Auditory event-related potentials as in vivo preclinical assays of circuit engagement for E/I-based therapeutic development
Auditory event-related potentials as in vivo preclinical assays of circuit engagement for E/I-based therapeutic development
批准号:
10717704
负责人:
DANIEL C. JAVITT
金额:
$81.95万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-01 至 2028-04-30
关键词:
AcuteAddressAffectAlgorithmsAnimal ModelAnimalsAuditoryAuditory areaBackBiological AssayBiological MarkersBrain regionCRISPR/Cas technologyCellsChronicClinicalClinical ResearchComplexComputer ModelsDendritesDevelopmentDiseaseDistalDrug Delivery SystemsElectrodesEmotionsEquilibriumEvaluationEvent-Related PotentialsFeedbackFrequenciesFutureGenerationsGenesGleanGlutamatesGlycineHTR2A geneHTR3A geneHomologous GeneHumanImpaired cognitionImpairmentIndividualInferior frontal gyrusInterneuronsInterventionInvestigationKetamineLocationMeasuresMemoryModelingMolecularMonkeysN-Methyl-D-Aspartate ReceptorsNerve DegenerationPatternPerformancePhasePhysiologicalPopulationPre-Clinical ModelPrimatesProcessProgram DevelopmentPsilocybinPsychosesRodentRodent ModelRoleSchizophreniaSerineSeveritiesSiteSomatostatinStimulusSuperior temporal gyrusSurfaceTestingThalamic structureTheta RhythmTranslatingValidationanalogantagonistauditory processingcell typeclinical investigationclinically relevantdensitydeviantdrug developmentearly screeningfunctional outcomesgamma-Aminobutyric Acidgenetic manipulationhigh riskhippocampal pyramidal neuronhuman datain vivoindexinginducible Creinformation processinginsightneurophysiologyneuropsychiatric disordernonhuman primatenovelnovel therapeutic interventionnovel therapeuticsoutcome predictionpharmacokinetics and pharmacodynamicsphonologypre-clinicalpreclinical developmentpreventreading abilityreceptor sensitivityremediationresponserestorationtheoriestherapeutic candidatetherapeutic developmenttherapy developmenttranslation to humansverbal
中文摘要
该应用程序响应PAR-22-170构建电路接合的体内临床前分析
英文摘要
This application responds to PAR-22-170 Building in vivo preclinical assays of circuit engagement for
application in therapeutic development. The project will optimize non-human primate (NHP) and rodent analogs
of human auditory mismatch negativity (MMN) for use in preclinical development programs. Deficits in MMN
generation have been extensively described in schizophrenia (Sz) and shown to correlate with cognitive
impairment and poor functional outcome in established Sz, and in conversion to Sz among individuals at clinical
high risk (CHR), demonstrating clinical relevance. MMN may also decrease in amplitude during the initial stages
of Sz, providing a target for development of treatments that may prevent neurodegeneration during initial stages
of the disorder. MMN indexes the integrity of early auditory processing (EAP) such as delayed tone matching
abilities, which are critical for processes such as auditory emotion recognition, verbal memory, and phonological
reading ability. Deficits in these processes, in turn, significantly predict outcome. In addition, local circuit
abnormalities that give rise to MMN impairments in auditory cortex may be present across brain regions. Insights
gleaned from investigation and remediation of MMN deficits may therefore be relevant across cortical regions. In
humans, MMN generation is inhibited reliably by N-methyl-D-aspartate receptors (NMDAR), suggesting
involvement of underlying glutamatergic mechanisms and local excitatory/inhibitory (E/I) balance. In spectral
analyses, MMN shows primary power within the theta frequency range, suggesting additional involvement of
somatostatin (SOM)-type GABA interneurons. MMN-like activity has been demonstrated in both NHP and
rodents, and in both species shows similar spectral content and NMDAR sensitivity to human MMN. The present
project will 1) further optimize these measures for use in early-stage drug development, while 2) also evaluating
their sensitivity and selectivity to compounds that do (e.g. NMDAR antagonists) and do not (e.g. 5-HT2A
antagonists) affect their generation in humans. These measures will then 3) be used to test specific local and
distributed circuit computational models to permit refinement in use of MMN paradigms across humans, NHP and
rodents. At the distributed network level, mechanistic testing will seek to refine emergent prediction error (PE)
based theories of MMN generation, which posit specific feed-forward and feed-back information flow among
primary auditory cortex (A1), superior temporal gyrus (STG) and inferior frontal gyrus (IFG), and to develop
spectral signatures of this information flow. At the local circuit level, mechanistic testing will assess the relative
contributions of specific interneuron populations using cell-specific genetic manipulation. Several compounds that
target NMDAR via the glycine/D-serine modulatory site (e.g. iclepertin, luvadaxisat) have shown promise for
treatment of Cognitive Impairment Associated with Sz (CIAS). The present pipeline will enable identification and
validation of additional targets within the E/I circuit and development of additional approaches for enhancement
of glutamatergic function and restoration of E/I balance across neuropsychiatric disorders.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10640071
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财政年份:2020
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批准号:8908263
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资助金额:$10.87万
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负责人:DANIEL C. JAVITT
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依托单位:
tDCS Augmentation of Cognitive Remediation in Schizophrenia
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批准号:8584098
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项目类别:
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资助金额:$26.32万
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财政年份:2013
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负责人:DANIEL C. JAVITT
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依托单位:
tDCS Augmentation of Cognitive Remediation in Schizophrenia
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批准号:8717732
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资助金额:$25.21万
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财政年份:2013
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依托单位:
The Conte Center for Schizophrenia Research
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批准号:8337017
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资助金额:$13.45万
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财政年份:2010
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负责人:DANIEL C. JAVITT
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依托单位:
Administrative
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批准号:8105225
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项目类别:
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资助金额:$37.02万
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财政年份:2010
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负责人:DANIEL C. JAVITT
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依托单位:
Multimodal assessment of sensory processing dysfunction in schizophrenia
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批准号:8105219
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资助金额:$21.34万
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财政年份:2010
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负责人:DANIEL C. JAVITT
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依托单位:
The Conte Center for Schizophrenia Research
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批准号:8061041
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项目类别:
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资助金额:$35.76万
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财政年份:2010
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负责人:DANIEL C. JAVITT
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依托单位:
The Conte Center for Schizophrenia Research
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批准号:7900006
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资助金额:$209.51万
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财政年份:2009
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依托单位:
The Conte Center for Schizophrenia Research
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批准号:8502370
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资助金额:$191.78万
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财政年份:2009
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负责人:DANIEL C. JAVITT
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依托单位:
The Conte Center for Schizophrenia Research
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批准号:8324646
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资助金额:$202.94万
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财政年份:2009
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负责人:DANIEL C. JAVITT
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依托单位:
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资助金额:$5.98万
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财政年份:2009
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负责人:DANIEL C. JAVITT
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依托单位:
Multimodal assessment of sensory processing dysfunction in schizophrenia
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批准号:7752209
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项目类别:
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资助金额:$22.92万
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财政年份:2009
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依托单位:
The Conte Center for Schizophrenia Research
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资助金额:$214.74万
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财政年份:2009
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财政年份:2009
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负责人:DANIEL C. JAVITT
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Sensory Processing Dysfunction in Neuropsychiatric Illness
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资助金额:$43.17万
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财政年份:2008
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负责人:DANIEL C. JAVITT
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依托单位:
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依托单位:
海外基金