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

此应用程序响应PAR-22-170构建体内临床前电路接合测试 在治疗开发中的应用。该项目将优化非人类灵长类(NHP)和啮齿动物的类似物 用于临床前开发计划的人类听觉失配负波(MMN)。MMN的赤字 在精神分裂症(Sz)中，代谢性被广泛地描述，并被证明与认知相关 已建立的Sz的损害和功能不良的结局，以及在临床上个体转变为Sz的情况 高风险(CHR)，显示出临床相关性。在最初阶段，MMN的幅度也可能降低 Sz，为开发可以防止初期神经变性的治疗方法提供了靶点 失调症的症状。MMN指标早期听觉处理(EAP)的完整性，如延迟音调匹配 能力，这对听觉情感识别、言语记忆和语音等过程至关重要 阅读能力。反过来，这些过程中的缺陷又极大地预测了结果。此外，本地电路 导致听觉皮质MMN损伤的异常可能存在于大脑各个区域。真知灼见 因此，从对MMN缺陷的调查和补救中收集的信息可能与大脑皮层区域相关。在……里面 人类，N-甲基-D-天冬氨酸受体(NMDAR)可靠地抑制MMN的产生，提示 谷氨酸能机制和局部兴奋/抑制(E/I)平衡的参与。在光谱中 分析表明，MMN在theta频率范围内显示出主要功率，表明MMN还参与了 生长抑素(SOM)型GABA中间神经元。在NHP和NHP中都显示出MMN样活性 这两个物种对人类MMN的光谱含量和NMDAR敏感性相似。现在 该项目将1)进一步优化这些措施，以用于早期药物开发，同时2)还将评估 它们对有作用的化合物(如NMDAR拮抗剂)和不起作用的化合物(如5-HT2A)的敏感性和选择性 拮抗剂)会影响它们在人类中的世代。然后，这些措施将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。在分布式网络级别，机械性测试将寻求改进紧急预测误差(PE) 基于MMN生成的理论，该理论假设特定的前馈和反馈信息流 初级听觉皮质(A1)、颞上回(STG)和额下回(IFG) 这一信息流的光谱特征。在本地电路级别，机械测试将评估相对 使用细胞特异性基因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(如iclepertin，luvadaxisat)靶向NMDAR已显示出有望 Sz相关认知障碍的治疗(CIAS)。目前这条管道将能够识别和 确认E/I电路内的其他目标，并开发其他增强方法 神经精神障碍的谷氨酸能功能和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.