (2) the use of autologous human iPS(-like) cells as appropriate starting materials for regenerative medicine, where necessary and significant; (3) establishment of autologous human iPS(-like) cell lines and their characterization; (4) cell banking and/or possible establishment of intermediate cell lines derived from autologous human iPS(-like) cells at appropriate stage(s) of a manufacturing process, if necessary; and (5) concerns about the presence of undifferentiated cells in the final product; such cells may cause ectopic tissue formation and/or tumorigenesis. The ultimate goal of this guidance is to provide suitable medical opportunities as soon as possible to the patients with severe diseases that are difficult to treat with conventional modalities

The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion

Background: Reward processing is fundamental for animals to survive and reproduce. Many studies have shown the importance of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in this process, but the strongly correlative link between the activity of DRN 5-HT neurons and rewarding/aversive potency is under debate. Our primary objective was to reveal this link using two different strategies to transduce DRN 5-HT neurons. Methods: For transduction of 5-HT neurons in wildtype mice, adeno-associated virus (AAV) bearing the mouse tryptophan hydroxylase 2 (TPH2) gene promoter was used. For transduction in Tph2-tTA transgenic mice, AAVs bearing the tTA-dependent TetO enhancer were used. To manipulate the activity of 5-HT neurons, optogenetic actuators (CheRiff, eArchT) were expressed by AAVs. For measurement of rewarding/aversive potency, we performed a nose-poke self-stimulation test and conditioned place preference (CPP) test. Results: We found that stimulation of DRN 5-HT neurons and their projections to the ventral tegmental area (VTA) increased the number of nose-pokes in self-stimulation test and CPP scores in both targeting methods. Concomitantly, CPP scores were decreased by inhibition of DRN 5-HT neurons and their projections to VTA. Conclusion: Our findings indicate that the activity of DRN 5-HT neurons projecting to the VTA is a key modulator of balance between reward and aversion

Dissociating orexin-dependent and -independent functions of orexin neurons using novel Orexin-Flp knock-in mice

Uninterrupted arousal is important for survival during threatening situations. Activation of orexin/hypocretin neurons is implicated in sustained arousal. However, orexin neurons produce and release orexin as well as several co-transmitters including dynorphin and glutamate. To disambiguate orexin-dependent and -independent physiological functions of orexin neurons, we generated a novel Orexin-flippase (Flp) knock-in mouse line. Crossing with Flp-reporter or Cre-expressing mice showed gene expression exclusively in orexin neurons. Histological studies confirmed that orexin was knock-out in homozygous mice. Orexin neurons without orexin showed altered electrophysiological properties, as well as received decreased glutamatergic inputs. Selective chemogenetic activation revealed that both orexin and co-transmitters functioned to increase wakefulness, however, orexin was indispensable to promote sustained arousal. Surprisingly, such activation increased the total time spent in cataplexy. Taken together, orexin is essential to maintain basic membrane properties and input-output computation of orexin neurons, as well as to exert awake-sustaining aptitude of orexin neurons

Inactivation of Serotonergic Neurons in the Rostral Medullary Raphé Attenuates Stress-Induced Tachypnea and Tachycardia in Mice

Note: This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The medullary raphé nuclei are involved in controlling cardiovascular, respiratory, and thermoregulatory functions, as well as mediating stress-induced tachycardia and hyperthermia. Although the serotonergic system of the medullary raphé has been suggested as the responsible entity, specific evidence has been insufficient. In the present study, we tested this possibility by utilizing an optogenetic approach. We used genetically modified mice [tryptophan hydroxylase 2 (Tph2); archaerhodopsin-T (ArchT) mice] in which ArchT, a green light-driven neuronal silencer, was selectively expressed in serotonergic neurons under the regulation of Tph2 promoters. We first confirmed that an intruder stress selectively activated medullary, but not dorsal or median raphé serotonergic neurons. This activation was suppressed by photo-illumination via a pre-implanted optical fiber, as evidenced by the decrease of a cellular activation marker protein in the neurons. Next, we measured electro cardiogram (ECG), respiration, body temperature (BT), and locomotor activity in freely moving mice during intruder and cage-drop stress tests, with and without photo-illumination. In the intruder test, photo inactivation of the medullary serotonergic neurons significantly attenuated tachycardia (362 ± 58 vs. 564 ± 65 bpm.min, n = 19, p = 0.002) and tachypnea (94 ± 82 vs. 361 ± 138 cpm.min, n = 9, p = 0.026), but not hyperthermia (1.0 ± 0.1 vs. 1.0 ± 0.1∘C.min, n = 19, p = 0.926) or hyperlocomotion (17 ± 4 vs. 22 ± 4, arbitrary, n = 19, p = 0.089). Similar results were obtained from cage-drop stress testing. Finally, photo-illumination did not affect the basal parameters of the resting condition. We conclude that a subpopulation of serotonergic neurons in the medullary raphé specifically mediate stress-induced tachypnea and tachycardia, which have little involvement in the basal determination of respiratory frequency (Res) and heart rate (HR), specifically mediate stress-induced tachycardia and tachypnea.This work was supported by JSPS KAKENHI Grants (16H05130, 16K13112 to TK and 18K07353 to IK-Y), CREST JST (JPMJCR1656 to AY), and Research Foundation for Opto-Science and Technology (to IK-Y)

Inactivation of Serotonergic Neurons in the Rostral Medullary Raphé Attenuates Stress-Induced Tachypnea and Tachycardia in Mice

The medullary raphé nuclei are involved in controlling cardiovascular, respiratory, and thermoregulatory functions, as well as mediating stress-induced tachycardia and hyperthermia. Although the serotonergic system of the medullary raphé has been suggested as the responsible entity, specific evidence has been insufficient. In the present study, we tested this possibility by utilizing an optogenetic approach. We used genetically modified mice [tryptophan hydroxylase 2 (Tph2); archaerhodopsin-T (ArchT) mice] in which ArchT, a green light-driven neuronal silencer, was selectively expressed in serotonergic neurons under the regulation of Tph2 promoters. We first confirmed that an intruder stress selectively activated medullary, but not dorsal or median raphé serotonergic neurons. This activation was suppressed by photo-illumination via a pre-implanted optical fiber, as evidenced by the decrease of a cellular activation marker protein in the neurons. Next, we measured electro cardiogram (ECG), respiration, body temperature (BT), and locomotor activity in freely moving mice during intruder and cage-drop stress tests, with and without photo-illumination. In the intruder test, photo inactivation of the medullary serotonergic neurons significantly attenuated tachycardia (362 ± 58 vs. 564 ± 65 bpm.min, n = 19, p = 0.002) and tachypnea (94 ± 82 vs. 361 ± 138 cpm.min, n = 9, p = 0.026), but not hyperthermia (1.0 ± 0.1 vs. 1.0 ± 0.1°C.min, n = 19, p = 0.926) or hyperlocomotion (17 ± 4 vs. 22 ± 4, arbitrary, n = 19, p = 0.089). Similar results were obtained from cage-drop stress testing. Finally, photo-illumination did not affect the basal parameters of the resting condition. We conclude that a subpopulation of serotonergic neurons in the medullary raphé specifically mediate stress-induced tachypnea and tachycardia, which have little involvement in the basal determination of respiratory frequency (Res) and heart rate (HR), specifically mediate stress-induced tachycardia and tachypnea