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

本申请响应PAR-22-170构建电路接合的体内临床前试验， 在治疗开发中的应用。该项目将优化非人类灵长类动物（NHP）和啮齿类动物类似物 用于临床前开发项目的人类听觉失配负波（MMN）。MMN赤字 在精神分裂症（Sz）中已广泛描述，并显示与认知相关。 在已建立的Sz中，以及在临床上个体中转换为Sz时， 高风险（CHD），证明临床相关性。MMN也可能在初始阶段振幅减小 的Sz，提供了一个目标，为发展的治疗，可以防止神经退行性疾病在初始阶段 精神紊乱的症状MMN对早期听觉处理（EAP）的完整性（如延迟音调匹配）进行了索引 能力，这是关键的过程，如听觉情感识别，言语记忆，语音 阅读能力反过来，这些过程中的缺陷可以显著预测结果。此外，本地电路 在听觉皮层中引起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的信息可能与皮质区域相关。在 在人类中，MMN的产生被N-甲基-D-天冬氨酸受体（NMDAR）可靠地抑制，这表明 涉及潜在的神经递质机制和局部兴奋/抑制（E/I）平衡。光谱 分析，MMN显示在θ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样活性已经在NHP和 啮齿类动物，并在这两个物种显示出相似的光谱内容和NMDAR敏感性，人类MMN。本 该项目将1）进一步优化这些措施，用于早期药物开发，同时2）还评估 它们对具有或不具有NMDAR活性的化合物（例如NMDAR拮抗剂）的敏感性和选择性（例如5-HT 2A 拮抗剂）影响它们在人类中的产生。这些措施将被用于测试特定的地方和 分布式电路计算模型，以允许在跨人类、NHP和 啮齿动物在分布式网络层面，机械测试将寻求改进紧急预测误差（PE） 基于MMN生成理论，描述了MMN生成过程中特定的前馈和反馈信息流， 初级听觉皮层（A1）、上级颞回（STG）和额下回（IFG）， 这些信息流的光谱特征在当地电路水平，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。的几种化合物 通过甘氨酸/D-丝氨酸调节位点靶向NMDAR（例如iclepertin，luvadaxisat）已显示出 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回路中的其他目标并开发其他增强方法 神经精神疾病的E/I平衡的恢复。

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.