Neuropsychopharmacology最新文献

{"title":"Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning.","authors":"Liam T McCrea, Rebecca E Batorsky, Joshua J Bowen, Hana Yeh, Jessica M Thanos, Ting Fu, Roy H Perlis, Steven D Sheridan","doi":"10.1038/s41386-025-02123-1","DOIUrl":"10.1038/s41386-025-02123-1","url":null,"abstract":"<p><p>Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. These compounds comprise a wide range of therapeutic classes with different mechanisms of action, including immunosuppressants, kinase inhibitors, antipsychotics, and epigenetic modulators. Image-based morphological measurements were calculated to measure the degree of ramified vs. ameboid morphotypes as an indicator of activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, and actin dynamics across confirmed compounds. In particular, multiple CNS-penetrant small molecules with prior FDA approval or demonstration of safety in vivo demonstrated modulatory effects on microglia. For example, identified drugs such as the tyrosine kinase inhibitors lapatinib, alectinib, and lazertinib and the epigenetic modulator vorinostat have been approved for various cancer treatments and are being investigated for other indications; however, they have not been extensively studied in patients for neurodevelopmental and neurodegenerative disorders. These potential disease-modifying agents represent high-priority candidates for repositioning studies in neurodevelopmental, neuroinflammatory, or neurodegenerative disorders.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030567","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":"Posttraining noradrenergic stimulation maintains hippocampal engram reactivation and episodic-like specificity of remote memory.","authors":"Kubra Gulmez Karaca, Sevgi Bahtiyar, Linde van Dongen, Oliver T Wolf, Erno J Hermans, Marloes J A G Henckens, Benno Roozendaal","doi":"10.1038/s41386-025-02122-2","DOIUrl":"https://doi.org/10.1038/s41386-025-02122-2","url":null,"abstract":"<p><p>Recent findings indicate that noradrenergic arousal maintains long-term episodic-like specificity of memory. However, the neural mechanism of how norepinephrine can alter the temporal dynamics of systems consolidation to maintain hippocampus dependency of remote memory is currently unknown. Memories are stored within ensembles of neurons that become activated during learning and display strengthened mutual plasticity and connectivity. This strengthened connectivity is believed to guide the coordinated reactivation of these neurons upon subsequent memory recall. Here, we used male transgenic FosTRAP2xtdTomato mice to investigate whether the noradrenergic stimulant yohimbine administered systemically immediately after an episodic-like object-in-context training experience maintained long-term memory specificity which was joined by an enhanced reactivation of training-activated cells within the hippocampus during remote retention testing. We found that saline-treated control mice time-dependently lost their episodic-like specificity of memory, which was associated with a shift in neuronal reactivation from the dorsal hippocampus to the prelimbic cortex at a 14-day retention test. Importantly, yohimbine-treated mice maintained episodic-like specificity of remote memory and retained high neuronal reactivation within the dorsal hippocampus, without a time-dependent increase in prelimbic cortex reactivation. These findings suggest that noradrenergic arousal shortly after training maintains episodic-like specificity of remote memory by strengthening the connectivity between training-activated hippocampal cells during consolidation, and provide a cellular model of how emotional memories remain vivid and detailed.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037611","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":"Antipsychotics cause reversible structural brain changes within one week","authors":"Pierluigi Selvaggi,&nbsp;Martin Osugo,&nbsp;Uzma Zahid,&nbsp;Ottavia Dipasquale,&nbsp;Thomas Whitehurst,&nbsp;Ellis Onwordi,&nbsp;George Chapman,&nbsp;Valeria Finelli,&nbsp;Ben Statton,&nbsp;Tobias C. Wood,&nbsp;Matthew B. Wall,&nbsp;Robin Murray,&nbsp;Mitul A. Mehta,&nbsp;Tiago Reis Marques,&nbsp;Oliver D. Howes","doi":"10.1038/s41386-025-02120-4","DOIUrl":"10.1038/s41386-025-02120-4","url":null,"abstract":"Determining the effects of antipsychotics on MRI brain structural metrics without the potential confounding effects related to the natural course of a psychotic illness is challenging. However, it is crucial to understand these effects to interpret the results of cross-sectional and longitudinal studies in medicated patients and, ultimately, to understand better the biological mechanisms driving antipsychotics’ effects. In this work, we aim to determine whether exposure to antipsychotics is associated with alterations in brain MRI structural metrics in the absence of disease effects. A randomized, double-blind, counter-balanced order, crossover, placebo-controlled study in healthy volunteers was performed. The study comprised two arms. Within arms, participants were randomized to receive daily doses of either the active compound (Arm 1= amisulpride 400 mg/day, N = 24; Arm 2= aripiprazole 10 mg/day, N = 24) for one week, followed by placebo or vice versa. We found increased MRI volume estimates in the left putamen and in the right caudate in the amisulpride condition as compared to placebo and increased right putamen volume estimates after aripiprazole compared to placebo. No other effects were found in cortical volume estimates, cortical thickness, cortical surface area, and T1-relaxation time. Striatal changes reversed within weeks of drug withdrawal. Short-term exposure to either one of two different antipsychotics results in a transient increase in striatal volume measured with T1-weighted MRI that normalizes rapidly on stopping treatment without cortical changes. Our findings suggest that striatal volumetric MRI differences detected in people with schizophrenia taking antipsychotics are, at least in part, attributable to pharmacological effects.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 8","pages":"1275-1283"},"PeriodicalIF":6.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02120-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012624","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":"Circular RNAs as a novel player in synaptic transmission and neuropsychiatric disorders","authors":"Ayça Olcay","doi":"10.1038/s41386-025-02121-3","DOIUrl":"10.1038/s41386-025-02121-3","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 8","pages":"1195-1196"},"PeriodicalIF":6.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990987","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":"Multi-ancestry genome-wide association meta-analysis of buprenorphine treatment response","authors":"Christal N. Davis,&nbsp;Yousef Khan,&nbsp;Richard C. Crist,&nbsp;Rachel Vickers-Smith,&nbsp;Emily E. Hartwell,&nbsp;Joel Gelernter,&nbsp;Kyle Kampman,&nbsp;Rachel L. Kember,&nbsp;Anne Le Moigne,&nbsp;Celine M. Laffont,&nbsp;Henry R. Kranzler","doi":"10.1038/s41386-025-02117-z","DOIUrl":"10.1038/s41386-025-02117-z","url":null,"abstract":"Although the mu-opioid partial agonist buprenorphine is increasingly being prescribed to treat opioid use disorder, patients’ responses to the drug vary and few clinical and no genetic predictors of treatment response have been identified. We conducted a genome-wide association study (GWAS) meta-analysis of buprenorphine treatment response (defined using urine drug screen results) in 4394 Veterans with opioid use disorder from the VA Million Veteran Program (751 of African-like ancestry [AFR] and 3643 of European-like ancestry [EUR]) and 296 participants from a clinical trial of extended-release buprenorphine (nAFR = 104, nEUR = 192). We conducted within-ancestry GWAS in both cohorts, followed by cross-ancestry, fixed-effects GWAS meta-analyses within and across cohorts. We also examined associations between demographic and clinical characteristics and buprenorphine treatment response. The cross-ancestry meta-analysis of both cohorts identified one genome-wide significant locus (rs149319538) that maps to SLC39A10, a gene that encodes a zinc transporter. Phenome-wide association analyses of the lead variant implicated connectivity of the uncinate fasciculus, a limbic white matter fiber tract. Of the clinical characteristics, only the presence of chronic pain and a lower maximum buprenorphine dosage were related to higher odds of treatment response in adjusted models. We report here the first genome-wide significant variant associated with buprenorphine treatment response. Larger samples are needed to replicate these findings and identify additional clinical and genetic factors that predict buprenorphine treatment efficacy to enable the use of a precision approach to OUD treatment.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1346-1353"},"PeriodicalIF":6.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02117-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045703","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":"Sequential decreases in basolateral amygdala response to threat predict failure to recover from PTSD.","authors":"Alyssa R Roeckner, Esther R-H Lin, Rebecca Hinrichs, Nathaniel G Harnett, Lauren A M Lebois, Sanne J H van Rooij, Timothy D Ely, Tanja Jovanovic, Vishnu P Murty, Steven E Bruce, Stacey L House, Francesca L Beaudoin, Xinming An, Thomas C Neylan, Gari D Clifford, Sarah D Linnstaedt, Laura T Germine, Scott L Rauch, John P Haran, Alan B Storrow, Christopher Lewandowski, Paul I Musey, Phyllis L Hendry, Sophia Sheikh, Christopher W Jones, Brittany E Punches, Robert A Swor, Lauren A Hudak, Jose L Pascual, Mark J Seamon, Elizabeth M Datner, Claire Pearson, David A Peak, Roland C Merchant, Robert M Domeier, Niels K Rathlev, Brian J O'Neil, Paulina Sergot, Leon D Sanchez, Jutta Joormann, John F Sheridan, Steven E Harte, Karestan C Koenen, Ronald C Kessler, Samuel A McLean, Kerry J Ressler, Jennifer S Stevens","doi":"10.1038/s41386-025-02115-1","DOIUrl":"https://doi.org/10.1038/s41386-025-02115-1","url":null,"abstract":"<p><p>Amygdala hyperreactivity early-post trauma has been a demonstrable neurobiological correlate of future posttraumautic stress disorder (PTSD). The basolateral amygdala (BLA) particularly is vital for fear memory and threat processing, but BLA functional dynamics following a traumatic event are unexplored. BLA reactivity to threat may be a trait that can predict PTSD and persist over time. Alternatively, BLA responsivity to threat cues may change over time and be related to PTSD severity. As part of a larger, multisite study, AURORA, participants 18-75 years old were enrolled in an emergency department (ED) within 72 h of a traumatic event (N = 304, 199 female). At 2-weeks and 6-months post-trauma, PTSD symptoms, BLA responses to threat (fearful>neutral faces), and functional connectivity (FC) during fMRI were assessed. Generalizability of findings was assessed in an external replication sample of ED patients (n = 33). Two weeks post-trauma right BLA reactivity positively predicted later PTSD severity. However, left BLA reactivity to threat at 6 months post-trauma was negatively associated with PTSD severity at that timepoint (ΔPseudo-R² = 0.04, IRR = 0.38, p < 0.001). In addition, a decrease in BLA reactivity from 2-weeks to 6-months predicted greater PTSD severity at 6 months (ΔPseudo-R² = 0.03, IRR = 0.58, p < 0.001). This replicated in the external sample. A reduction in left BLA FC with the dorsal attention network predicted increased PTSD severity over time. These findings support a shift in BLA function within the first 6 months post-trauma that predicts PTSD pathology and stand in contrast to prior conceptualizations of amygdala hyperreactivity as a trait-like PTSD risk factor.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019979","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":"A Drd1-cre mouse line with nucleus accumbens gene dysregulation exhibits blunted fentanyl seeking.","authors":"Annalisa Montemarano, Logan D Fox, Farrah A Alkhaleel, Alexandria E Ostman, Hajra Sohail, Samiksha Pandey, Laura B Murdaugh, Megan E Fox","doi":"10.1038/s41386-025-02116-0","DOIUrl":"10.1038/s41386-025-02116-0","url":null,"abstract":"<p><p>The synthetic opioid fentanyl remains abundant in the illicit drug supply, contributing to tens of thousands of overdose deaths every year. Despite this, the neurobiological effects of fentanyl use remain largely understudied. The nucleus accumbens (NAc) is a central locus promoting persistent drug use and relapse, largely dependent on activity of dopamine D1 receptors. NAc D1 receptor-expressing medium spiny neurons (D1-MSNs) undergo molecular and physiological neuroadaptations in response to chronic fentanyl that may promote relapse. Here, we obtained Drd1-cre^120Mxu mice to investigate D1-dependent mechanisms of fentanyl relapse. We serendipitously discovered this mouse line has reduced fentanyl seeking, despite similar intravenous fentanyl self-administration, similar sucrose self-administration and seeking, and greater fentanyl-induced locomotion compared to wildtype counterparts. We found drug-naïve Drd1-cre^120Mxu mice have elevated D1 receptor expression in NAc and increased sensitivity to the D1 receptor agonist SKF-38393. After fentanyl self-administration, Drd1-cre^120Mxu mice exhibit divergent expression of MSN markers, opioid receptors, glutamate receptor subunits, and TrkB which may underly their blunted fentanyl seeking. Finally, we show fentanyl-related behavior is unaltered by chemogenetic manipulation of NAc core D1-MSNs in Drd1-cre^120Mxu mice. Conversely, chemogenetic stimulation of ventral mesencephalon-projecting NAc core MSNs (putative D1-MSNs) in wildtype mice recapitulated the blunted fentanyl seeking of Drd1-cre^120Mxu mice, supporting a role for aberrant D1-MSN signaling in this behavior. Together, our data uncover alterations in NAc gene expression and function with implications for susceptibility and resistance to developing fentanyl use disorder.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021641","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":"Development of the McLean Hospital MENTOR Program to enhance mental health career pathways","authors":"Courtney Beard,&nbsp;Michaela B. Swee,&nbsp;Zelda McGhee,&nbsp;Fran Barth,&nbsp;Kimberly Arditte Hall,&nbsp;Nicole Rossi,&nbsp;Catharyn Gildesgame,&nbsp;Kerry Ressler","doi":"10.1038/s41386-025-02118-y","DOIUrl":"10.1038/s41386-025-02118-y","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 8","pages":"1197-1199"},"PeriodicalIF":6.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009063","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":"Changes in nucleus accumbens core translatome accompanying incubation of cocaine craving","authors":"Alex B. Kawa,&nbsp;Joel G. Hashimoto,&nbsp;Madelyn M. Beutler,&nbsp;Marina Guizzetti,&nbsp;Marina E. Wolf","doi":"10.1038/s41386-025-02112-4","DOIUrl":"10.1038/s41386-025-02112-4","url":null,"abstract":"In the ‘incubation of cocaine craving’ model of relapse, rats exhibit progressive intensification (incubation) of cue-induced craving over several weeks of forced abstinence from cocaine self-administration. The expression of incubated craving depends on plasticity of excitatory synaptic transmission in nucleus accumbens core (NAcC) medium spiny neurons (MSN). Previously, we found that the maintenance of this plasticity and the expression of incubation depends on ongoing protein translation, and the regulation of translation is altered after incubation of cocaine craving. Here we used male and female rats that express Cre recombinase in either dopamine D1 receptor- or adenosine 2a (A2a) receptor-expressing MSN to express a GFP-tagged ribosomal subunit in a cell-type specific manner, enabling us to use Translating Ribosome Affinity Purification (TRAP) to isolate actively translating mRNAs from both MSN subtypes for analysis by RNA-seq. We compared rats that self-administered saline or cocaine. Saline rats were assessed on abstinence day (AD) 1, while cocaine rats were assessed on AD1 or AD40-50. For both D1-MSN and A2a-MSN, there were few differentially translated genes between saline and cocaine AD1 groups. In contrast, pronounced differences in the translatome were observed between cocaine rats on AD1 and AD40-50, and this was far more robust in D1-MSN. Notably, all comparisons revealed sex differences in translating mRNAs. Sequencing results were validated by qRT-PCR for several genes of interest. This study, the first to combine TRAP-seq, transgenic rats, and a cocaine self-administration paradigm, identifies translating mRNAs linked to incubation of cocaine craving in D1-MSN and A2a-MSN of the NAcC.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 8","pages":"1305-1316"},"PeriodicalIF":6.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026115","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":"A rat model of volitional mutual social interactions.","authors":"Cody A Lis, Antonino Casile, Bronte Feulner, Jonathan Garcia, Rajtarun Madangopal, Kimberly M Papastrat, Zhengyi Huang, Amanda Pacheco-Spiewak, Leslie A Ramsey, Marco Venniro","doi":"10.1038/s41386-025-02113-3","DOIUrl":"https://doi.org/10.1038/s41386-025-02113-3","url":null,"abstract":"<p><p>Social interactions are essential for building societies and fostering cooperation among individuals. These behaviors are governed by complex norms and signaling mechanisms promoting mutual engagement. While animal models are often used to study social behaviors, they typically focus on one individual, overlooking the role and motivation of an otherwise passive social partner. Here, we developed a model where resident and partner rats voluntarily engage in mutual social interactions. In this model, the resident initiates interaction by pressing a lever to activate cues for the partner, who responds by pressing an additional lever, leading to social interaction. To test motivation for mutual social interaction, we increased the effort required for both residents and partners either concurrently or independently. We further investigated the mechanisms underlying these interactions by manipulating the norepinephrine system both systemically and centrally during mutual social interactions. Both male and female paired rats consistently demonstrate mutual motivation to engage in social interactions, regardless of their roles. The rats effectively coordinate their actions, showing low latency and high engagement frequency even as effort demands increase. The average social score analysis identified a significant proportion of highly motivated social pairs. Manipulating the norepinephrine system selectively disrupted the distribution of highly motivated social pairs, emphasizing its role in regulating social interactions. Ablating norepinephrine terminals had no impact on motivation for food rewards, further confirming that central norepinephrine manipulation specifically affects mutual social interactions. Our findings provide insight into the fundamental behavioral and neurobiological mechanisms underlying sociability and complex social structures in rodents.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036683","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}