Article
Neurosciences
Lukasz Chrobok, Anna Alwani, Kamil Pradel, Jasmin Daniela Klich, Marian Henryk Lewandowski
Summary: This study investigates the role of the olivary pretectal nucleus (OPN) in regulating circadian rhythms, showing that its neurons increase firing rate during the behaviorally quiescent light phase, and exhibit different responses to orexin A and PAC1 receptor activation. These findings suggest a daily modulation of OPN activity via intrinsic and extrinsic mechanisms, providing insights into the temporal physiology of this brain structure.
Article
Pharmacology & Pharmacy
Masatomo Ishioh, Tsukasa Nozu, Saori Miyagishi, Sho Igarashi, Takuya Funayama, Masumi Ohhira, Toshikatsu Okumura
Summary: Intestinal barrier dysfunction, known as leaky gut, is associated with various diseases such as dementia and irritable bowel syndrome (IBS). This study revealed that basal forebrain cholinergic neurons (BFCNs) improve leaky gut through adenosine A2B signaling and the vagal pathway. Additionally, BFCNs mediate the improvement of intestinal barrier function induced by orexin or butyrate.
BIOCHEMICAL PHARMACOLOGY
(2022)
Editorial Material
Neurosciences
Jacqueline B. Mehr, Michelle M. Bilotti, Morgan H. James
Summary: This article discusses how the hypothalamic orexin system is now linked with motivated behavior and becomes overactive in addicted states, offering potential therapeutic opportunities for substance use disorders based on normalizing orexin function.
TRENDS IN NEUROSCIENCES
(2021)
Article
Neurosciences
Azar Omrani, Veronne A. J. de Vrind, Bart Lodder, Iris Stoltenborg, Karlijn Kooij, Inge G. Wolterink-Donselaar, Mieneke C. M. Luijendijk-Berg, Keith M. Garner, Lisanne J. van't Sant, Annemieke Rozeboom, Suzanne L. Dickson, Frank J. Meye, Roger A. H. Adan
Summary: The study identified that leptin targets multiple inputs to the dopamine system to reduce food reward seeking. Leptin enhances the activity of GABA neurons in the VTA, inhibiting dopamine neurons projecting to the nucleus accumbens. Additionally, lateral hypothalamic LepR-expressing neurons indirectly modulate dopamine neurons and increase motivation for food reward only in mice in positive energy balance.
BIOLOGICAL PSYCHIATRY
(2021)
Article
Multidisciplinary Sciences
Rebecca Evans, Haruhide Kimura, Robert Alexander, Ceri H. Davies, Helene Faessel, Deborah S. Hartman, Takashi Ishikawa, Emiliangelo Ratti, Kohei Shimizu, Motohisa Suzuki, Shinichiro Tanaka, Hiroshi Yukitake, Yves Dauvilliers, Emmanuel Mignot
Summary: Narcolepsy is a sleep disorder that can be classified into type 1 and type 2. The drug danavorexton shows promising results in treating narcolepsy by targeting both orexin 1 and orexin 2 receptors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Eun-Jin Kim, Oh-Sang Kwon, Chang-Gi Hur, Marie Merci Nyiramana, Dong-Kun Lee, Seong-Geun Hong, Jaehee Han, Dawon Kang
Summary: This study identified the effect of GABAR agonists on K-2P channel expression and activity in neuroblastic B35 cells. Muscimol, a GABA(A)R agonist, was found to significantly increase TREK-2 expression and activity, potentially reducing cellular excitability in GABAergic neurons through activating the TREK-2 channel.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Shi-Bin Li, Valentina Martinez Damonte, Chong Chen, Gordon X. Wang, Justus M. Kebschull, Hiroshi Yamaguchi, Wen-Jie Bian, Carolin Purmann, Reenal Pattni, Alexander Eckehart Urban, Philippe Mourrain, Julie A. Kauer, Gregory Scherrer, Luis de Lecea
Summary: Sleep quality declines with age and this study identified hyperexcitable hypocretin/orexin (Hcrt/OX) neurons as drivers of sleep fragmentation during aging. Activation of Hcrt neurons increased wakefulness and aged Hcrt neurons showed hyperexcitability and impaired M-current. Disruption of Kcnq2/3 genes in young mice led to sleep destabilization resembling aging-associated sleep fragmentation.
Article
Chemistry, Medicinal
Keita Iio, Tsuyoshi Saitoh, Ryuichiro Ohshita, Tsubasa Hino, Mao Amezawa, Yoshiaki Takayama, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
Summary: A novel series of 1-amino-tetralin derivatives were designed and synthesized, and the introduction of a N-methyl-(3-methoxyphenyl)acetamide unit significantly enhanced the agonist potency. The results showed that the stereochemistry played a significant role in the selectivity and agonist activity of the orexin receptors. These findings provide important information for the development of OX1R selective agonists.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Tsubasa Hino, Tsuyoshi Saitoh, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
Summary: A series of novel naphthalene derivatives were synthesized and evaluated as agonists for orexin receptors. Conformational analysis and docking simulation provided insights into the active conformation and pharmacophore orientation of the compounds, leading to the discovery of a potent candidate for narcolepsy treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Clinical Neurology
Tobias Di Marco, Thomas E. Scammell, Michael Meinel, Dalma Seboek Kinter, Alexandre N. Datta, Gary Zammit, Yves Dauvilliers
Summary: The study aimed to explore the effect of daridorexant, a dual orexin receptor antagonist, on nighttime wake bouts and their correlation with daytime functioning. Results showed that daridorexant reduced the number and duration of long wake bouts during the night compared with placebo, corresponding with improved daytime functioning.
Review
Clinical Neurology
Maria P. Mogavero, Alessandro Silvani, Giuseppe Lanza, Lourdes M. DelRosso, Luigi Ferini-Strambi, Raffaele Ferri
Summary: After describing orexins and their roles in sleep and medical disorders, the article discusses the clinical evidence on the effects of DORAs and SORAs on insomnia to provide recommendations for further assessment in personalized and precision medicine. Trials with orexin receptor antagonists have shown potential as a valid therapeutic option for insomnia in various medical conditions, but more studies are needed to determine the most suitable options for different patient populations.
NATURE AND SCIENCE OF SLEEP
(2023)
Article
Pharmacology & Pharmacy
Anthony Markham
Summary: Daridorexant, an orally administered dual orexin receptor antagonist, has been approved in the USA for the treatment of insomnia based on the results of pivotal phase III trials.
Review
Neurosciences
Natasha C. Dale, Daniel Hoyer, Laura H. Jacobson, Kevin D. G. Pfleger, Elizabeth K. M. Johnstone
Summary: The orexin system consists of two G protein-coupled receptors, OX1 and OX2 receptors, along with two endogenous agonists. Orexin receptor coupling is diverse and can vary depending on tissue, cell, and context. Ligands, receptor-protein interactions, and cellular environment play important roles in the G protein coupling profiles of the orexin receptors. This has implications for understanding the function of the orexin system and developing drugs targeting it.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Behavioral Sciences
Takashi Ishikawa, Hiroe Hara, Ayumi Kawano, Haruhide Kimura
Summary: Narcolepsy type 1 (NT1) is a neurological disorder characterized by excessive daytime sleepiness and other symptoms. The novel drug danavorexton is being evaluated for its potential in treating NT1. Preclinical studies have shown that danavorexton promotes wakefulness, reduces fragmentation of wakefulness, and suppresses weight gain in a mouse model of NT1. These findings provide valuable insights into the pathophysiology of NT1 and the potential therapeutic effects of OX2R agonists.
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
(2022)
Article
Endocrinology & Metabolism
Bin Li, Leilei Chang, Xiaochun Peng
Summary: Orexin, mainly synthesized in the lateral hypothalamus/perifornical area, is implicated in feeding, sleep-wake cycles, and reward. Activation of OX2R in the NAc shell has been found to play a role in regulating acute stress-induced anxiety, suggesting OX2R antagonist as a potential treatment for anxiety disorders.
PSYCHONEUROENDOCRINOLOGY
(2021)
Article
Neurosciences
Yuka Kasahara, Daiki Masukawa, Yoshie Nakamura, Koshi Murata, Tatsuo Hashimoto, Kohtaro Takizawa, Motokazu Koga, Fumio Nakamura, Yugo Fukazawa, Kengo Funakoshi, Yoshio Goshima
Summary: The study suggests that DOPA-GPR143 signaling may be involved in the nicotine action in the nigrostriatal and mesolimbic dopaminergic systems.
NEUROSCIENCE RESEARCH
(2021)
Article
Endocrinology & Metabolism
Chie Umatani, Nagisa Yoshida, Eri Yamamoto, Yasuhisa Akazome, Yasutaka Mori, Shinji Kanda, Kataaki Okubo, Yoshitaka Oka
Summary: Animals use multiple sensory cues to perform sexual behaviors, but the neural mechanisms behind integrating these cues and regulating motivation for sexual behaviors are not well understood. This study focuses on TN-GnRH neurons, which co-express NPFF and GnRH3, and demonstrates their role in modulating certain neuronal circuits for controlling behavioral motivation. Specifically, NPFF activates neurons in the preoptic area, leading to an increase in motivation for male sexual behaviors. These findings contribute to our understanding of the functional significance of peptidergic neuromodulation in response to sensory information from the external environments.
Article
Endocrinology & Metabolism
Kana Ikegami, Sho Kajihara, Chie Umatani, Mikoto Nakajo, Shinji Kanda, Yoshitaka Oka
Summary: Using a non-mammalian model of medaka, it was found that 17 beta-estradiol could promote the upregulation of GnRH1 neuronal activity, triggering the GnRH surge, and the combined action of estrogen and time signals is crucial for triggering ovulation at the appropriate time.
JOURNAL OF NEUROENDOCRINOLOGY
(2022)
Review
Endocrinology & Metabolism
Satoshi Ogawa, Naoyuki Yamamoto, Hanako Hagio, Yoshitaka Oka, Ishwar S. Parhar
Summary: Three paralogous genes for GnRH and GnRH receptors exist in non-mammalian vertebrates. The migration of GnRH neurons in the brain is evolutionally conserved across different species. Each GnRH system has distinctive anatomical and physiological characteristics, and functions differently based on their origin and expression patterns.
JOURNAL OF NEUROENDOCRINOLOGY
(2022)
Article
Neurosciences
Yoshiteru Shimoda, Kaoru Beppu, Yoko Ikoma, Yosuke M. Morizawa, Satoshi Zuguchi, Utaro Hino, Ryutaro Yano, Yuki Sugiura, Satoru Moritoh, Yugo Fukazawa, Makoto Suematsu, Hajime Mushiake, Nobukazu Nakasato, Masaki Iwasaki, Kenji F. Tanaka, Teiji Tominaga, Ko Matsui
Summary: This study found that optogenetic neuronal stimulation can induce hyperexcitability in the rat brain, but continued stimulation can lead to a state resistant to seizures induction. Moderate astrocyte activation was associated with the acquisition of resilience in the brain.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Immunology
Yosuke Danjo, Eiji Shigetomi, Yukiho J. Hirayama, Kenji Kobayashi, Tatsuya Ishikawa, Yugo Fukazawa, Keisuke Shibata, Kenta Takanashi, Bijay Parajuli, Youichi Shinozaki, Sun Kwang Kim, Junichi Nabekura, Schuichi Koizumi
Summary: The activation of astrocytes plays a crucial role in brain plasticity and the development of neurological disorders. The presence of mGluR5 in astrocytes, which is absent under normal conditions, is essential for regulating synaptic plasticity and neuronal activity, particularly in the somatosensory cortex.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Multidisciplinary Sciences
Sachiko Fujiwara, Thanh Phuong Nguyen, Kyoko Furuse, Yugo Fukazawa, Tetsuhisa Otani, Mikio Furuse
Summary: The interaction of claudins with ZO proteins is not a prerequisite for tight junction formation at the most apical part of cell-cell contacts.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Article
Neurosciences
Ayako Maegawa, Koshi Murata, Kazuki Kuroda, Shigeharu Fujieda, Yugo Fukazawa
Summary: This study investigated whether the D1- and D2-expressing neurons in the olfactory tubercle (OT) express opioid peptide precursors. The results showed that Pdyn was mainly expressed by D1-expressing cells, while Penk was mainly expressed by D2-expressing cells in the dense cell layer (DCL) of the OT. Additionally, a larger population of Pdyn-Penk-Drd1 co-expressing cells was found in the anteromedial OT compared to the anterolateral OT.
FRONTIERS IN NEURAL CIRCUITS
(2022)
Article
Multidisciplinary Sciences
Aki Takahashi, Romain Durand-de Cuttoli, Meghan E. Flanigan, Emi Hasegawa, Tomomi Tsunematsu, Hossein Aleyasin, Yoan Cherasse, Ken Miya, Takuya Okada, Kazuko Keino-Masu, Koshiro Mitsui, Long Li, Vishwendra Patel, Robert D. Blitzer, Michael Lazarus, Kenji F. Tanaka, Akihiro Yamanaka, Takeshi Sakurai, Sonoko Ogawa, Scott J. Russo
Summary: The glutamatergic projections from the lateral habenula (LHb) to the dorsal raphe nucleus (DRN) modulate male mice's aggressive behavior. Inhibition of LHb-DRN projection blocks the increase in aggression after social instigation. The activity of this pathway is not necessary for the expression of species-typical aggressive behavior but essential for the increase in aggression resulting from social instigation.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Akira C. Saito, Chisato Endo, Yugo Fukazawa, Tomohito Higashi, Hideki Chiba
Summary: MarvelD3 does not affect the morphology of TJ strands and barrier function in MDCK II cells. The carboxy-terminal cytoplasmic tail of tricellulin is dispensable for barrier improvement.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Article
Clinical Neurology
Rocio Alfaro-Ruiz, Carolina Aguado, Alejandro Martin-Belmonte, Ana Esther Moreno-Martinez, Jesus Merchan-Rubira, Felix Hernandez, Jesus Avila, Yugo Fukazawa, Rafael Lujan
Summary: N-methyl-D-aspartate receptors are important in Alzheimer's disease, and their expression and localization differ at synaptic and extrasynaptic sites, which is associated with accumulation of phospho-tau.
Article
Neurosciences
Yosuke M. Morizawa, Mami Matsumoto, Yuka Nakashima, Narumi Endo, Tomomi Aida, Hiroshi Ishikane, Kaoru Beppu, Satoru Moritoh, Hitoshi Inada, Noriko Osumi, Eiji Shigetomi, Schuichi Koizumi, Guang Yang, Hirokazu Hirai, Kohichi Tanaka, Kenji F. Tanaka, Nobuhiko Ohno, Yugo Fukazawa, Ko Matsui
Summary: The study found that motor learning induces synaptic engulfment by cerebellar Bergmann glia (BG), which contributes to synaptic pruning during the improvement of motor adaptation.
NATURE NEUROSCIENCE
(2022)
Article
Clinical Neurology
Alejandro Martin-Belmonte, Carolina Aguado, Rocio Alfaro-Ruiz, Ana Esther Moreno-Martinez, Luis de la Ossa, Ester Aso, Laura Gomez-Acero, Ryuichi Shigemoto, Yugo Fukazawa, Francisco Ciruela, Rafael Lujan
Summary: Studies have shown a reduction in GIRK channel density, a decrease in co-clustering between GABA(B) receptors and GIRK2 channels, leading to dysregulation in GABA signaling via GIRK channels in an Alzheimer's disease animal model.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Rocio Alfaro-Ruiz, Carolina Aguado, Alejandro Martin-Belmonte, Ana Esther Moreno-Martinez, Jesus Merchan-Rubira, Felix Hernandez, Jesus Avila, Yugo Fukazawa, Rafael Lujan
Summary: The accumulation of tau proteins in diseases like Alzheimer's disease is associated with alterations in glutamate receptor dynamics, leading to synaptic dysfunction. This study investigated the impact of tau pathology on AMPAR expression, density, and distribution in the hippocampus of P301S mice. The results showed that the accumulation of phospho-tau resulted in reduced AMPAR density in excitatory synapses on pyramidal cell spines and interneuron dendrites, as well as at extrasynaptic sites in CA1 pyramidal cells and interneurons. These findings suggest that tau pathology disrupts AMPAR trafficking and synaptic transmission, contributing to the pathological events in Alzheimer's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Clinical Neurology
Tomomi Tsunematsu, Sumire Matsumoto, Mirna Merkler, Shuzo Sakata
Summary: P-waves, known as an electrophysiological signature of rapid eye movement (REM) sleep, are also observed during non-REM (NREM) sleep. Recent studies have discovered that P-waves in NREM sleep are functionally coupled with hippocampal sharp wave ripples (SWRs). The waveform shapes and local neural ensemble dynamics of P-waves in NREM sleep are similar to those in REM sleep in a short timescale. However, the dynamics of mesopontine cholinergic neurons and the coupling of P-waves with SWRs differ between NREM and REM sleep.