Publications by authors named "Ken-Ichi Inoue"

98 Publications

Effects of Optogenetic Suppression of Cortical Input on Primate Thalamic Neuronal Activity during Goal-Directed Behavior.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Mar 23.

Department of Physiology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.

The motor thalamus relays signals from subcortical structures to the motor cortical areas. Previous studies in songbirds and rodents suggest that cortical feedback inputs crucially contribute to the generation of movement-related activity in the motor thalamus. In primates, however, it remains uncertain whether the corticothalamic projections may play a role in shaping neuronal activity in the motor thalamus. Here, using an optogenetic inactivation technique with the viral vector system expressing halorhodopsin, we investigated the role of cortical input in modulating thalamic neuronal activity during goal-directed behavior. In particular, we assessed whether the suppression of signals originating from the supplementary eye field at the corticothalamic terminals could change the task-related neuronal modulation in the oculomotor thalamus in monkeys performing a self-initiated saccade task. We found that many thalamic neurons exhibited changes in their firing rates depending on saccade direction or task event, indicating that optical stimulation exerted task-specific effects on neuronal activity beyond the global changes in baseline activity. These results suggest that the corticothalamic projections might be actively involved in the signal processing necessary for goal-directed behavior. However, we also found that some thalamic neurons exhibited overall, non-task-specific changes in the firing rate during optical stimulation, even in control animals without vector injections. The stimulation effects in these animals started with longer latency, implying a possible thermal effect on neuronal activity. Thus, our results not only reveal the importance of direct cortical input in neuronal activity in the primate motor thalamus, but also provide useful information for future optogenetic studies.
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http://dx.doi.org/10.1523/ENEURO.0511-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009665PMC
March 2021

MacaquePose: A Novel "In the Wild" Macaque Monkey Pose Dataset for Markerless Motion Capture.

Front Behav Neurosci 2020 18;14:581154. Epub 2021 Jan 18.

Department of Human Intelligence Systems, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan.

Video-based markerless motion capture permits quantification of an animal's pose and motion, with a high spatiotemporal resolution in a naturalistic context, and is a powerful tool for analyzing the relationship between the animal's behaviors and its brain functions. Macaque monkeys are excellent non-human primate models, especially for studying neuroscience. Due to the lack of a dataset allowing training of a deep neural network for the macaque's markerless motion capture in the naturalistic context, it has been challenging to apply this technology for macaques-based studies. In this study, we created MacaquePose, a novel open dataset with manually labeled body part positions (keypoints) for macaques in naturalistic scenes, consisting of >13,000 images. We also validated the application of the dataset by training and evaluating an artificial neural network with the dataset. The results indicated that the keypoint estimation performance of the trained network was close to that of a human-level. The dataset will be instrumental to train/test the neural networks for markerless motion capture of the macaques and developments of the algorithms for the networks, contributing establishment of an innovative platform for behavior analysis for non-human primates for neuroscience and medicine, as well as other fields using macaques as a model organism.
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http://dx.doi.org/10.3389/fnbeh.2020.581154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874091PMC
January 2021

Nonhuman Primate Optogenetics: Current Status and Future Prospects.

Adv Exp Med Biol 2021 ;1293:345-358

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Aichi, Japan.

Nonhuman primates (NHPs) have widely and crucially been utilized as model animals for understanding various higher brain functions and neurological disorders since their behavioral actions mimic both normal and disease states in humans. To know about how such behaviors emerge from the functions and dysfunctions of complex neural networks, it is essential to define the role of a particular pathway or neuron-type constituting these networks. Optogenetics is a potential technique that enables analyses of network functions. However, because of the large size of the NHP brain and the difficulty in creating genetically modified animal models, this technique is currently still hard to apply effectively and efficiently to NHP neuroscience. In this article, we focus on the issues that should be overcome for the development of NHP optogenetics, with special reference to the gene introduction strategy. We review the recent breakthroughs that have been made in NHP optogenetics to address these issues and discuss future prospects regarding more effective and efficient approaches to successful optogenetic manipulation in NHPs.
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http://dx.doi.org/10.1007/978-981-15-8763-4_22DOI Listing
February 2021

Time-restricted feeding prevents high-fat and high-cholesterol diet-induced obesity but fails to ameliorate atherosclerosis in apolipoprotein E-knockout mice.

Exp Anim 2020 Dec 3. Epub 2020 Dec 3.

Comprehensive Research Facilities for Advanced Medical Science, Research Center for Advanced Medical Science, Dokkyo Medical University.

One of the leading risk factors for atherosclerosis is obesity, which is commonly caused by a nutrient-rich Western-style diet, sedentary behaviors, and shift work. Time-restricted (TR) feeding and intermittent fasting are both known to prevent overweight and adiposity, improve glucose tolerance, and decrease plasma cholesterol in high-fat diet-induced obese mice. Here we examined the overall effects of TR feeding of a Western diet (fat, 40.5 Kcal%; cholesterol, 0.21 g%) using 8-week-old Apoe mice. Mice were assigned into three groups: (1) an ad libitum (AL) group fed an AL Western diet, (2) a TR group with restricted access to a Western diet (15 h/day, 12:00 to 3:00 Zeitgeber time [ZT]); and (3) an Ex/TR group fed a TR Western diet and subjected to physical exercise at 12:00 ZT. Mice in the AL group gained body weight rapidly during the 14-week observation period. With TR feeding, excessive weight gain, liver adiposity, visceral fat, and brown adipose tissue volume were effectively suppressed. Although TR feeding failed to decrease Oil Red O-stained aortic plaques in Apoe mice, physical exercise significantly decreased them. Neither TR feeding with exercise nor that without exercise decreased the mean area under the curve of the plasma cholesterol level or the fasting plasma glucose. Collectively, TR feeding of a Western diet prevented the development of obesity but failed to ameliorate atherosclerosis in Apoe mice.
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http://dx.doi.org/10.1538/expanim.20-0112DOI Listing
December 2020

Probing the electrode-solution interfaces in rechargeable batteries by sum-frequency generation spectroscopy.

J Chem Phys 2020 Nov;153(17):170902

Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.

An in-depth understanding of the electrode-electrolyte interaction and electrochemical reactions at the electrode-solution interfaces in rechargeable batteries is essential to develop novel electrolytes and electrode materials with high performance. In this perspective, we highlight the advantages of the interface-specific sum-frequency generation (SFG) spectroscopy on the studies of the electrode-solution interface for the Li-ion and Li-O batteries. The SFG studies in probing solvent adsorption structures and solid-electrolyte interphase formation for the Li-ion battery are briefly reviewed. Recent progress on the SFG study of the oxygen reaction mechanisms and stability of the electrolyte in the Li-O battery is also discussed. Finally, we present the current perspective and future directions in the SFG studies on the electrode-electrolyte interfaces toward providing deeper insight into the mechanisms of discharging/charging and parasitic reactions in novel rechargeable battery systems.
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http://dx.doi.org/10.1063/5.0026283DOI Listing
November 2020

Reorientation-induced relaxation of free OH at the air/water interface revealed by ultrafast heterodyne-detected nonlinear spectroscopy.

Nat Commun 2020 Oct 22;11(1):5344. Epub 2020 Oct 22.

Molecular Spectroscopy Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

The uniqueness of water originates from its three-dimensional hydrogen-bond network, but this hydrogen-bond network is suddenly truncated at the interface and non-hydrogen-bonded OH (free OH) appears. Although this free OH is the most characteristic feature of interfacial water, the molecular-level understanding of its dynamic property is still limited due to the technical difficulty. We study ultrafast vibrational relaxation dynamics of the free OH at the air/water interface using time-resolved heterodyne-detected vibrational sum frequency generation (TR-HD-VSFG) spectroscopy. With the use of singular value decomposition (SVD) analysis, the vibrational relaxation (T) times of the free OH at the neat HO and isotopically-diluted water interfaces are determined to be 0.87 ± 0.06 ps (neat HO), 0.84 ± 0.09 ps (HO/HOD/DO = 1/2/1), and 0.88 ± 0.16 ps (HO/HOD/DO = 1/8/16). The absence of the isotope effect on the T time indicates that the main mechanism of the vibrational relaxation of the free OH is reorientation of the topmost water molecules. The determined sub-picosecond T time also suggests that the free OH reorients diffusively without the switching of the hydrogen-bond partner by the topmost water molecule.
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http://dx.doi.org/10.1038/s41467-020-19143-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581742PMC
October 2020

An Open Resource for Non-human Primate Optogenetics.

Authors:
Sébastien Tremblay Leah Acker Arash Afraz Daniel L Albaugh Hidetoshi Amita Ariana R Andrei Alessandra Angelucci Amir Aschner Puiu F Balan Michele A Basso Giacomo Benvenuti Martin O Bohlen Michael J Caiola Roberto Calcedo James Cavanaugh Yuzhi Chen Spencer Chen Mykyta M Chernov Andrew M Clark Ji Dai Samantha R Debes Karl Deisseroth Robert Desimone Valentin Dragoi Seth W Egger Mark A G Eldridge Hala G El-Nahal Francesco Fabbrini Frederick Federer Christopher R Fetsch Michal G Fortuna Robert M Friedman Naotaka Fujii Alexander Gail Adriana Galvan Supriya Ghosh Marc Alwin Gieselmann Roberto A Gulli Okihide Hikosaka Eghbal A Hosseini Xing Hu Janina Hüer Ken-Ichi Inoue Roger Janz Mehrdad Jazayeri Rundong Jiang Niansheng Ju Kohitij Kar Carsten Klein Adam Kohn Misako Komatsu Kazutaka Maeda Julio C Martinez-Trujillo Masayuki Matsumoto John H R Maunsell Diego Mendoza-Halliday Ilya E Monosov Ross S Muers Lauri Nurminen Michael Ortiz-Rios Daniel J O'Shea Stéphane Palfi Christopher I Petkov Sorin Pojoga Rishi Rajalingham Charu Ramakrishnan Evan D Remington Cambria Revsine Anna W Roe Philip N Sabes Richard C Saunders Hansjörg Scherberger Michael C Schmid Wolfram Schultz Eyal Seidemann Yann-Suhan Senova Michael N Shadlen David L Sheinberg Caitlin Siu Yoland Smith Selina S Solomon Marc A Sommer John L Spudich William R Stauffer Masahiko Takada Shiming Tang Alexander Thiele Stefan Treue Wim Vanduffel Rufin Vogels Matthew P Whitmire Thomas Wichmann Robert H Wurtz Haoran Xu Azadeh Yazdan-Shahmorad Krishna V Shenoy James J DiCarlo Michael L Platt

Neuron 2020 12 19;108(6):1075-1090.e6. Epub 2020 Oct 19.

Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Marketing, Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA.

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs.
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http://dx.doi.org/10.1016/j.neuron.2020.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962465PMC
December 2020

Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.

Nat Neurosci 2020 09 6;23(9):1157-1167. Epub 2020 Jul 6.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.
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http://dx.doi.org/10.1038/s41593-020-0661-3DOI Listing
September 2020

Primate Amygdalo-Nigral Pathway for Boosting Oculomotor Action in Motivating Situations.

iScience 2020 Jun 23;23(6):101194. Epub 2020 May 23.

Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

A primary function of the primate amygdala is to modulate behavior based on emotional cues. To study the underlying neural mechanism, we first inactivated the amygdala locally and temporarily by injecting a GABA agonist. Then, saccadic eye movements and gaze were suppressed only on the contralateral side. Next, we performed optogenetic activation after injecting a viral vector into the amygdala. Optical stimulation in the amygdala excited amygdala neurons, whereas optical stimulation of axon terminals in the substantia nigra pars reticulata inhibited nigra neurons. Optical stimulation in either structure facilitated saccades to the contralateral side. These data suggest that the amygdala controls saccades and gaze through the basal ganglia output to the superior colliculus. Importantly, this amygdala-derived circuit mediates emotional context information, whereas the internal basal ganglia circuit mediates object value information. This finding demonstrates a basic mechanism whereby basal ganglia output can be modulated by other areas conveying distinct information.
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http://dx.doi.org/10.1016/j.isci.2020.101194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281789PMC
June 2020

Surgical Injury and Ischemia Prime the Adipose Stromal Vascular Fraction and Increase Angiogenic Capacity in a Mouse Limb Ischemia Model.

Stem Cells Int 2020 18;2020:7219149. Epub 2020 May 18.

Comprehensive Research Facilities for Advanced Medical Science, Research Center for Advanced Medical Science, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan.

The adipose-derived stromal vascular fraction (SVF) is an effective source for autologous cell transplantation. However, the quality and quantity of SVFs vary depending on the patient's age, complications, and other factors. In this study, we developed a method to reproducibly increase the cell number and improve the quality of adipose-derived SVFs by surgical procedures, which we term "wound repair priming." Subcutaneous fat from the inguinal region of BALB/c mice was surgically processed (primed) by mincing adipose parenchyma (injury) and ligating the subcutaneous fat-feeding artery (ischemia). SVFs were isolated on day 0, 1, 3, 5, or 7 after the priming procedures. Gene expression levels of the primed SVFs were measured via microarray and pathway analyses which were performed for differentially expressed genes. Changes in cellular compositions of primed SVFs were analyzed by flow cytometry. SVFs were transplanted into syngeneic ischemic hindlimbs to measure their angiogenic and regeneration potential. Hindlimb blood flow was measured using a laser Doppler blood perfusion imager, and capillary density was quantified by CD31 staining of ischemic tissues. Stabilization of HIF-1 alpha and VEGF-A synthesis in the SVFs were measured by fluorescent immunostaining and Western blotting, respectively. As a result, the number of SVFs per fat weight was increased significantly on day 7 after priming. Among the differentially expressed genes were innate immunity-related signals on both days 1 and 3 after priming. In primed SVFs, the CD45-positive blood mononuclear cell fraction decreased, and the CD31-CD45-double negative mesenchymal cell fraction increased on day 7. The F4/80-positive macrophage fraction was increased on days 1 and 7 after priming. There was a serial decrease in the mesenchymal-gated CD34-positive adipose progenitor fraction and mesenchymal-gated CD140A-positive/CD9-positive preadipocyte fraction on days 1 and 3. Transplantation of primed SVFs resulted in increased capillary density and augmented blood flow, improving regeneration of the ischemic limbs. HIF-1 alpha was stabilized in the primed cutaneous fat , and VEGF-A synthesis of the primed SVFs was on a peak on 5 days after priming. Wound repair priming thus resulted in SVFs with increased number and augmented angiogenic potential.
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http://dx.doi.org/10.1155/2020/7219149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251464PMC
May 2020

Monitoring of the Unsaturated Phospholipid Monolayer Oxidation in Ambient Air by HD-SFG Spectroscopy.

J Phys Chem B 2020 06 16;124(25):5246-5250. Epub 2020 Jun 16.

Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.

The pulmonary surfactant monolayer is indispensable for the respiratory system. Recently, it was reported that some unsaturated lipids of the pulmonary surfactants are oxidized by low-level ozone in ambient air. However, the molecular-level understanding of the reaction mechanism is still limited due to technical difficulties. We applied heterodyne-detected sum frequency generation (HD-SFG) spectroscopy to probe the reaction process of an unsaturated phospholipid monolayer (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine, POPC), which is one of the major lipids in the pulmonary surfactant, under low-level ozone (30 ± 5 ppb). The HD-SFG spectroscopy realized the accurate peak assignments of the spectra and the identification of molecular species with high sensitivity, which were impossible with previous measurements. The time-resolved spectra indicated that the C═C moiety in the unsaturated alkyl chain is selectively oxidized by ozone with a time constant of 22 ± 3 min by first-order reaction kinetics. Furthermore, it was revealed for the first time that the reaction product of the POPC monolayer under low-level ozone is not the carboxylic form but the aldehyde form based on the vibrational spectroscopy results. The present study has deepened our molecular-level understanding of the oxidation mechanism of unsaturated lipids that are widely found in many biological systems.
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http://dx.doi.org/10.1021/acs.jpcb.0c03408DOI Listing
June 2020

Pronuclear Microinjection during S-Phase Increases the Efficiency of CRISPR-Cas9-Assisted Knockin of Large DNA Donors in Mouse Zygotes.

Cell Rep 2020 05;31(7):107653

Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan. Electronic address:

In CRISPR-Cas9-assisted knockin (KI) in zygotes, a remaining challenge is routinely achieving high-efficiency KI of large (kilobase-sized) DNA elements. Here, we focus on the timing of pronuclear injection and establish a reliable homologous recombination (HR)-based method to generate large KIs in zygotes compared with two other types of KI strategies involving distinct DNA repair pathways. At the ROSA26 locus, pronuclear injection with CRISPR RNA (crRNA), trans-activating crRNA (tracrRNA), and Cas9 protein at the S phase by using the HR-based method yields the most efficient and accurate KIs (up to 70%). This approach is also generally effective for generating large KI alleles at other gene loci. We further apply our method to efficiently obtain biallelic ROSA26 KIs by sequential injection into both pronuclei. Our results suggest that delivery of genome editing components and donor DNA into S-phase zygotes is critical for efficient KI of large DNA elements.
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http://dx.doi.org/10.1016/j.celrep.2020.107653DOI Listing
May 2020

Optogenetic manipulation of a value-coding pathway from the primate caudate tail facilitates saccadic gaze shift.

Nat Commun 2020 04 20;11(1):1876. Epub 2020 Apr 20.

Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

In the primate basal ganglia, the caudate tail (CDt) encodes the historical values (good or bad) of visual objects (i.e., stable values), and electrical stimulation of CDt evokes saccadic eye movements. However, it is still unknown how output from CDt conveys stable value signals to govern behavior. Here, we apply a pathway-selective optogenetic manipulation to elucidate how such value information modulates saccades. We express channelrhodopsin-2 in CDt delivered by viral vector injections. Selective optical activation of CDt-derived terminals in the substantia nigra pars reticulata (SNr) inhibits SNr neurons. Notably, these SNr neurons show inhibitory responses to good objects. Furthermore, the optical stimulation causes prolonged excitation of visual-saccadic neurons in the superior colliculus (SC), and induces contralateral saccades. These SC neurons respond more strongly to good than to bad objects in the contralateral hemifield. The present results demonstrate that CDt facilitates saccades toward good objects by serial inhibitory pathways through SNr.
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http://dx.doi.org/10.1038/s41467-020-15802-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171130PMC
April 2020

Myasthenia Gravis with Anti-Muscle-Specific Tyrosine Kinase Antibody during Pregnancy and Risk of Neonatal Myasthenia Gravis: A Case Report and Review of the Literature.

Case Rep Neurol 2020 Jan-Apr;12(1):114-120. Epub 2020 Mar 17.

Department of Neurology, Fukuoka University School of Medicine, Fukuoka, Japan.

A 31-year-old woman presented with a nasal voice, dysarthria, and upper limb weakness during her first pregnancy. Soon after delivery of her first baby, her symptoms disappeared. At the age of 34 years, during her second pregnancy, her nasal voice re-appeared. After delivery of the second baby, her nasal voice worsened, and bilateral eyelid ptosis and easy fatigability were also evident. She was referred to our hospital. Because of her myasthenic symptoms and anti-muscle-specific tyrosine kinase (MuSK) antibody (Ab)-positive status, she was diagnosed as having myasthenia gravis (MG). Her symptoms were worse than those in her first pregnancy. She was treated with oral steroid and double filtration plasmapheresis. After initiation of treatment, her myasthenic symptoms improved completely. In addition, her baby developed transient neonatal MG (TNMG) on the fourth day after birth and then gradually recovered over 30 days. It should be noted that symptoms of patients with anti-MuSK Ab-positive MG (MuSK-MG) can deteriorate during pregnancy, and the babies delivered of patients with MuSK-MG have a high probability of developing TNMG.
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http://dx.doi.org/10.1159/000506189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154260PMC
March 2020

Hidden Isolated OH at the Charged Hydrophobic Interface Revealed by Two-Dimensional Heterodyne-Detected VSFG Spectroscopy.

Angew Chem Int Ed Engl 2020 06 15;59(24):9498-9505. Epub 2020 Apr 15.

Molecular Spectroscopy Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.

Water around hydrophobic groups mediates hydrophobic interactions that play key roles in many chemical and biological processes. Thus, the molecular-level elucidation of the properties of water in the vicinity of hydrophobic groups is important. We report on the structure and dynamics of water at two oppositely charged hydrophobic ion/water interfaces, that is, the tetraphenylborate-ion (TPB )/water and tetraphenylarsonium-ion (TPA )/water interfaces, which are clarified by two-dimensional heterodyne-detected vibrational sum-frequency generation (2D HD-VSFG) spectroscopy. The obtained 2D HD-VSFG spectra of the anionic TPB interface reveal the existence of distinct π-hydrogen bonded OH groups in addition to the usual hydrogen-bonded OH groups, which are hidden in the steady-state spectrum. In contrast, 2D HD-VSFG spectra of the cationic TPA interface only show the presence of usual hydrogen-bonded OH groups. The present study demonstrates that the sign of the interfacial charge governs the structure and dynamics of water molecules that face the hydrophobic region.
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http://dx.doi.org/10.1002/anie.202002368DOI Listing
June 2020

New Cerebello-Cortical Pathway Involved in Higher-Order Oculomotor Control.

Cerebellum 2020 Jun;19(3):401-408

Department of Neurophysiology, School of Medicine, Juntendo University, Tokyo, 113-8421, Japan.

The cerebellum and the basal ganglia play an important role in the control of voluntary eye movement associated with complex behavior, but little is known about how cerebellar projections project to cortical eye movement areas. Here we used retrograde transneuronal transport of rabies virus to identify neurons in the cerebellar nuclei that project via the thalamus to supplementary eye field (SEF) of the frontal cortex of macaques. After rabies injections into the SEF, many neurons in the restricted region, the ventral aspects of the dentate nucleus (DN), the caudal pole of the DN, and the posterior interpositus nucleus (PIN) were labeled disynaptically via the thalamus, whereas no neuron labeling was found in the anterior interpositus nucleus (AIN). The distribution of the labeled neurons was dorsoventrally different from that of DN and PIN neurons labeled from the motor cortex. In the basal ganglia, a large number of labeled neurons were confined to the dorsomedial portion of the internal segment of the globus pallidus (GPi) as more neurons were labeled in the inner portion of the GPi (GPii) than in the outer portion of the GPi (GPio). This is the first evidence of a projection between cerebellum/basal ganglia and the SEF that could enable the cerebellum to modulate the cognitive control of voluntary eye movement.
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http://dx.doi.org/10.1007/s12311-020-01108-8DOI Listing
June 2020

Layer specificity of inputs from supplementary motor area and dorsal premotor cortex to primary motor cortex in macaque monkeys.

Sci Rep 2019 12 3;9(1):18230. Epub 2019 Dec 3.

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Aichi, 484-8506, Japan.

The primate frontal lobe processes diverse motor information in parallel through multiple motor-related areas. For example, the supplementary motor area (SMA) is mainly involved in internally-triggered movements, whereas the premotor cortex (PM) is highly responsible for externally-guided movements. The primary motor cortex (M1) deals with both aspects of movements to execute a single motor behavior. To elucidate how the cortical motor system is structured to process a variety of information, the laminar distribution patterns of signals were examined between SMA and M1, or PM and M1 in macaque monkeys by using dual anterograde tract-tracing. Dense terminal labeling was observed in layers 1 and upper 2/3 of M1 after one tracer injection into SMA, another tracer injection into the dorsal division of PM resulted in prominent labeling in the deeper portion of layer 2/3. Weaker labeling was also visible in layer 5 in both cases. On the other hand, inputs from M1 terminated in both the superficial and the deep layers of SMA and PM. The present data indicate that distinct types of motor information are arranged in M1 in a layer-specific fashion to be orchestrated through a microcircuit within M1.
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http://dx.doi.org/10.1038/s41598-019-54220-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890803PMC
December 2019

Identification of neuron-type specific promoters in monkey genome and their functional validation in mice.

Biochem Biophys Res Commun 2019 10 23;518(4):619-624. Epub 2019 Aug 23.

Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. Electronic address:

Viral gene delivery is one of the most versatile techniques for elucidating the mechanisms underlying brain dysfunction, such as neuropsychiatric disorders. Due to the complexity of the brain, expression of genetic tools, such as channelrhodopsin and calcium sensors, often has to be restricted to a specified cell type within a circuit implicated in these disorders. Only a handful of promoters targeting neuronal subtypes are currently used for viral gene delivery. Here, we isolated conserved promoter regions of several subtype-specific genes from the macaque genome and investigated their functionality in the mouse brain when used within lentiviral vectors (LVVs). Immunohistochemical analysis revealed that transgene expression induced by the promoter sequences for somatostatin (SST), cholecystokinin (CCK), parvalbumin (PV), serotonin transporter (SERT), vesicular acetylcholine transporter (vAChT), substance P (SP) and proenkephalin (PENK) was largely colocalized with specific markers for the targeted neuronal populations. Moreover, by combining these results with in silico predictions of transcription factor binding to the isolated sequences, we identified transcription factors possibly underlying cell-type specificity. These findings lay a foundation for the expansion of the current toolbox of promoters suitable for elucidating these neuronal phenotypes.
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http://dx.doi.org/10.1016/j.bbrc.2019.08.101DOI Listing
October 2019

Optogenetic recruitment of spinal reflex pathways from large-diameter primary afferents in non-transgenic rats transduced with AAV9/Channelrhodopsin 2.

J Physiol 2019 10 28;597(19):5025-5040. Epub 2019 Aug 28.

Department of Neurophysiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Key Points: We demonstrated optical activation of primary somatosensory afferents with high selectivity to fast-conducting fibres by means of adeno-associated virus 9 (AAV9)-mediated gene transduction in dorsal root ganglion (DRG) neurons. AVV9 expressing green fluorescent protein showed high selectivity and transduction efficiency for fast-conducting, large-sized DRG neurons. Compared with conventional electrical stimulation, optically elicited volleys in primary afferents had higher sensitivity with stimulus amplitude, but lower sensitivity with stimulus frequency. Optically elicited dorsal root volleys activated postsynaptic neurons in the segmental spinal pathway. This proposed technique will help establish the causal relationships between somatosensory afferent inputs and neural responses in the CNS as well as behavioural outcomes in higher mammals where transgenic animals are not available.

Abstract: Previously, fundamental structures and their mode of action in the spinal reflex circuit were determined by confirming their input-output relationship using electrophysiological techniques. In those experiments, the electrical stimulation of afferent fibres was used as a core element to identify different types of reflex pathways; however, a major disadvantage of this technique is its non-selectivity. In this study, we investigated the selective activation of large-diameter afferents by optogenetics combined with a virus vector transduction technique (injection via the sciatic nerve) in non-transgenic male Jcl:Wistar rats. We found that green fluorescent protein gene transduction of rat dorsal root ganglion (DRG) neurons with a preference for medium-to-large-sized cells was achieved using the adeno-associated virus 9 (AAV9) vector compared with the AAV6 vector (P = 0.021). Furthermore, the optical stimulation of Channelrhodopsin 2 (ChR2)-expressing DRG neurons (transduced by AAV9) produced compound action potentials in afferent nerves originating from fast-conducting nerve fibres. We also confirmed that physiological responses to different stimulus amplitudes were comparable between optogenetic and electrophysiological activation. However, compared with electrically elicited responses, the optically elicited responses had lower sensitivity with stimulus frequency. Finally, we showed that afferent volleys evoked by optical stimulation were sufficient to activate postsynaptic neurons in the spinal reflex arc. These results provide new ways for understanding the role of sensory afferent input to the central nervous system regarding behavioural control, especially when genetically manipulated animals are not available, such as higher mammals including non-human primates.
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http://dx.doi.org/10.1113/JP278292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851594PMC
October 2019

Cancer-associated fibroblasts show heterogeneous gene expression and induce vascular endothelial growth factor A () in response to environmental stimuli.

Ann Gastroenterol Surg 2019 Jul 9;3(4):416-425. Epub 2019 Apr 9.

Department of Gastroenterological Surgery Ibaraki Medical Center Tokyo Medical University Tokyo Japan.

Aim: Cancer-associated fibroblasts (CAF) play a crucial role in angiogenesis in the complex tumor microenvironment. However, fibroblasts show extensive heterogeneity and their dynamic functions against stressors remain largely unknown.

Methods: We collected patient-derived CAF and carried out perturbation-based monitoring of the dynamic functions. Clinically relevant experimental stimuli were defined as follows: hypoxia, cisplatin, fluorouracil, coculture with cancer spheroids (interaction through paracrine signals). We selected 18 marker genes that encode components for fibroblast activation, intracellular communication, and extracellular matrix remodeling. Quantitative reverse transcription polymerase chain reaction was carried out for data collection and statistical analyses were carried out using SPSS software.

Results: Kruskal-Wallis multivariate analysis of variance showed that variations in expression of 11 marker genes were explained, in part, by a difference in tissue of origin. Friedman and two-sided Wilcoxon signed rank tests detected significant perturbations in expression of marker genes. Paracrine signal from cancer spheroids induced vascular endothelial growth factor A () in CAF but not in fetal lung fibroblasts.

Conclusion: We have established perturbation-based monitoring of patients' CAF. Further data collection and individual patient follow up is ongoing to identify critical determinants of disease outcome.
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http://dx.doi.org/10.1002/ags3.12249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635680PMC
July 2019

A note on retrograde gene transfer efficiency and inflammatory response of lentiviral vectors pseudotyped with FuG-E vs. FuG-B2 glycoproteins.

Sci Rep 2019 03 5;9(1):3567. Epub 2019 Mar 5.

Systems Neuroscience Section, Department of Neuroscience, Primate Research Institute, Kyoto University, Inuyama, Aichi, 484-8506, Japan.

Pseudotyped lentiviral vectors give access to pathway-selective gene manipulation via retrograde transfer. Two types of such lentiviral vectors have been developed. One is the so-called NeuRet vector pseudotyped with fusion glycoprotein type E, which preferentially transduces neurons. The other is the so-called HiRet vector pseudotyped with fusion glycoprotein type B2, which permits gene transfer into both neurons and glial cells at the injection site. Although these vectors have been applied in many studies investigating neural network functions, it remains unclear which vector is more appropriate for retrograde gene delivery in the brain. To compare the gene transfer efficiency and inflammatory response of the NeuRet vs. HiRet vectors, each vector was injected into the striatum in macaque monkeys, common marmosets, and rats. It was revealed that retrograde gene delivery of the NeuRet vector was equal to or greater than that of the HiRet vector. Furthermore, inflammation characterized by microglial and lymphocytic infiltration occurred when the HiRet vector, but not the NeuRet vector, was injected into the primate brain. The present results indicate that the NeuRet vector is more suitable than the HiRet vector for retrograde gene transfer in the primate and rodent brains.
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http://dx.doi.org/10.1038/s41598-019-39535-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400974PMC
March 2019

Effect of hydrogen-bond on ultrafast spectral diffusion dynamics of water at charged monolayer interfaces.

J Chem Phys 2019 Feb;150(5):054705

Molecular Spectroscopy Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

Ultrafast hydrogen-bond fluctuation dynamics of water at charged monolayer interfaces were studied by the use of steady-state and 2D heterodyne-detected vibrational sum frequency generation (HD-VSFG) spectroscopy. Specifically, the effect of hydrogen-bond ability of the interface on the dynamics was investigated by comparing two monolayer interfaces that provide different hydrogen bond abilities: hydrogen bonding octadecylammonium (ODA) monolayer (pH = 2) and non-hydrogen bonding 1,2-dipalmitoyl-3-trimethyl-ammonium propane (DPTAP) monolayer. The steady-state HD-VSFG spectra and their ionic strength dependence revealed that water molecules at both of ODA and DPTAP interfaces are H-down oriented, pointing their H away from the interface, and that the contributions of the electrical double layer in the interfacial spectra of these interfaces are comparable to each other. However, 2D HD-VSFG data clearly indicated that the ultrafast hydrogen-bond fluctuation of water at the ODA interface is significantly suppressed, compared to that at the DPTAP interfaces. The obtained results suggest that the hydrogen-bond fluctuation of the topmost interfacial water at a positively charged interface is significantly affected by the hydrogen-bonding ability of the interface even in the case that the interfacial water molecules act as a hydrogen-bond acceptor to the head group of the monolayer.
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http://dx.doi.org/10.1063/1.5081077DOI Listing
February 2019

Enhancement of the transduction efficiency of a lentiviral vector for neuron-specific retrograde gene delivery through the point mutation of fusion glycoprotein type E.

J Neurosci Methods 2019 01 19;311:147-155. Epub 2018 Oct 19.

Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan. Electronic address:

Background: Pseudotyping of a lentiviral vector with fusion glycoproteins composed of rabies virus glycoprotein (RVG) and vesicular stomatitis virus glycoprotein (VSVG) segments achieves high gene transfer efficiency through retrograde transport in the nervous system. In our previous study, we determined the junction of RVG/VSVG segments of glycoproteins that enhances the transduction efficiency of the neuron-specific retrograde gene transfer (NeuRet) vector (termed fusion glycoprotein type E or FuG-E).

New Method: We aimed to optimize the amino acid residue at position 440 in the membrane-proximal region of FuG-E to improve the efficiency of retrograde gene transfer in the brain.

Results: We constructed variants of FuG-E with 18 kinds of single amino acid substitutions at residue 440 to generate lentiviral vectors pseudotyped with these variants, and tested in vivo gene transfer of the vectors in the mouse brain. The FuG-E (P440E) variant, in which proline was substituted by glutamate at residue 440 in FuG-E, showed the greatest retrograde gene transfer efficiency in the brain, bearing the property of the NeuRet vector. The FuG-E (P440E) pseudotype also displayed efficient retrograde gene transfer in the common marmoset brain.

Comparison With Existing Methods: The NeuRet vector with the FuG-E (P440E) variant demonstrated higher retrograde gene transfer efficiency into different neural pathways compared with the parental FuG-E vector.

Conclusions: The FuG-E (P440E) pseudotype provides a powerful tool to investigate neural circuit mechanisms underlying various brain functions and for gene therapy trials of neurological and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.jneumeth.2018.10.023DOI Listing
January 2019

Autologous and heterotopic transplantation of adipose stromal vascular fraction ameliorates stress urinary incontinence in rats with simulated childbirth trauma.

Regen Ther 2018 Jun 22;8:9-14. Epub 2017 Dec 22.

Department of Urology, Continence Center, Dokkyo Medical University, Kitakobayashi, Mibu, Tochigi, 321-0293, Japan.

Introduction: Autologous transplantation of adipose stromal vascular fraction (SVF) is a cost-effective and technically accessible option for cell therapy. Clinical study of SVF transplantation for male stress urinary incontinence (SUI) is underway, but the effectiveness remains unknown for female SUI, majority of which is caused by childbirth trauma.

Methods: Vaginal Distension (VD) rats were generated as model for female SUI. To quantitate the severity of SUI, leak point pressure (LPP) was measured by placing a bladder catheter. There was a characteristic waveform of LPP with two-peaks, and we counted the second peak as an LPP value. Adipose SVF was separated from inguinal fat and delivered into external urethral sphincter (EUS) through transperineal injection. LPP was measured 7 or 14 days after SVF transplantation. Tissue damage and collagen synthesis around the EUS were visualized by Masson's trichrome and eosin staining. Antibody against α-smooth muscle actin (α-SMA) was used to stain smooth muscle or activated stromal cells. Donor SVF cells were distinguished from recipient EUS tissue by tracking with transgene.

Results: VD procedure decreased the frequency at which the normal LPP waveform appeared and lowered the LPP value. SVF injection normalized the waveform as well as the level of LPP. VD disrupted histological structure of EUS and SVF failed to differentiate into striatal muscles. Instead, SVF increased α-SMA positive cells and collagen synthesis but the phenomena depended on VD stimulus. GFP tracking indicated that the transplanted SVF cells persisted for four weeks and synthesized α-SMA protein simultaneously.

Conclusions: Autologous transplantation of adipose SVF displayed bulking effects through collagen synthesis. However, such heterotopic activation was dependent on tissue damage.
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http://dx.doi.org/10.1016/j.reth.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147152PMC
June 2018

Causal Role of Neural Signals Transmitted From the Frontal Eye Field to the Superior Colliculus in Saccade Generation.

Front Neural Circuits 2018 28;12:69. Epub 2018 Aug 28.

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.

The frontal eye field (FEF) and superior colliculus (SC) are major and well-studied components of the oculomotor system. The FEF sends strong projections to the SC directly, and neurons in these brain regions transmit a variety of signals related to saccadic eye movements. Electrical microstimulation and pharmacological manipulation targeting the FEF or SC affect saccadic eye movements. These data suggest the causal contribution of each region to saccade generation. To understand how the brain generates behavior, however, it is critical not only to identify the structures and functions of individual regions, but also to elucidate how they interact with each other. In this review article, we first survey previous works that aimed at investigating whether and how the FEF and SC interact to regulate saccadic eye movements using electrophysiological and pharmacological techniques. These works have reported what signals FEF neurons transmit to the SC and what roles such signals play in regulating oculomotor behavior. We then highlight a recent attempt of our own that has applied an optogenetic approach to stimulate the neural pathway from the FEF to the SC in nonhuman primates. This study has shown that optogenetic stimulation of the FEF-SC pathway is sufficiently effective not only to modulate SC neuron activity, but also to evoke saccadic eye movements. Although the oculomotor system is a complex neural network composed of numbers of cortical and subcortical regions, the optogenetic approach will provide a powerful strategy for elucidating the role of each neural pathway constituting this network.
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http://dx.doi.org/10.3389/fncir.2018.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120992PMC
March 2019

Recruitment of calbindin into nigral dopamine neurons protects against MPTP-Induced parkinsonism.

Mov Disord 2019 02 30;34(2):200-209. Epub 2018 Aug 30.

Systems Neuroscience Section, Department of Neuroscience, Primate Research Institute, Kyoto University, Inuyama, Aichi, Japan.

Background: Parkinson's disease is caused by dopamine deficiency in the striatum, which is a result of loss of dopamine neurons from the substantia nigra pars compacta. There is a consensus that a subpopulation of nigral dopamine neurons that expresses the calcium-binding protein calbindin is selectively invulnerable to parkinsonian insults. The objective of the present study was to test the hypothesis that dopamine neuron degeneration might be prevented by viral vector-mediated gene delivery of calbindin into the dopamine neurons that do not normally contain it.

Methods: A calbindin-expressing adenoviral vector was injected into the striatum of macaque monkeys to be conveyed to cell bodies of nigral dopamine neurons through retrograde axonal transport, or the calbindin-expressing lentiviral vector was injected into the nigra directly because of its predominant uptake from cell bodies and dendrites. The animals in which calbindin was successfully recruited into nigral dopamine neurons were administered systemically with MPTP.

Results: In the monkeys that had received unilateral vector injections, parkinsonian motor deficits, such as muscular rigidity and akinesia/bradykinesia, appeared predominantly in the limbs corresponding to the non-calbindin-recruited hemisphere after MPTP administration. Data obtained from tyrosine hydroxylase immunostaining and PET imaging for the dopamine transporter revealed that the nigrostriatal dopamine system was preserved better on the calbindin-recruited side. Conversely, on the non-calbindin-recruited control side, many more dopamine neurons expressed α-synuclein.

Conclusions: The present results indicate that calbindin recruitment into nigral dopamine neurons protects against the onset of parkinsonian insults, thus providing a novel approach to PD prevention. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.107DOI Listing
February 2019

Segmentation of the rabies virus genome.

Virus Res 2018 07 19;252:68-75. Epub 2018 May 19.

Nihon University Veterinary Research Center, Fujisawa, Kanagawa 252-0880, Japan. Electronic address:

We established a system for the recovery of a segmented recombinant rabies virus, the virus genome RNA of which was divided into two parts: segment 1 encoding the nucleoprotein, phosphoprotein, matrix protein, and glycoprotein genes, and segment 2 encoding the large RNA-dependent RNA polymerase gene. The morphology of the segmented recombinant rabies virus was bullet-like in shape with a length of approximately 130 nm, which is shorter than the 200-nm long non-segmented recombinant rabies virus. The segmented recombinant rabies virus was maintained for at least 18 passages. The virus multiplication rate of the segmented recombinant rabies virus was lower than that of the non-segmented recombinant rabies virus during the passages, and the relative amounts of virus genome RNAs for segment 1 and segment 2 differed in the supernatant of the segmented recombinant rabies virus infected cells. These results suggest that the segmented recombinant rabies virus packages either segment 1 or segment 2 into each virus particle. Thus, co-infection with segmented recombinant rabies virus particles packaging segment 1 or segment 2 may be necessary for the production of progeny virus.
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http://dx.doi.org/10.1016/j.virusres.2018.05.017DOI Listing
July 2018

Mobilization of progenitor cells and assessment of vessel healing after second generation drug-eluting stenting by optical coherence tomography.

Int J Cardiol Heart Vasc 2018 Mar 16;18:17-24. Epub 2018 Feb 16.

Division of Cardiovascular Medicine, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Background: Bone marrow-derived progenitor cells likely contribute to both endothelial- and smooth muscle cell-dependent healing responses in stent-injured vessel sites. This study aimed to assess mobilization of progenitor cells and vessel healing after zotarolimus-eluting (ZES) and everolimus-eluting (EES) stents.

Methods And Results: In 63 patients undergoing coronary stent implantation, we measured circulating CD34 + CD133 + CD45low cells and serum levels of biomarkers relevant to stem cell mobilization. In 31 patients of them, we assessed vessel healing within the stented segment using optical coherence tomography (OCT) imaging. The CD34 + CD133 + CD45low cells increased 68 ± 59% 7 days after bare metal stent (BMS), 10 ± 53% after ZES ( < 0.01 vs BMS), 3 ± 49% after EES ( < 0.001 vs BMS), compared with baseline. Percent change in CD34 + CD133 + CD45low cells was positively correlated with that in stromal cell-derived factor (SDF)-1α ( = 0.29,  = 0.034). Percentage of uncovered struts was higher in the EES group (14.4 ± 17.3%), compared with the BMS (0.7 ± 1.3,  < 0.01) and ZES (0.4 ± 0.5,  < 0.01) groups. The change in CD34 + CD133 + CD45low cells showed positive correlation with OCT-quantified mean neointimal area ( = 0.48, P < 0.01). Finally, circulating mononuclear cells obtained from 5 healthy volunteers were isolated to determine the effect of sirolimus, zotarolimus and everolimus on vascular cell differentiation. The differentiation of mononuclear cells into endothelial-like cells was dose-dependently suppressed by sirolimus, zotarolimus, and everolimus.

Conclusions: Mobilization of progenitor cells was suppressed, and differentiation of mononuclear cells into endothelial-like cells was inhibited, in association with increased number of uncovered stent struts, even after second generation drug-eluting stenting. These data suggest that new approaches are necessary to enhance stent healing.
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http://dx.doi.org/10.1016/j.ijcha.2017.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854838PMC
March 2018

Multisynaptic Projections from the Amygdala to the Ventral Premotor Cortex in Macaque Monkeys: Anatomical Substrate for Feeding Behavior.

Front Neuroanat 2018 19;12. Epub 2018 Jan 19.

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.

The amygdala codes the visual-gustatory/somatosensory valence for feeding behavior. On the other hand, the ventral premotor cortex (PMv) plays a central role in reaching and grasping movements prerequisite for feeding behavior. This implies that object valence signals derived from the amygdala may be crucial for feeding-related motor actions exerted by PMv. However, since no direct connectivity between the amygdala and PMv has been reported, the structural basis of their functional interactions still remains elusive. In the present study, we employed retrograde transneuronal labeling with rabies virus to identify the amygdalar origin and possible route of multisynaptic projections to PMv in macaque monkeys. Histological analysis of the distribution pattern of labeled neurons has found that PMv receives disynaptic input primarily from the basal nucleus, especially from its intermediate subdivision. It has also been revealed that the medial (e.g., the cingulate motor areas, CMA) and lateral (e.g., the insular cortices) cortical areas, and the cholinergic cell group 4 in the basal forebrain probably mediate the projections from the amygdala to PMv. Such multisynaptic pathways might represent amygdalar influences on PMv functions for feeding behavior.
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http://dx.doi.org/10.3389/fnana.2018.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780351PMC
January 2018

Nonhuman Primate Optogenetics: Recent Advances and Future Directions.

J Neurosci 2017 11;37(45):10894-10903

Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom NE2 4HH.

Optogenetics is the use of genetically coded, light-gated ion channels or pumps (opsins) for millisecond resolution control of neural activity. By targeting opsin expression to specific cell types and neuronal pathways, optogenetics can expand our understanding of the neural basis of normal and pathological behavior. To maximize the potential of optogenetics to study human cognition and behavior, optogenetics should be applied to the study of nonhuman primates (NHPs). The homology between NHPs and humans makes these animals the best experimental model for understanding human brain function and dysfunction. Moreover, for genetic tools to have translational promise, their use must be demonstrated effectively in large, wild-type animals such as Rhesus macaques. Here, we review recent advances in primate optogenetics. We highlight the technical hurdles that have been cleared, challenges that remain, and summarize how optogenetic experiments are expanding our understanding of primate brain function.
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http://dx.doi.org/10.1523/JNEUROSCI.1839-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678022PMC
November 2017