Haichang Luo , Allison Anderson , Ikuo Masuho , Ezequiel Marron Fernandez de Velasco , Lutz Birnbaumer , Kirill A. Martemyanov , Kevin Wickman
{"title":"Receptor-dependent influence of R7 RGS proteins on neuronal GIRK channel signaling dynamics","authors":"Haichang Luo , Allison Anderson , Ikuo Masuho , Ezequiel Marron Fernandez de Velasco , Lutz Birnbaumer , Kirill A. Martemyanov , Kevin Wickman","doi":"10.1016/j.pneurobio.2024.102686","DOIUrl":"10.1016/j.pneurobio.2024.102686","url":null,"abstract":"<div><div>Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inwardly rectifying K<sup>+</sup> (GIRK or Kir3) channels mediate postsynaptic inhibition evoked by G protein-coupled receptors (GPCRs) that signal via inhibitory G proteins. GIRK-dependent signaling is modulated by Regulator of G protein Signaling proteins RGS6 and RGS7, but their selectivity for distinct GPCR-GIRK signaling pathways in defined neurons is unclear. We compared how RGS6 and RGS7 impact GIRK channel regulation by the GABA<sub>B</sub> receptor (GABA<sub>B</sub>R), 5HT<sub>1A</sub> receptor (5HT<sub>1A</sub>R), and A<sub>1</sub> adenosine receptor (A<sub>1</sub>R) in hippocampal neurons. Our data show that RGS6 and RGS7 make non-redundant contributions to GABA<sub>B</sub>R- and 5HT<sub>1A</sub>R-GIRK signaling and compartmentalization and suggest that GPCR-G protein preferences and the substrate bias of RGS proteins, as well as receptor-dependent differences in Gα<sub>o</sub> engagement and effector access, shape GPCR-GIRK signaling dynamics in hippocampal neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"243 ","pages":"Article 102686"},"PeriodicalIF":6.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aníbal Sánchez de la Torre , Sara Ezquerro-Herce , Alba Huerga-Gómez , Ester Sánchez-Martín , Juan Carlos Chara , Carlos Matute , Krisztina Monory , Susana Mato , Beat Lutz , Manuel Guzmán , Tania Aguado , Javier Palazuelos
{"title":"CB1 receptors in NG2 cells mediate cannabinoid-evoked functional myelin regeneration","authors":"Aníbal Sánchez de la Torre , Sara Ezquerro-Herce , Alba Huerga-Gómez , Ester Sánchez-Martín , Juan Carlos Chara , Carlos Matute , Krisztina Monory , Susana Mato , Beat Lutz , Manuel Guzmán , Tania Aguado , Javier Palazuelos","doi":"10.1016/j.pneurobio.2024.102683","DOIUrl":"10.1016/j.pneurobio.2024.102683","url":null,"abstract":"<div><div>Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells. By using conditional genetic mouse models, here we found that cannabinoid CB<sub>1</sub> receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB<sub>1</sub> receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway. Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not <em>Ng2</em>-CB<sub>1</sub>-deficient mice. Overall, this study identifies CB<sub>1</sub> receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"243 ","pages":"Article 102683"},"PeriodicalIF":6.7,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Ramírez-Sánchez, A. Mondragón-García, J. Garduño, F. Hernández-Vázquez, S. Ortega-Tinoco, S. Hernández-López
{"title":"Opposing effects of nicotine on hypothalamic arcuate nucleus POMC and NPY neurons","authors":"E. Ramírez-Sánchez, A. Mondragón-García, J. Garduño, F. Hernández-Vázquez, S. Ortega-Tinoco, S. Hernández-López","doi":"10.1016/j.pneurobio.2024.102682","DOIUrl":"10.1016/j.pneurobio.2024.102682","url":null,"abstract":"<div><div>The hypothalamic arcuate nucleus (ARC) contains two main populations of neurons essential for energy homeostasis: neuropeptide Y (NPY) neurons, which are orexigenic and stimulate food intake, and proopiomelanocortin (POMC) neurons, which have an anorexigenic effect. Located near the blood-brain barrier, ARC neurons sense blood-borne signals such as leptin, insulin, and glucose. Exogenous substances, such as nicotine, can also alter ARC neuron activity and energy balance. Nicotine, an addictive drug used worldwide, inhibits appetite, and reduces body weight, although its mechanisms in regulating ARC neurons are not well understood. Using electrophysiological techniques in brain slices, we investigated the effects of nicotine on POMC and NPY neurons at physiological glucose concentrations. We found that nicotine increased the firing rate of POMC and inhibited NPY neurons. Additionally, nicotine-enhanced glutamatergic inputs to POMC cells and GABAergic inputs to NPY neurons, mediated by α7 and α4β2 nicotinic acetylcholine receptors (nAChRs), respectively. These findings can contribute to the understanding of the anorexigenic effects of nicotine in smokers.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102682"},"PeriodicalIF":6.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amelia Pizzella , Eduardo Penna , Yan Liu , Natalia Abate , Enza Lacivita , Marcello Leopoldo , Carla Perrone-Capano , Marianna Crispino , Michel Baudry , Xiaoning Bi
{"title":"Alterations of synaptic plasticity in Angelman syndrome model mice are rescued by 5-HT7R stimulation","authors":"Amelia Pizzella , Eduardo Penna , Yan Liu , Natalia Abate , Enza Lacivita , Marcello Leopoldo , Carla Perrone-Capano , Marianna Crispino , Michel Baudry , Xiaoning Bi","doi":"10.1016/j.pneurobio.2024.102684","DOIUrl":"10.1016/j.pneurobio.2024.102684","url":null,"abstract":"<div><div>Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectrum Disorders (ASD). It is known that stimulation of the serotonin receptor 7 (5-HT7R) can rescue some of the behavioral and neuroplasticity dysfunctions in animal models of Fragile X and Rett syndrome, two pathologies associated with ASD. In view of these observations, we hypothesised that alterations of 5-HT7R signalling might also be involved in AS. To test this hypothesis, we stimulated 5-HT7R with the selective agonist LP-211 to investigate its possible beneficial effects on synaptic dysfunctions and altered behavior in the AS mice model. In mutant mice, we observed impairment of the synaptic machinery of protein synthesis, which was reversed by 5-HT7R activation. Moreover, stimulation of 5-HT7R was able to: i) enhance dendritic spine density in hippocampal neurons, which was reduced in AS mice; ii) restore impaired long-term potentiation (LTP) in hippocampal slices of the AS mice; iii) improve cognitive performance of the mutant animals subjected to the fear conditioning paradigm. Altogether, our results, showing beneficial effects of 5-HT7R stimulation in restoring molecular and cognitive deficits associated with AS, suggest that targeting 5-HT7R could be a promising therapeutic approach for the pathology.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102684"},"PeriodicalIF":6.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Konstantin Yenkoyan , Artem Grigoryan , Viera Kutna , Susan Shorter , Valerie B. O’Leary , Reza Asadollahi , Saak V. Ovsepian
{"title":"Cerebellar impairments in genetic models of autism spectrum disorders: A neurobiological perspective","authors":"Konstantin Yenkoyan , Artem Grigoryan , Viera Kutna , Susan Shorter , Valerie B. O’Leary , Reza Asadollahi , Saak V. Ovsepian","doi":"10.1016/j.pneurobio.2024.102685","DOIUrl":"10.1016/j.pneurobio.2024.102685","url":null,"abstract":"<div><div>Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordinates a range of motor, affective and cognitive processes. Despite well-described circuits and integrative mechanisms, specific changes that underlie cerebellar impairments in ASD remain elusive. Studies in experimental animals have been critical in uncovering molecular pathology and neuro-behavioural correlates, providing a model for investigating complex disease conditions. Herein, we review commonalities and differences of the most extensively characterised genetic lines of ASD with reference to the cerebellum. We revisit structural, functional, and molecular alterations which may contribute to neurobehavioral phenotypes. The cross-model analysis of this study provides an integrated outlook on the role of cerebellar alterations in pathobiology of ASD that may benefit future translational research and development of therapies.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102685"},"PeriodicalIF":6.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Myung Ji Kwak , Su Jeong Choi , Wen Ting Cai , Bo Ram Cho , Joonyeup Han , Jong Woo Park , Lars Björn Riecken , Helen Morrison , Se-Young Choi , Wha Young Kim , Jeong-Hoon Kim
{"title":"Manipulation of radixin phosphorylation in the nucleus accumbens core modulates risky choice behavior","authors":"Myung Ji Kwak , Su Jeong Choi , Wen Ting Cai , Bo Ram Cho , Joonyeup Han , Jong Woo Park , Lars Björn Riecken , Helen Morrison , Se-Young Choi , Wha Young Kim , Jeong-Hoon Kim","doi":"10.1016/j.pneurobio.2024.102681","DOIUrl":"10.1016/j.pneurobio.2024.102681","url":null,"abstract":"<div><div>Ezrin-Radixin-Moesin (ERM) proteins are actin-binding proteins that contribute to morphological changes in dendritic spines. Despite their significant role in regulating spine structure, the role of ERM proteins in the nucleus accumbnes (NAcc) is not well known, especially in in the context of risk-reward decision-making. Here, we measured the relationship between synaptic excitation and inhibition (E/I ratio) from medium spiny neurons in the NAcc core obtained in the rat after a rat gambling task (rGT). Then, after surgery of a phosphomimetic pseudo-active mutant form of radixin (Rdx-T564D) in the NAcc core, we examined its role in synaptic plasticity and the accompanying risk-choice behavior in rGT. We found that basal E/I ratio in the NAcc core was higher in risk-averse rats than risk-seeking rats. However, it was significantly reduced in risk-averse rats similar to that in risk-seeking rats in the presence of Rdx-T564D in the NAcc core. Furthermore, the head sizes of spines were shifted in risk-averse rats expressing Rdx-T564D in the NAcc core, similar to those observed in risk-seeking rats. The effects of Rdx-T564D in risk-averse rats were again manifested as behavioral changes, with reduced selection of optimal choices and increased selection of disadvantageous ones. In this study, we demonstrated that manipulation of radixin phosphorylation status in the NAcc core can alter glutamatergic synaptic transmission and spine structure at this site, as well as risk choice behaviors in the rGT. These novel findings illustrate that radixin in the NAcc core plays a significant role in determining risk preference during the rGT.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102681"},"PeriodicalIF":6.7,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2ALS phenotypes in Drosophila melanogaster","authors":"Ranchana Yeewa , Apiwat Sangphukieo , Phatcharida Jantaree , Wasinee Wongkummool , Titaree Yamsri , Siwat Poompouang , Parunya Chaiyawat , Luca Lo Piccolo , Salinee Jantrapirom","doi":"10.1016/j.pneurobio.2024.102674","DOIUrl":"10.1016/j.pneurobio.2024.102674","url":null,"abstract":"<div><div>Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism <em>Drosophila melanogaster</em> demonstrated that elevated levels of <em>Drosophila</em> ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2<sup>ALS</sup> pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in <em>Drosophila</em> UBQLN2<sup>ALS</sup> model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2<sup>ALS</sup> and other ER stress-related conditions.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102674"},"PeriodicalIF":6.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuronal threshold functions: Determining symptom onset in neurological disorders","authors":"Luc Jordi , Ole Isacson","doi":"10.1016/j.pneurobio.2024.102673","DOIUrl":"10.1016/j.pneurobio.2024.102673","url":null,"abstract":"<div><div>Synaptic networks determine brain function. Highly complex interconnected brain synaptic networks provide output even under fluctuating or pathological conditions. Relevant to the treatment of brain disorders, understanding the limitations of such functional networks becomes paramount. Here we use the example of Parkinson’s Disease (PD) as a system disorder, with PD symptomatology emerging only when the functional reserves of neurons, and their interconnected networks, are unable to facilitate effective compensatory mechanisms. We have denoted this the “threshold theory” to account for how PD symptoms develop in sequence. In this perspective, threshold functions are delineated in a quantitative, synaptic, and cellular network context. This provides a framework to discuss the development of specific symptoms. PD includes dysfunction and degeneration in many organ systems and both peripheral and central nervous system involvement. The threshold theory accounts for and explains the reasons why parallel gradually emerging pathologies in brain and peripheral systems generate specific symptoms only when functional thresholds are crossed, like tipping points. New and mounting evidence demonstrate that PD and related neurodegenerative diseases are multisystem disorders, which transcends the traditional brain-centric paradigm. We believe that representation of threshold functions will be helpful to develop new medicines and interventions that are specific for both pre- and post-symptomatic periods of neurodegenerative disorders.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102673"},"PeriodicalIF":6.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael A. Hahn , Janna D. Lendner , Matthias Anwander , Katarina S.J. Slama , Robert T. Knight , Jack J. Lin , Randolph F. Helfrich
{"title":"A tradeoff between efficiency and robustness in the hippocampal-neocortical memory network during human and rodent sleep","authors":"Michael A. Hahn , Janna D. Lendner , Matthias Anwander , Katarina S.J. Slama , Robert T. Knight , Jack J. Lin , Randolph F. Helfrich","doi":"10.1016/j.pneurobio.2024.102672","DOIUrl":"10.1016/j.pneurobio.2024.102672","url":null,"abstract":"<div><div>Sleep constitutes a brain state of disengagement from the external world that supports memory consolidation and restores cognitive resources. The precise mechanisms how sleep and its varied stages support information processing remain largely unknown. Synaptic scaling models imply that daytime learning accumulates neural information, which is then consolidated and downregulated during sleep. Currently, there is a lack of in-vivo data from humans and rodents that elucidate if, and how, sleep renormalizes information processing capacities. From an information-theoretical perspective, a consolidation process should entail a reduction in neural pattern variability over the course of a night. Here, in a cross-species intracranial study, we identify a tradeoff in the neural population code during sleep where information coding efficiency is higher in the neocortex than in hippocampal archicortex in humans than in rodents as well as during wakefulness compared to sleep. Critically, non-REM sleep selectively reduces information coding efficiency through pattern repetition in the neocortex in both species, indicating a transition to a more robust information coding regime. Conversely, the coding regime in the hippocampus remained consistent from wakefulness to non-REM sleep. These findings suggest that new information could be imprinted to the long-term mnemonic storage in the neocortex through pattern repetition during sleep. Lastly, our results show that task engagement increased coding efficiency, while medically-induced unconsciousness disrupted the population code. In sum, these findings suggest that neural pattern variability could constitute a fundamental principle underlying cognitive engagement and memory formation, while pattern repetition reflects robust coding, possibly underlying the consolidation process.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"242 ","pages":"Article 102672"},"PeriodicalIF":6.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mario O. Caracci , Héctor Pizarro , Carlos Alarcón-Godoy , Luz M. Fuentealba , Pamela Farfán , Raffaella De Pace , Natacha Santibañez , Viviana A. Cavieres , Tammy P. Pástor , Juan S. Bonifacino , Gonzalo A. Mardones , María-Paz Marzolo
{"title":"Corrigendum to “The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for hereditary spastic paraplegia” [Progr. Neurobiol. 234(2024)102575]","authors":"Mario O. Caracci , Héctor Pizarro , Carlos Alarcón-Godoy , Luz M. Fuentealba , Pamela Farfán , Raffaella De Pace , Natacha Santibañez , Viviana A. Cavieres , Tammy P. Pástor , Juan S. Bonifacino , Gonzalo A. Mardones , María-Paz Marzolo","doi":"10.1016/j.pneurobio.2024.102662","DOIUrl":"10.1016/j.pneurobio.2024.102662","url":null,"abstract":"","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"241 ","pages":"Article 102662"},"PeriodicalIF":6.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}