Functional and behavioral dissection of higher order thalamocortical circuits in schizophrenia.

精神分裂症高阶丘脑皮质回路的功能和行为解剖。

• 批准号: 10633810
• 负责人: Neil D. Woodward
• 金额: $ 45.3万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-03 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633810
• 关键词: Affect; Anatomy; Animal Model; Attention; Behavior; Behavioral; Behavioral Model; Biological Markers; Brain; Cell Nucleus; Cognition; Cognitive; Conflict (Psychology); Cues; Data; Decision Making; Diffuse; Dissection; Dorsal; Equilibrium; Exhibits; Fingerprint; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Human; Impaired cognition; Impairment; Individual; Intervention; Link; Maps; Medial Dorsal Nucleus; Methods; Mus; Neurobiology; Neurosciences; Noise; Outcome; Pathway interactions; Patients; Pattern; Performance; Process; Property; Pulvinar structure; Regulation; Rest; Rodent; Role; Schizophrenia; Sensory; Signal Transduction; Stream; Structure; Symptoms; Testing; Thalamic structure; Uncertainty; Variant; Visual; Visuospatial; Work; attentional control; attentional modulation; behavior measurement; cognitive function; density; effective intervention; feature extraction; graph theory; innovation; neural; nonhuman primate; optogenetics; translational framework; visual object processing

ABSTRACT Project 5 (P5) will address Center Aim 2 by characterizing mediodorsal (MD) nucleus and pulvinar (PUL) circuit dysfunction in schizophrenia across levels of analysis, including functional connectivity with cortex, localized activation during cognition, and behavior. The structure, connectivity, and function of the thalamus are abnormal in schizophrenia. Thalamic abnormalities are especially pronounced in the MD nucleus and PUL. How MD and PUL dysfunction contributes to the symptoms and associated features of schizophrenia is largely unknown posing a significant challenge to developing effective interventions. One of the motivating factors of this Center application is that the MD and PUL are not only causally involved in cognition, but anatomically and functionally heterogenous. Consequently, dissecting higher-order thalamocortical circuits across levels of analysis is essential for understanding the functional consequences of thalamic dysfunction in schizophrenia and identifying targets for intervention. Working synergistically with P4 resting-state fMRI studies in healthy individuals and supporting by Core C, Aim 1 will use innovative methods to test the hypothesis that functional connectivity of MD and PUL subdivisions is abnormal in schizophrenia and further determine if the alterations are diffuse, or isolated to specific MD and PUL subdivisions. Informed by basic neuroscience discoveries motivating P1 and P2, Aim 2 will characterize dorsal and ventral pulvinar circuits during attention in schizophrenia. Deficits in attention are ubiquitous in schizophrenia and may serve as a viable biomarker. We hypothesize that such deficits may be caused by aberrant engagement of the PUL in regulating information flow across the dorsal and ventral visual streams. We will test this hypothesis by acquiring simultaneous brain (fMRI) and behavior measurements in patients and healthy individuals. Aim 3 will use a variant of the Center’s Hierarchical Decision Making (HDM) paradigm to investigate MD-PFC pathways for regulating cortical excitation/inhibition. Animal models developed by P3 indicate that resolving sensory uncertainty during decision making depends on different MD-PFC pathways: one for suppressing noise (conflict) by increasing cortical inhibition, the other for enhancing signal (sparseness) by decreasing inhibition. Building on preliminary behavioral data with leaders of P3 implicating impaired decision making under sensory conflict, we will determine if schizophrenia is associated with impaired decision making under uncertainty when task cues are sparse (low signal), conflicting (high noise), or both. Furthermore, we will test the hypothesis that MD dysfunction is associated with impaired attentional control under uncertainty in schizophrenia and determine whether MD dysfunction is more prominent in sparseness- or conflict-based uncertainty. Core B will provide critical support for modelling behavioral data (Aims 2, 3) to allow cross-species comparisons. The overall outcomes of P5 will provide the foundation for developing interventions for correcting thalamocortical dysfunction and cognitive impairment in schizophrenia.

抽象的 项目5（P5）将通过表征MediaDorsal（MD）核和Pulvinar（PUL）电路来解决中心目标2 跨分析水平的精神分裂症功能障碍，包括与皮质的功能连通性，局部 认知和行为期间的激活。丘脑的结构，连通性和功能是异常的 在精神分裂症中。丘脑异常在MD核和PUL中特别明显。 MD和 脉冲功能障碍有助于精神分裂症的符号和相关特征，在很大程度上未知 对制定有效的干预措施构成重大挑战。该中心的激励因素之一 应用是MD和PUR不仅在认知中随意参与，而且在解剖学上和功能上都参与 异源。因此，跨分析层面剖析高阶丘脑皮层电路是 了解精神分裂症中丘脑功能障碍的功能后果至关重要 干预的目标。在健康个体中与P4静止状态fMRI研究协同工作， 核心C的支持，AIM 1将使用创新方法来检验以下假设。 MD和PUL细分在精神分裂症中是异常的，进一步确定改变是分散的，还是 分离为特定的MD和PUL细分。由基本的神经科学发现，激励P1和 P2，AIM 2将在精神分裂症的注意力期间表征背侧和腹侧脉冲电路。缺陷 精神分裂症中的注意力无处不在，可以作为可行的生物标志物。我们假设这种缺陷 可能是由于PUL在横跨背和腹侧的调节信息流中异常参与而引起的 视觉流。我们将通过获得同时大脑（fMRI）和行为测量来检验这一假设 在患者和健康的个体中。 AIM 3将使用中心层次决策的变体（HDM） 范式研究MD-PFC途径，以进行调节性刺激/抑制作用。动物模型开发了 由P3表明，决策过程中解决感觉不确定性取决于不同的MD-PFC途径： 一种用于抑制噪声（冲突），通过增加皮质抑制，另一个用于增强信号（稀疏） 通过减少抑制作用。与P3领导者的初步行为数据建立在初步行为数据的基础上 在感官冲突下，我们将确定精神分裂症是否与决策受损有关 在任务提示稀疏（低信号），冲突（高噪声）或两者之间的不确定性下。此外，我们会的 测试MD功能障碍与不确定性下的注意力控制受损有关的假设 精神分裂症并确定MD功能障碍是否在基于冲突或冲突的稀疏性或冲突中更为突出 不确定。核心B将为建模行为数据提供关键支持（目标2，3），以允许跨物种 比较。 P5的总体结果将为制定纠正干预措施提供基础 精神分裂症的丘脑皮质功能障碍和认知障碍。