Faculty Profiles - MIZOGUCHI, Hiroyuki

Alzheimer's Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment Reviewed Open Access

Nakai, T; Yamada, K; Mizoguchi, H

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol. 22 ( 11 ) 2021.6

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.

DOI： 10.3390/ijms22115549

Analysis of Reelin signaling and neurodevelopmental trajectory in primary cultured cortical neurons with RELN deletion identified in schizophrenia Reviewed Open Access

Tsuneura, Y; Sawahata, M; Itoh, N; Miyajima, R; Mori, D; Kohno, T; Hattori, M; Sobue, A; Nagai, T; Mizoguchi, H; Nabeshima, T; Ozaki, N; Yamada, K

NEUROCHEMISTRY INTERNATIONAL Vol. 144 page： 104954 2021.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Neurochemistry International

Reelin, an extracellular matrix protein, is secreted by Cajal-Retzius cells and plays crucial roles in the development of brain structures and neuronal functions. Reductions in Reelin cause the brain dysfunctions associated with mental disorders, such as schizophrenia. A recent genome-wide copy number variation analysis of Japanese schizophrenia patients identified a novel deletion in RELN encoding Reelin. To clarify the pathophysiological role of the RELN deletion, we developed transgenic mice carrying the RELN deletion (Reln-del) and found abnormalities in their brain structures and social behavior. In the present study, we performed an in vitro analysis of Reelin expression, intracellular Reelin signaling, and the morphology of primary cultured cortical neurons from wild-type (WT) and Reln-del mice. Reelin protein levels were lower in Reln-del neurons than in WT neurons. Dab1 expression levels were significantly higher in Reln-del neurons than in WT neurons, suggesting that Reelin signaling was decreased in Reln-del neurons. Reelin was mainly expressed in γ-aminobutyric acid (GABA)-ergic inhibitory neurons, but not in parvalbumin (PV)-positive neurons. A small proportion of Ca2+/calmodulin-dependent protein kinase II α subunit (CaMKIIα)-positive excitatory neurons also expressed Reelin. In comparisons with WT neurons, significant decreases were observed in neurite lengths and branch points as well as in the number of postsynaptic density protein 95 (PSD95) immunoreactive puncta in Reln-del neurons. A disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS-3) is a protease that inactivates Reelin by cleavage at the N-t site. The knockdown of ADAMTS-3 by short hairpin RNAs suppressed Reelin cleavage in conditioned medium and reduced Dab1 expression, indicating that Reelin signaling was enhanced in the primary cultured cortical neurons of WT and heterozygous Reln-del. Accordingly, the inhibition of ADAMTS-3 may be a potential candidate in the clinical treatment of schizophrenia by enhancing Reelin signaling in the brain.

DOI： 10.1016/j.neuint.2020.104954

REM sleep-active MCH neurons are involved in forgetting hippocampus-dependent memories Reviewed Open Access

Izawa, S; Chowdhury, S; Miyazaki, T; Mukai, Y; Ono, D; Inoue, R; Ohmura, Y; Mizoguchi, H; Kimura, K; Yoshioka, M; Terao, A; Kilduff, TS; Yamanaka, A

SCIENCE Vol. 365 ( 6459 ) page： 1308 - + 2019.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Science

The neural mechanisms underlying memory regulation during sleep are not yet fully understood.We found that melanin concentrating hormone-producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs.Wake- and REM sleep- active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state-dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep-active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.

DOI： 10.1126/science.aax9238

Maternal separation as a risk factor for aggravation of neuropathic pain in later life in mice

Preproenkephalin-expressing ventral pallidal neurons control inhibitory avoidance learning Reviewed Open Access

Macpherson, T; Mizoguchi, H; Yamanaka, A; Hikida, T

NEUROCHEMISTRY INTERNATIONAL Vol. 126 page： 11 - 18 2019.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Neurochemistry International

The ventral pallidum (VP) is a critical component of the basal ganglia neurocircuitry regulating learning and decision making; however, its precise role in controlling associative learning of environmental stimuli conditioned to appetitive or aversive outcomes is still unclear. Here, we investigated the expression of preproenkephalin, a polypeptide hormone previously shown to be expressed in nucleus accumbens neurons controlling aversive learning, within GABAergic and glutamatergic VP neurons. Next, we explored the behavioral consequences of chemicogenetic inhibition or excitation of preproenkephalin-expressing VP neurons on associative learning of reward- or aversion-paired stimuli in autoshaping and inhibitory avoidance tasks, respectively. We reveal for the first time that preproenkephalin is expressed predominantly in GABAergic rather than glutamatergic VP neurons, and that excitation of these preproenkephalin-expressing VP neurons was sufficient to impair inhibitory avoidance learning. These findings indicate the necessity for inhibition of preproenkephalin-expressing VP neurons for avoidance learning, and suggest these neurons as a potential therapeutic target for psychiatric disorders associated with maladaptive aversive learning.

DOI： 10.1016/j.neuint.2019.02.011

Hiroyuki Mizoguchi, Kazuya Fukumoto, Gaku Sakamoto, Shijie Jin, Asako Toyama, Tian Wang, Akio Suzumura, Jun Sato

Behavioural Brain Research Vol. 359 page： 942 - 949 2019.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

Psychological stresses such as social loss and separation during childhood induce hardship, referred to as emotional pain. These experiences are well-documented risk factors for the development of physical pain in adulthood. However, the underlying neuronal mechanisms of this exacerbation of pain are largely unknown, and consequently there is no effective pharmacotherapy. In this study, we sought to determine whether infant maternal separation (MS) contributes to aggravation of neuropathic pain in adult mice. MS increased anxiety- and depression-like behavioral responses to adult stress. In MS animals, chronic constriction injury (CCI) heightened the sensory dimension of chronic pain relative to that of control mice. However, MS mice treated with fluoxetine for 4 weeks after MS did not exhibit augmentation of allodynia, and their emotional response was attenuated. Microglia were more abundant in the spinal cord in MS/CCI mice than in control/CCI mice. These results suggest that emotional impairment is related to augmentation of neuropathic pain, and that dysfunction of microglial activation contributes to heightened pain sensitivity.

DOI： 10.1016/j.bbr.2018.06.015

Nicotine and varenicline ameliorate changes in reward-based choice strategy and altered decision-making in methamphetamine-treated rats

Hiroyuki Mizoguchi, Tian Wang, Mizuki Kusaba, Kazuya Fukumoto, Kiyofumi Yamada

Behavioural Brain Research Vol. 359 page： 935 - 941 2019.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

Patients suffering from neuropsychiatric disorders such as substance use and addiction disorders show impaired decision-making, which may be associated with their psychiatric disorders. Previously, using a gambling test for rodents, we demonstrated that methamphetamine-dependent rats showed alterations in their decision-making strategy. In this study, we investigated the effect of nicotine on impaired decision-making strategy in rats which have been treated repeatedly with methamphetamine. Nicotine has previously been shown to have therapeutic effects on attentional and cognitive abnormalities in psychosis. Rats were administered methamphetamine subcutaneously (sc) at 4 mg/kg once a day, for 30 days, and their decision-making was then assessed with a rodent gambling task. We found that methamphetamine-treated rats preferred the high-risk/high-return actions, which is consistent with our previous findings. Methamphetamine-induced impairment of decision-making was reversed by daily nicotine treatment (0.3 mg/kg, sc). This effect was associated with the reduction of lose-shift behavior after negative reward prediction error. Repeated treatment with nicotine had no effects on arm-choice behavior in naïve rats. Varenicline, an α4β2-nicotinic acetylcholine receptor partial agonist, also ameliorated the altered decision-making in methamphetamine-treated rats. Our findings suggest that nicotine treatment is useful for ameliorating the altered decision-making caused by methamphetamine treatment, and that the α4β2-nicotinic acetylcholine receptor is a therapeutic target for poor decision-making.

DOI： 10.1016/j.bbr.2018.06.016

Physiological centers of decision-making: manipulation of neural activity in insular cortex by AAV Open Access

Mizoguchi Hiroyuki, Yamada Kiyofumi

Folia Pharmacologica Japonica Vol. 153 ( 5 ) page： 224 - 230 2019

Language：Japanese Publisher：The Japanese Pharmacological Society

Decision-making is a key activity process that influences many aspects of daily living and both mental and physical health. In general, healthy participants reveal rational choice, but patients with neuropsychiatric disorders reveal irrational and risky choice in decision-making. Addiction is one of typical diseases revealed risky decision-making, addicts select risky action and options that confer short-term rewards at the cost of long-term disadvantages. Thus, irrational and risky decision-making is recognized as a core problem in patients with neuropsychiatric disorders, and a better understanding of the mechanisms underlying altered decision-making would provide insights into potential therapeutic approaches for these diseases. However, the neural pathway and substrates underlying these deficits are particularly unknown. Recently, we found that insular cortex is one of key regions for risky decision-making in an animal model of methamphetamine addiction, by using the designer receptor exclusively activated by designer drug (DREADD) technology, and that GABAergic dysfunction in insular cortex is involved in evaluating the subjective value of reward and reward prediction error. These brain dysfunctions would be related to risk taking behavior in addiction. In this review, we introduced the possible neural pathway related to risky decision-making and behavioral changes in choice strategy using adeno associated virus (AAV).

DOI： 10.1254/fpj.153.224

Optimization of operant test for testing risky decision-making in mice

Mizoguchi Hiroyuki, Wang Tian, Saifullah Md. Ali Bin, Fukumoto Kazuya, Yamada Kiyofumi

Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. 92 ( 0 ) page： 1-P-023 - P-023 2019

Language：Japanese Publisher：Japanese Pharmacological Society

Decision making in complex and uncertain situations is a fundamental adaptive process resulting from the integration of several executive functions. Impaired decision-making is a symptomatic feature of a number of psychiatric disorders. In general, patients with psychiatric disorders show a propensity to prefer actions associated with large short-term gains but long-term losses preferentially to those associated with small but long-term gains. They are more likely to select risky options and show an altered temporal horizon of risks and benefits. Moreover, clinical studies report that dopamine therapy induce impaired decision-making in patients with dopaminergic dysfunction such as Parkinson's disease and Redox-less syndrome. Thus, to establish and optimize the animal model of impaired decision-making is important for development of new therapeutic strategy in these disorders.To clarify the underlying neurobiology of decision-making, we conducted a study in healthy mice by using a mouse gambling operant test based on uncertainty and conflicting choices. Mice chose the low-risk / low-reward option on the reward amount- and provability-dependent manner. Our findings suggest that healthy mice prefer risk-aversive choice in this operant test as dose man in Iowa gambling test.

DOI： 10.1254/jpssuppl.92.0_1-p-023

Behavioral characterization of APP knock-in mice model in touchscreen-based tests aiming early detection of Alzheimer's disease.

Saifullah MD. Ali Bin, Komine Okiru, Sobue Akira, Yamanaka Koji, Mizoguchi Hiroyuki

Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. 92 ( 0 ) page： 1-P-041 - P-041 2019

Language：Japanese Publisher：Japanese Pharmacological Society

Alzheimer's disease (AD) is a progressive disease characterized by loss of memory and other important mental functions. Accumulation of amyloid beta (Aβ) and fibrillary tangles are the main pathological hallmarks of this disease. Emerging data suggest that the disease process begins years before clinical diagnostic confirmation; thus, methods to improve early detection would provide opportunities for early intervention to delay progressive cognitive decline and disease onset. In our research we assessed the cognitive abilities of APPNL-G-F/NL-G-F knock-in (APP-KI) mice with a touch screen-based automated test battery and water maze test. These tests are mainly dependent on the brain regions that are prone to Aβ accumulation at the earliest stages of the disease. We subjected male 6- and 11-months old APP-KI mice in water maze test where only older mice showed significantly worsened behavior than wild-type mice. However, using touchscreen based behavioral test it was possible to detect cognitive impairment in APP-KI mice at an early (4 months) stage while classical behavioral tests shows comparable results between wild-type and disease model mice.

DOI： 10.1254/jpssuppl.92.0_1-p-041

Basic researches to support the symbiotic society with dementia

Yanai Shuichi, Takase Kenkichi, Yamaguchi Tetsuo, Uchida Sae, Izuo Naotaka, Mizoguchi Hiroyuki, Inagaki Hiroki, Kusaka Nahoko

The Proceedings of the Annual Convention of the Japanese Psychological Association Vol. 82 ( 0 ) page： SS-029 - SS-029 2018.9

AN OPERANT TASK FOR TESTING RISKY DECISION-MAKING IN MICE

Wang T., Fukumoto K., Mizoguchi H., Yamada K.

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Vol. 42 page： 48A - 48A 2018.8

ギャンブル障害の現状と薬剤師の役割 Reviewed

溝口博之

医薬ジャーナル Vol. 54(4) page： 1037 - 1040 2018

GAP junction/hemichannel blockers ameliorate the disease progression of FTLD/ALS mice

Takeuchi H, Mizoguchi H, Tanaka F, Suzumura A

JOURNAL OF THE NEUROLOGICAL SCIENCES Vol. 381 page： 714 - 715 2017.10

創薬標的としてのnAChR：精神疾患患者で喫煙率が高い理由！？

溝口博之

ファルマシア Vol. 53 ( 9 ) page： 923 - 923 2017

Language：Japanese Publisher：公益社団法人日本薬学会

前頭前皮質は高次の学習記憶を司る脳部位であり，ニコチン性アセチルコリン受容体(nAChR)を介したアセチルコリン神経の投射・支配を受けている．統合失調症などの精神疾患患者は，前頭前皮質の機能が低下(hypofrontality)しており，また，喫煙率が高い傾向がある．最近，ゲノムワイド関連解析により，nAChRのα5サブユニットを司るヒトCHRNA5遺伝子に一塩基多型(SNP)が存在することが分かり，この変異が喫煙や統合失調症のリスクを高める可能性が報告された．基礎研究においても，マウスのα5サブユニット遺伝子を欠損させると，前頭前皮質の形態学的変化や行動に異常が生じることが報告されているが，ヒト遺伝子多型が，細胞活性あるいは神経回路にどのような影響をもたらすのか，さらには統合失調症患者で観察されるような行動障害や，hypofrontalityを引き起こすかは不明である． 本稿では，ヒトα5サブユニット変異体(α5SNP)を発現するマウスを用いて，α5SNPがもたらす皮質機能障害について検討したKoukouliらの研究を紹介する． なお，本稿は下記の文献に基づいて，その研究成果を紹介するものである. 1) Tobacco and Genetics Consortium., Nat. Genet., 42, 441–447(2010). 2) Schizophrenia Working Group of the Psychiatric Genomics Consortium., Nature, 511, 421–427(2014). 3) Proulx E. et al., Cell. Mol. Life Sci., 71, 1225-1244(2014). 4) Koukouli F. et al., Nat. Med., 23, 347–354(2017).

DOI： 10.14894/faruawpsj.53.9_923

Hypothalamic peptidergic neurons regulates sleep/wakefulness and memory

Izawa, S; Inoue, R; Mukai, Y; Terao, A; Chowdhury, S; Mizoguchi, H; Yamanaka, A

JOURNAL OF SLEEP RESEARCH Vol. 25 page： 115 - 116 2016.9

Disrupted axon-glia interactions at the paranode in myelinated nerves cause axonal degeneration and neuronal cell death in the aged Caspr mutant mouse shambling

Takagishi, Y; Katanosaka, K; Mizoguchi, H; Murata, Y

NEUROBIOLOGY OF AGING Vol. 43 page： 34 - 46 2016.7

Language：English Publisher：Neurobiology of Aging

Emerging evidence suggests that axonal degeneration is a disease mechanism in various neurodegenerative diseases and that the paranodes at the nodes of Ranvier may be the initial site of pathogenesis. We investigated the pathophysiology of the disease process in the central and peripheral nervous systems of a Caspr mutant mouse, shambling (shm), which is affected by disrupted paranodal structures and impaired nerve conduction of myelinated nerves. The shm mice manifest a progressive neurological phenotype as mice age. We found extensive axonal degeneration and a loss of neurons in the central nervous system and peripheral nervous system in aged shm mice. Axonal alteration of myelinated nerves was defined by abnormal distribution and expression of neurofilaments and derangements in the status of phosphorylated and non/de-phosphorylated neurofilaments. Autophagy-related structures were also accumulated in degenerated axons and neurons. In conclusion, our results suggest that disrupted axon-glia interactions at the paranode cause the cytoskeletal alteration in myelinated axons leading to neuronal cell death, and the process involves detrimental autophagy and aging as factors that promote the pathogenesis.

DOI： 10.1016/j.neurobiolaging.2016.03.020

Usefulness of DREADD technology combined with adeno-associated virus vector in behavioral pharmacology

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments Reviewed

Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, Nakashima K, Ochiai H, Takeuchi S, Kiyota A, Fukumoto K, Iwama S, Takagishi Y, Hayashi Y, Arima H, Komatsu Y, Murata Y, Oiso Y

Journal of the American Society of Nephrology Vol. 27 ( 3 ) page： 766 - 80 2016.3

Mizoguchi, H; Yamanaka, A; Yamada, K

JOURNAL OF PHARMACOLOGICAL SCIENCES Vol. 130 ( 3 ) page： S73 - S73 2016.3

Insular neural system controls decision-making in healthy and methamphetamine-treated rats Reviewed

Hiroyuki Mizoguchi, Kentaro Katahira, Ayumu Inutsuka, Kazuya Fukumoto, Akihiro Nakamura, Tian Wang, Taku Nagai, Jun Sato, Makoto Sawada, Hideki Ohira, Akihiro Yamanaka, Kiyofumi Yamada

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 112 ( 29 ) page： E3930 - 9 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.

DOI： 10.1073/pnas.1418014112