Auditory event-related potentials as in vivo preclinical assays of circuit engagement for E/I-based therapeutic development

听觉事件相关电位作为基于 E/I 的治疗开发的电路参与的体内临床前测定

• 批准号: 10717704
• 负责人: DANIEL C. JAVITT
• 金额: $ 81.95万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717704
• 关键词: Acute; Address; Affect; Algorithms; Animal Model; Animals; Auditory; Auditory area; Back; Biological Assay; Biological Markers; Brain region; CRISPR/Cas technology; Cells; Chronic; Clinical; Clinical Research; Complex; Computer Models; Dendrites; Development; Disease; Distal; Drug Delivery Systems; Electrodes; Emotions; Equilibrium; Evaluation; Event-Related Potentials; Feedback; Frequencies; Future; Generations; Genes; Glean; Glutamates; Glycine; HTR2A gene; HTR3A gene; Homologous Gene; Human; Impaired cognition; Impairment; Individual; Inferior frontal gyrus; Interneurons; Intervention; Investigation; Ketamine; Location; Measures; Memory; Modeling; Molecular; Monkeys; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Pattern; Performance; Phase; Physiological; Population; Pre-Clinical Model; Primates; Process; Program Development; Psilocybin; Psychoses; Rodent; Rodent Model; Role; Schizophrenia; Serine; Severities; Site; Somatostatin; Stimulus; Superior temporal gyrus; Surface; Testing; Thalamic structure; Theta Rhythm; Translating; Validation; analog; antagonist; auditory processing; cell type; clinical investigation; clinically relevant; density; deviant; drug development; early screening; functional outcomes; gamma-Aminobutyric Acid; genetic manipulation; high risk; hippocampal pyramidal neuron; human data; in vivo; indexing; inducible Cre; information processing; insight; neurophysiology; neuropsychiatric disorder; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; outcome prediction; pharmacokinetics and pharmacodynamics; phonology; pre-clinical; preclinical development; prevent; reading ability; receptor sensitivity; remediation; response; restoration; theories; therapeutic candidate; therapeutic development; therapy development; translation to humans; verbal

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.

该应用程序对PAR-22-170在体内临床前测定电路参与的建筑物的响应 在治疗发展中的应用。该项目将优化非人类灵长类动物（NHP）和啮齿动物类似物 用于临床前开发计划中的人类听觉不匹配负面性（MMN）。 MMN的缺陷 在精神分裂症（SZ）中已经广泛描述了产生，并证明与认知相关 既定的SZ的损伤和功能效果不佳，以及临床上个体的SZ转换为SZ 高风险（CHR），证明临床相关性。 MMN在初始阶段也可能会减少振幅 SZ的of，提供了开发可能在初始阶段进行神经退行性的治疗的目标 疾病。 MMN索引了早期听觉处理（EAP）的完整性，例如延迟音调匹配 能力，这对于诸如听觉情绪识别，言语记忆和语音学等过程至关重要 阅读能力。这些过程中的缺陷又可以显着预测结果。此外，本地电路 在大脑区域之间可能存在导致听觉皮层损伤的MMN损伤的异常。见解 因此，从研究和修复MMN缺陷中收集的是在皮质区域之间的相关性。在 人类，MMN产生被N-甲基-D-天冬氨酸受体（NMDAR）可靠地抑制，这表明 基本的谷氨酸能机制和局部兴奋/抑制（E/I）平衡的参与。在光谱中 分析，MMN显示了theta频率范围内的主要力量，这表明 生长抑素（SOM） - 型GABA中间神经元。 NHP和 啮齿动物，并且在这两个物种中都表现出相似的光谱含量和NMDAR对人MMN的敏感性。现在 项目1）进一步优化这些措施以在早期药物开发中使用，而2）也评估 它们对具有的化合物（例如NMDAR拮抗剂）而不（例如5-HT2A）的敏感性和选择性 对抗者）影响他们在人类中的一代。然后，这些措施将3）用于测试特定的本地和 分布式电路计算模型，以允许在人类，NHP和 啮齿动物。在分布式网络级别，机械测试将寻求完善紧急预测错误（PE） 基于MMN生成的理论，该理论提出了特定的进料和回馈信息流 一级听觉皮层（A1），上颞回（STG）和下额回（IFG），并发展 此信息流的光谱签名。在本地电路级别，机械测试将评估相对 使用细胞特异性遗传操纵的特定中间神经元种群的贡献。几种化合物 通过甘氨酸/D丝氨酸调节位点（例如Iclepertin，luvadaxisat）的靶NMDAR显示出对 与SZ相关的认知障碍的治疗（CIAS）。当前管道将启用身份证明和 在E/I电路中验证其他目标，并开发了增强的其他方法 谷氨酸能功能和跨神经精神疾病的E/I平衡的恢复。