1,266 research outputs found

    Chemogenetic attenuation of cortical seizures in nonhuman primates

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    「てんかん」の発生を時間的・空間的にピンポイントで抑える画期的な治療法を開発 --世界で初めてサルでの有効性を実証、臨床応用に向け大きく前進--. 京都大学プレスリリース. 2023-03-01.Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool—designer receptors exclusively activated by designer drugs (DREADDs)—for treating focal seizure in a nonhuman primate model. Acute infusion of the GABAA receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model

    Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

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    Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents canbe induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreasedstriatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic systemin the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2Rabnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) invivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anteriorcingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, ahigh affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation ofdopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC ofoffspring, similar to the neuronal pathology reported in patients with schizophrenia

    Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

    No full text
    Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents canbe induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreasedstriatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic systemin the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2Rabnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) invivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anteriorcingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, ahigh affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation ofdopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC ofoffspring, similar to the neuronal pathology reported in patients with schizophrenia

    Neural network of superiority illusion predicts the level of dopamine in striatum

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    In evaluating the personality attributes and performance of the self, people are inclined to view themselves superior to others, a phenomenon known as superiority illusion (SI). This illusive outlook pervades people’s thoughts, creating hope for the future and promoting mental health. Although a specific cortico-striatal functional connectivity (FC) under dopaminergic modulation was previously shown to be implicated in SI, the underlying whole-brain mechanisms have remained unclarified. Herein, to reveal the neural network subserving individual’s SI, we conducted a data-driven, machine-learning investigation to explore the resting-state FC network across the whole brain. Using the locally-acquired resting-state functional magnetic resonance imaging data (n = 123), we identified a set of 15 FCs most informative in classifying individuals with higher-versus lower-than-average levels of SI in evaluating positive trait words (area under the curve [AUC] = 0.81). Among the 15 FCs, the contribution level to the classification was 11% by the previously-highlighted cortico-striatal FC alone, but 60% by the encompassing cortico-limbico-striatal network cluster. A newly-identified, cortico-thalamic FC and another FC cluster also demonstrated substantial contribution. The classification accuracy was generalized into an independent cohort (n = 36; AUC = 0.73). Importantly, using the same set of 15 FCs, we achieved prediction on an individual’s level of striatal dopamine D2 receptor availability (Pearson correlation, r = 0.46, P = 0.005). This is the first successful identification of the whole-brain neural network that simultaneously predicts the behavioral manifestation and molecular underpinning of an essential psychological process that promotes well-being and mental health.Significance Statement Superiority illusion (SI) is a basic self-referential framework that pervades people’s thoughts and promotes well-being and mental health. An aberrant form of SI has been reported in psychiatric conditions such as depression. Our hypothesis-free, data-driven investigation revealed the spatially-distributed neural network that for the first time achieved prediction on an individual’s levels of SI and the striatal dopaminergic transmission simultaneously. In principle, this multiple-biological-layer framework can be applicable to any behavioral trait to establish a link with its underlying neural network and neurochemical properties, which could quantitatively present the relation of its aberrant form with the pathophysiology of neuropsychiatric disorders. Future clinical research may aid in deriving a diagnostic biomarker for examining the related behavioral and neurochemical characteristics within individuals

    Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

    No full text
    Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents canbe induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreasedstriatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic systemin the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2Rabnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) invivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anteriorcingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, ahigh affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation ofdopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC ofoffspring, similar to the neuronal pathology reported in patients with schizophrenia

    Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy

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    Intracellular accumulation of filamentous tau aggregates with progressive neuronalloss is a common characteristic of tauopathies. Although the neurodegenerativemechanism of tau-associatedpathology remains unclear, molecular elements capableof degrading and/or sequestering neurotoxic tau species may suppress neurodegenerativeprogression. Here, we provide evidence that p62/SQSTM1, a ubiquitinatedcargo receptor for selective autophagy, acts protectively against neuronal death andneuroinflammation provoked by abnormal tau accumulation. P301S mutant tau transgenicmice (line PS19) exhibited accumulation of neurofibrillary tangles with localizationof p62 mostly in the brainstem, but neuronal loss with few neurofibrillary tanglesin the hippocampus. In the hippocampus of PS19 mice, the p62 level was lower comparedto the brainstem, and punctate accumulation of phosphorylated tau unaccompaniedby co-localizationof p62 was observed. In PS19 mice deficient in p62 (PS19/p62-KO),increased accumulation of phosphorylated tau, acceleration of neuronalloss, and exacerbation of neuroinflammation were observed in the hippocampus ascompared with PS19 mice. In addition, increase of abnormal tau and neuroinflammationwere observed in the brainstem of PS19/p62-KO.Immunostaining and dot-blotanalysis with an antibody selectively recognizing tau dimers and higher-orderoligomersrevealed that oligomeric tau species in PS19/p62-KOmice were significantly accumulatedas compared to PS19 mice, suggesting the requirement of p62 to eliminatedisease-relatedoligomeric tau species. Our findings indicated that p62 exerts neuroprotectionagainst tau pathologies by eliminating neurotoxic tau species, suggestingthat the manipulative p62 and selective autophagy may provide an intrinsic therapyfor the treatment of tauopathy.

    PET-based classification of corticobasal syndrome.

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    Corticobasal degeneration (CBD) is the most common neuropathological substrate for clinically diagnosed corticobasal syndrome (CBS), while identifying CBD pathology in living individuals has been challenging. This study aimed to examine the capability of positron emission tomography (PET) to detect CBD-type tau depositions and neuropathological classification of CBS

    Chemogenetic suppression of pharmacologically induced frontal lobe epilepsy in a macaque monkey

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    Rationale: Medical treatments and surgical lesions of epilepsy sometimes lead to unexpected side effects by affecting the surrounding normal tissues, and therefore, a more focused and on-demand approach is desirable. DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) is a recently developed “chemogenetics” tool that combines genetically introduced functional proteins (artificial receptors) and pharmacologically introduced chemicals (actuator drugs), offering focused and on-demand control of neuronal activities. We have recently developed a potent and selective actuator drug, Deschloroclozapine (DCZ), whose radiolabeled form can be used as a PET tracer to monitor DREADD expression in vivo. This study examined the utility of DREADDs on epilepsy treatment using a pharmacological model of epilepsy in a non-human primate (NHP).Methods: We injected virus vectors carrying hM4Di, an inhibitory DREADD gene (AAV2.1-hSyn-FLAG-hM4Di-IRES-AcGFP) to the putative hand/arm-region of the motor cortex in a cynomolgus macaque. Five weeks after the vector injection, hM4Di expression was confirmed using PET imaging with [11C]DCZ. We performed additional surgery to open a cranial window and placed an epidural electrocorticogram (ECoG) electrode array and a chronic chamber to approach the target region. Acute injections of bicuculline methiodide (6~12 µg) into the hM4Di-expressing region were conducted to start artificial epilepsy. DCZ (100~200 µg/kg) or control vehicle (2% DMSO in saline) were injected intramuscularly while we monitored the ECoG and video for seizure and body responses. Nissl and anti-GFP antibody staining were performed after the animal was euthanized, and cardially fixated.Results: Bicuculline injection caused paroxysmal cortical discharges with twitching and stiffening of the right arm. Recurrent cortical discharges (status epilepticus) spreading over a wider area of the cortex soon followed coinciding with hemi- and whole-body convulsions. Intramuscular injection of DCZ (100~200 µg/kg), but not the control vehicle (2% DMSO in saline), attenuated the body convulsions and spreading of recurrent seizures. Post-mortem histology confirmed the preserved cell condition of the DCZ-expressing cortex, but with some reduction of the layer 5 large pyramidal cells in the bicuculline-injected subregion.Conclusions: Although further study is needed, these preliminary results are the first to demonstrate in an NHP model that epilepsy can be suppressed using the DREADD system, suggesting its promising utility for future clinical applications.AES 202
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