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.

该应用程序响应 PAR-22-170 构建电路参与的体内临床前测定 在治疗开发中的应用。该项目将优化非人类灵长类动物 (NHP) 和啮齿动物类似物 人类听觉失配负性（MMN）的研究用于临床前开发项目。 MMN 赤字 精神分裂症（Sz）中的一代已被广泛描述，并被证明与认知相关 已建立的 Sz 以及临床个体向 Sz 转换的损伤和功能结果不佳 高风险（CHR），证明临床相关性。 MMN 的振幅在初始阶段也可能会减小 Sz，为开发可预防初始阶段神经退行性变的治疗方法提供了目标 的疾病。 MMN 对早期听觉处理 (EAP) 的完整性进行索引，例如延迟音调匹配 能力，这对于听觉情感识别、言语记忆和语音等过程至关重要 阅读能力。这些过程中的缺陷反过来又可以显着预测结果。另外，本地电路 导致听觉皮层 MMN 损伤的异常可能存在于整个大脑区域。见解 因此，从 MMN 缺陷的调查和补救中收集到的信息可能与整个皮质区域相关。在 在人类中，MMN 的生成受到 N-甲基-D-天冬氨酸受体 (NMDAR) 的可靠抑制，这表明 涉及潜在的谷氨酸能机制和局部兴奋/抑制（E/I）平衡。在光谱中 分析，MMN 显示了 theta 频率范围内的主要功率，表明额外的参与 生长抑素 (SOM) 型 GABA 中间神经元。 MMN 样活性已在 NHP 和 啮齿类动物，这两个物种都对人类 MMN 表现出相似的光谱内容和 NMDAR 敏感性。现在的 项目将 1) 进一步优化这些措施用于早期药物开发，同时 2) 还评估 它们对起作用（例如 NMDAR 拮抗剂）和不起作用（例如 5-HT2A）的化合物的敏感性和选择性 拮抗剂）影响它们在人类中的产生。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允许在人类、NHP 和 啮齿动物。在分布式网络层面，机械测试将寻求细化紧急预测误差（PE） 基于 MMN 生成理论，该理论提出了特定的前馈和反馈信息流 初级听觉皮层（A1）、颞上回（STG）和额下回（IFG），并发育 该信息流的光谱特征。在本地电路层面，机械测试将评估相对 使用细胞特异性遗传操作的特定中间神经元群体的贡献。几种化合物 通过甘氨酸/D-丝氨酸调节位点（例如 iclepertin、luvadaxisat）靶向 NMDAR 已显示出有望 治疗与 Sz 相关的认知障碍 (CIAS)。目前的管道将能够识别和 验证 E/I 电路内的其他目标并开发其他增强方法 谷氨酸能功能和神经精神疾病 E/I 平衡的恢复。