Neuropsychopharmacology最新文献

{"title":"VTA-ACC dopaminergic circuit mediates trait anxiety-related observational learning of social avoidance in male mice","authors":"Ming Li, Kun Ren, Chi Cui, Yulong Shi, Jie Lei, Tongxia Li, Jian Yang, Xiang Peng, Xueke Yang, Yibo Yao, Gangan Luo, Junsong Du, Sitong Chen, Pei Zhang, Bo Tian","doi":"10.1038/s41386-025-02139-7","DOIUrl":"10.1038/s41386-025-02139-7","url":null,"abstract":"Social animals encounter both environmental and social stress, yet the mechanisms by which individuals with different levels of trait anxiety cope with these stressors, as well as the neurobiological links between trait anxiety and social cognition, remain incompletely understood. Here, male mice are classified into high-trait anxiety (HTA) and low-trait anxiety (LTA) groups based on their anxiety responses to elevated platform exposure in the open field test. Under observational learning-based vicarious social defeat stress (VSDS), HTA mice exhibit less social avoidance behavior toward CD1 aggressors than LTA mice. Fiber photometry reveals that HTA mice display higher activity of ventral tegmental area (VTA) dopaminergic (VTADA) neurons during environmental stress, while LTA mice exhibit greater VTADA neurons activity under social stress. Viral tracing identifies the connectivity of VTADA neurons and anterior cingulate cortex (ACC). Optogenetic and chemogenetic manipulations demonstrate that VTA-ACC dopaminergic circuit is necessary and sufficient for VSDS-induced social avoidance behavior in HTA and LTA mice. RNA-sequencing suggested that VTA neuroinflammatory signaling may be a key factor contributing to the difference between HTA and LTA mice. Thus, this study reveals a neural circuit mechanism for trait anxiety-related observational learning of social avoidance behavior in male mice, and provides a molecular mechanism in shaping trait anxiety.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1364-1375"},"PeriodicalIF":6.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The neural and psychophysiological effects of cannabidiol in youth with alcohol use disorder: A randomized controlled clinical trial","authors":"Anna E. Kirkland, Brittney D. Browning, Lindsay R. Meredith, Elizabeth Robertson, Cori Herring, Rachel L. Tomko, Kevin M. Gray, Lindsay M. Squeglia","doi":"10.1038/s41386-025-02141-z","DOIUrl":"10.1038/s41386-025-02141-z","url":null,"abstract":"Novel treatment evaluation for youth with alcohol use disorder (AUD) is needed. Cannabidiol (CBD), a constituent of the Cannabis sativa plant, may be a promising candidate pharmacotherapy due to its potential therapeutic properties and preclinical research suggesting it decreases alcohol use. Due to limited data in humans, rigorous screening of the acute neural, psychophysiological, and alcohol-related effects of CBD is indicated to assess its viability as a potential treatment for youth AUD. Using a within-subjects, randomized, double-blind, placebo-controlled design, we tested acute multi-modal effects of CBD (600 mg) in non-treatment seeking youth with AUD (N = 36; ages 17–22; 69% female). Outcomes included (1) glutamate+glutamine (Glx) and GABA levels in the anterior cingulate cortex measured with proton magnetic resonance spectroscopy; (2) whole-brain and a priori region-of-interest neural alcohol cue-reactivity measured with functional MRI; (3) psychophysiological response to alcohol olfactory cues measured by self-reported acute alcohol craving, heart rate variability, and skin conductance; and (4) alcohol use. No CBD-associated adverse events were observed. There were no effects of acute CBD administration, compared to placebo, on any outcomes of interest. This is the first adequately powered medication screening study for the use of CBD in youth with AUD. We did not detect significant effects of CBD on neurometabolic, neurobehavioral, psychophysiological, or alcohol use outcomes in this sample. Future studies may benefit from chronic administration to better understand substance-related effects. Clinicaltrials.gov NCT05317546 https://clinicaltrials.gov/study/NCT05317546","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1482-1492"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02141-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prefrontal corticotropin-releasing factor promotes resilience to social stress","authors":"Ya-Tao Wang, Yong Li, Meng-Yun Li, Yue-Ming Zhang, Yue Wang, Qi-Qi Xu, Rong-Yu Liu, Xin-Ya Qin, Qing-Hong Shan, Yu Wang, Jiang-Ning Zhou, Peng Chen","doi":"10.1038/s41386-025-02148-6","DOIUrl":"10.1038/s41386-025-02148-6","url":null,"abstract":"Variations in individual coping styles have been linked to either resilience or vulnerability towards stress, thereby influencing the probability of developing stress-related disorders. The involvement of corticotropin-releasing factor (CRF) neurons within the medial prefrontal cortex (mPFC) plays a crucial role in modulating behavioral responses to stressful situations. In this study utilizing a mouse model of social defeat stress (SDS), we demonstrate how coordinated activation and localized release of CRF within the mPFC contribute to promoting adaptive responses under stressful conditions leading to enhanced resilience against subsequent challenges. Specifically, during SDS exposure, heightened activity levels were observed among mPFC CRF neurons coincide with increased local release triggered by active exploration and defensive behaviors, while decreased responses were detected upon exposure to aggression. Interestingly, the CRF neural activity and local release responding to coping behaviors throughout chronic social defeat stress (CSDS) differed between susceptible and resilient mice. Furthermore, activation of CRF receptor 1 (CRFR1) signaling in the mPFC enhanced active coping behaviors and conferred resilience to CSDS, while inhibition of CRF system promoted passive coping behaviors and induced susceptibility to sub-threshold SDS. Additionally, inhibition of CRFR1 in the mPFC nullified the pro-resilience effect elicited by activation of CRF neurons during CSDS. The collective findings provide evidence supporting the crucial role of local endogenous CRF derived from mPFC CRF neurons in maintaining resilience through active coping styles when confronted with social stress. Moreover, these results suggest that targeting the mPFC CRF system could hold promise as a therapeutic approach for managing stress-related disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1620-1630"},"PeriodicalIF":6.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sitagliptin as a therapeutic approach for social anxiety disorder: the role of DPP4 and NPY in modulating social fear and comorbid depressive-like behavior in mice","authors":"Iulia Zoicas, Christiane Mühle, Stephan von Hörsten, Anne-Christine Plank, Johannes Kornhuber","doi":"10.1038/s41386-025-02146-8","DOIUrl":"10.1038/s41386-025-02146-8","url":null,"abstract":"We have previously shown that neuropeptide Y (NPY) reduces social fear in an animal model that closely mimics the key behavioral symptoms of social anxiety disorder (SAD). Since NPY cannot yet be routinely administered to patients, we investigated the effects of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor approved for the treatment of type 2 diabetes mellitus, on social fear and comorbid depression in mice. In addition to its well-known effects on glucose metabolism, sitagliptin also prevents the degradation of NPY, thereby increasing its concentration in the blood and the brain. We show that sitagliptin administration via drinking water (50 and 100 mg/kg/day, for 4 weeks) not only reduced social fear but also prevented the onset of comorbid depressive-like behavior in outbred CD1 mice. A similar phenotype was observed in homozygous DPP4-deficient mice, emphasizing the role of DPP4 in regulating these behaviors. However, in NPY-deficient mice, sitagliptin showed reduced efficacy, suggesting that NPY plays an important role in mediating the effects of sitagliptin on social fear and comorbid depression. These findings have important clinical implications, indicating that early intervention with sitagliptin could be an effective strategy for treating SAD, alleviating both core symptoms and reducing the risk of developing comorbid mood disorders that often complicate treatment outcomes.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1724-1731"},"PeriodicalIF":6.6,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02146-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Merkel cell stimulation in fear and sensory signaling","authors":"Austin C. Korgan, Rodrigo Orso, Isabelle J. Sibley, Kathryn E. Prendergast, Tanja Jovanovic, Tracy L. Bale","doi":"10.1038/s41386-025-02144-w","DOIUrl":"10.1038/s41386-025-02144-w","url":null,"abstract":"Stress and traumatic experiences have significant and lasting effects on sensory systems. We recently identified unique expression of proteins associated with epidermal skin cells (keratinocytes) and mechanosensory Merkel cells (MC) in circulating extracellular vesicles from adult women who had experienced sexual trauma specifically during adolescence, biologically linking trauma exposure with a specific neuron-like skin cell. Here, we aimed to develop and validate a preclinical mouse model utilizing chemogenetic (DREADD Gq) activation of a population of MC. Using a reporter line, we confirmed the expected pattern of the Krt14 Cre in specific MC skin areas and that these tissues expressed relevant MC marker genes similarly between male and female mice. Chemogenetic stimulation of MC produced robust neuronal activation of the insular cortex (IC), a brain region relevant to somatosensory and valence integration. To determine if the mice could detect MC activation, home cage behaviors following CNO treatment significantly increased nest grooming time. Conditioned place preference further revealed an avoidance response following MC stimulation; an effect that was stronger in female mice. Finally, to connect back to our trauma question, we examined MC activation in fear conditioning and identified deficits in fear extinction. Overall, these studies validate utilization of this preclinical model in further investigating the mechanosensory system and its potential involvement in PTSD symptoms and therapeutic interventions. Ongoing studies will focus on critical developmental periods relevant to both MC development and sex differences associated with trauma vulnerability and potential sensory based therapeutic options for PTSD-related symptoms.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1395-1405"},"PeriodicalIF":6.6,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02144-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One step at a time: use of single-session rTMS to test novel targets for substance use disorders","authors":"Heather Burrell Ward","doi":"10.1038/s41386-025-02149-5","DOIUrl":"10.1038/s41386-025-02149-5","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1317-1318"},"PeriodicalIF":6.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02149-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking","authors":"Kate Z. Peters, Zuzana Pedan, Romarua Agbude, Emily C. Woods, Oliver G. Steele, Nobuyoshi Suto, Scott B. Kinghorn, Olga Tsaponina, Eisuke Koya","doi":"10.1038/s41386-025-02142-y","DOIUrl":"10.1038/s41386-025-02142-y","url":null,"abstract":"Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or ‘neuronal ensembles’ in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify ‘anti-craving’ relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of ‘originally’, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost – resulting in their persistent activation and non-cue selective activation or ‘excitatory overdrive’. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting ‘inhibitory underdrive’. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory ‘overdrive’ and inhibitory ‘underdrive’ likely underlies EE’s anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1472-1481"},"PeriodicalIF":6.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02142-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conditioned versus innate effort-based tasks reveal divergence in antidepressant effect on motivational state in male mice","authors":"Foteini Xeni, Caterina Marangoni, Lynn Lin, Emma S. J. Robinson, Megan G. Jackson","doi":"10.1038/s41386-025-02140-0","DOIUrl":"10.1038/s41386-025-02140-0","url":null,"abstract":"Antidepressant-induced apathy syndrome is reported in a high number of patients. It is characterised by loss of motivation for daily activities and emotional blunting. It has a negative impact on quality of life and treatment outcome, yet the changes in underlying neurobiology driving this syndrome remain unclear. To begin to address this, a comprehensive understanding of how different classes of antidepressant treatment impact on behaviours relevant to apathy is critical. Rodent motivation for reward is commonly assessed using effort-based operant conditioning paradigms such as the Effort for Reward task. However, motivation to perform spontaneous/innate behaviours may provide additional insight into changes in behaviour reflective of daily activities. We tested the acute and chronic effects of antidepressants on the Effort for Reward task, and the spontaneous/innate Effort-Based Forage task. Acute treatment revealed important divergence in drug effect between tasks, where selective serotonin reuptake inhibitor (SSRI)/serotonin and noradrenaline reuptake inhibitor (SNRI) treatment impaired foraging behaviour in the Effort Based Forage task, but enhanced high-effort, high-value reward responding in the Effort for Reward task. Treatment with a noradrenaline reuptake inhibitor (NRI) or multimodal agent impaired foraging behaviour but did not affect high reward responding in the Effort for Reward task. Conversely, chronic treatment with an SSRI but not SNRI enhanced motivated foraging behaviour but led to a general impairment in Effort for Reward task output. Together, these data demonstrate that SSRI treatment induces opposing effects on conditioned versus innate motivation which may have significant translational relevance when interpreting drug effect. Further, these behavioural effects differ depending on whether antidepressants are acutely or chronically administered.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1732-1742"},"PeriodicalIF":6.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02140-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network homeostasis: functional brain network alterations and relapse in remitted late-life depression","authors":"Andrew R. Gerlach, Helmet T. Karim, Antonija Kolobaric, Brian D. Boyd, Kevin Kahru, Robert T. Krafty, Olusola Ajilore, Warren D. Taylor, Carmen Andreescu","doi":"10.1038/s41386-025-02138-8","DOIUrl":"10.1038/s41386-025-02138-8","url":null,"abstract":"Late-life depression (LLD) is highly recurrent and associated with disability and increased mortality. In this study, we aim to identify neurobiological factors that are prospectively associated with relapse risk in late-life depression. We recruited 145 older adults (age ≥ 60): 102 recently remitted LLD participants and 43 healthy comparisons. Participants underwent baseline MRI and evaluation of depression symptoms/status for up to 2 years. We evaluated intrinsic network connectivity for 111 participants (39 healthy comparisons, 47 stable remitted, 25 relapsed). Compared to healthy comparisons, LLD participants had lower connectivity within the somatomotor network and greater connectivity between the executive control and default mode networks (DMN). Lower connectivity of DMN to somatomotor and salience networks was associated with relapse. Overall, connectivity of relapse participants was more similar to healthy comparisons than connectivity of stable remitted participants was. We found robust differences in network functional connectivity between stable remitted and relapsed participants. We also found evidence of neural “scarring,” or persistent functional network differences at baseline in all participants with a history of depression. Alterations in DMN connectivity were observed most prominently. Notably, the network structure of relapsed participants was more similar to healthy comparisons than stable remitted participants. These findings indicate that remission is associated with persistent functional network alterations while vulnerability to relapse is associated with a failure to establish a new stable homeostatic functional network structure.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1493-1501"},"PeriodicalIF":6.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02138-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct structural deficits in treatment-resistant schizophrenia and their putative neurotransmitter basis: a source-based morphometry analysis","authors":"Huan Huang, Xiaowei Wang, Xuan Qin, Rui Xu, Ying Xiong, Cheng Chen, Qirong Wan, Hao Liu, Chang Shu, Wei Yuan, Yunlong Peng, Yuan Zhou, Huiling Wang, Lena Palaniyappan","doi":"10.1038/s41386-025-02135-x","DOIUrl":"10.1038/s41386-025-02135-x","url":null,"abstract":"Schizophrenia is associated with widespread gray matter reduction. This is influenced by the underlying connectivity, resulting in covarying patterns of structural changes that are more pronounced in treatment-resistant individuals. However, it remains uncertain whether a distinct network of brain regions, with specific neurotransmitter basis, forms the substrate for treatment resistance in schizophrenia. We investigated the structural covariance networks (SCN) in 198 individuals; 55 with treatment-resistant schizophrenia (TRS) and 79 without TRS (non-TRS) in active symptomatic phase, and 64 healthy controls (HC) using Calhoun’s Source-Based Morphometry. We mapped the putative neurotransmitter basis of the SCNs using a PET-based chemoarchitectural atlas. Twelve independent components (i.e., SCNs) were identified. A prefrontal-limbic SCN had lower gray matter volume (GMV) in TRS compared to HC and non-TRS (F = 7.757, p < 0.001, FDR-corrected). Spatial correlation with chemoarchitectural atlas revealed predominant contributions from serotonergic [5HT1b and 5HT2a], glutamatergic [mGluR5], histaminergic [H3], and opioid [MOR] receptors for this TRS-related SCN (all pspin-permutation < 0.05, FDR-corrected). A different SCN comprised of dorsal fronto-temporal and parieto-occipital regions, not associated with  any specific neurotransmitter distribution, exhibited reduced GMV in both TRS and non-TRS groups vs. HC (F = 7.239, p < 0.001, FDR-corrected). Amidst the generic GMV reduction that is shared with non-TRS patients, patients with TRS have specific prefrontal-limbic structural deficits with a unique non-dopaminergic chemoarchitecture. These findings indicate a putative molecular and structural basis for poor treatment response, guiding the development of second- and third-line pharmacotherapies for TRS.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1807-1816"},"PeriodicalIF":6.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}