Two-photon analysis of circuit-level mechanisms of schizophrenia biomarkers

精神分裂症生物标志物电路级机制的双光子分析

• 批准号: 8833735
• 负责人: Jordan P Hamm
• 金额: $ 4.99万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833735
• 关键词: 3-Dimensional; Affect; Animal Experimentation; Animals; Behavioral; Benchmarking; Biological; Biological Assay; Biological Markers; Calcium; Cells; Cerebrum; Chronic; Clinical; Clinical Research; Cognitive; Constitutional; Coupled; Diagnosis; Diagnostic; Disease; Disease model; Electroencephalography; Exhibits; Functional disorder; Genetic; Human; Image; Imaging Techniques; Individual; Interneurons; Intervention; Ion Channel; Ketamine; Knowledge; Label; Link; Measurable; Measures; Methods; Microelectrodes; Microscopy; Modality; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Opsin; Optical Methods; Parvalbumins; Patients; Pattern; Phenotype; Population; Population Dynamics; Population Heterogeneity; Positioning Attribute; Process; Process Measure; Property; Psychotic Disorders; Research; Resolution; Saline; Scalp structure; Schizophrenia; Sensory; Sensory Process; Shapes; Somatostatin; Stereotyping; Stimulus; Testing; Training; Transgenic Mice; Transgenic Organisms; Vasoactive Intestinal Peptide; Viral; Vision; Visual; Visual Cortex; Vocabulary; Work; awake; base; cell assembly; cell type; deviant; follow-up; in vivo; insight; mouse model; neural patterning; novel; optical imaging; optogenetics; public health relevance; relating to nervous system; tool; two-photon; visual process; visual processing

 DESCRIPTION (provided by applicant): Research into the biological substrate of schizophrenia (SZ) over the past several decades has focused on identifying empirical markers of the disorder which are more proximal to etiological processes than the phenomenological symptomology on which the diagnosis is based. Such biomarkers suggest fundamental disruptions in sensory cortical processing, carry the potential to explain phenomenological and higher order cognitive aspects of the disorder, and provide a critical translational strategy for targeted clinical intervention. Despite some encouraging leads, we still do not understand the pathophysiology behind most biomarkers, or how the measures themselves relate to the essential computations of the cerebral cortical circuit, limiting their utility as translational tols and theoretical benchmarks. Recent advances in transgenic and optical imaging in mice provide exciting new tools with which these specific questions can be answered. The proposed project will use cutting-edge two-photon optical imaging and photostimulation methods to identify the microcircuit level substrate of two established oscillatory biomarkers of SZ: alpha and gamma-band synchronization in visual cortex. Specifically, we will use chronic ketamine exposure in mice to generate a model of disordered sensoricortical processing and measure spontaneous and visually evoked oscillatory dynamics in V1 with dense microelectrode recordings. We will then (AIM1) employ state-of-the-art fast 3D 2- photon Ca2+ imaging to measure the multicellular activity of cortical microcircuits in vivo, describing how oscillatory biomarkers relate to the patterned activity of local cell assemblies and to the function of specific inhibitory interneuron subpopulations with demonstrated disease relevance. Based on these findings, we will then (AIM2) employ optogenetic manipulation of cortical cells in the same imaging/stimulation context to assess casual links between oscillatory biomarkers of SZ, circuit dynamics, and the function of local inhibitory interneuron populations. These studies will yield i) key biomechanistic information for interpreting measures in humans, helping to mature them from biomarkers to clinical assays, and ii) potentially novel insights into how these measures and the psychotic states they mark (e.g. SZ) relate to the emergent patterns of neural activity and their associated network-level dynamics. Moreover, the proposed work will build directly on my graduate work on sensory biomarkers of psychotic disturbance by identifying the cortical substrate of these measures and expanding my expertise into the visual domain, animal research, two-photon optical imaging and photostimutlation with optogenetics. This training will position me to pursue follow-up studies in genetic mouse models of SZ and which further explore the behavioral/perceptual consequences of disrupted microcircuit dynamics, sensory modalities other than vision, and intervention strategies based on these bioassays.

 描述（由申请人提供）：过去几十年来，对精神分裂症（SZ）的生物学基础的研究重点是确定该疾病的经验标志物，这些标志物比诊断所依据的现象学症状更接近于病因学过程。生物标志物表明感觉皮层处理存在根本性破坏，有可能解释该疾病的现象学和高阶认知方面，并为临床针对性干预提供关键的转化策略，尽管有一些令人鼓舞的线索，但我们仍然认为。仍然不了解大多数生物标志物背后的病理生理学，或者这些测量本身如何与大脑皮层回路的基本计算相关，这限制了它们作为转化工具和理论基准的实用性，小鼠转基因和光学成像的最新进展提供了令人兴奋的新工具。拟议的项目将使用尖端的双光子光学成像和光刺激方法来识别 SZ 的两种已建立的振荡生物标记物的微电路水平基质：α 和伽马带。具体来说，我们将使用小鼠的长期接触氯胺酮来生成感觉皮层处理紊乱的模型，并通过密集的微电极记录测量 V1 中的自发和视觉诱发的振荡动力学，然后我们将 (AIM1) 采用状态。 -艺术快速 3D 2- 光子 Ca2+ 成像，用于测量体内皮质微电路的多细胞活动，描述振荡生物标志物如何与局部的模式活动相关基于这些发现，我们将（AIM2）在相同的成像/刺激背景下对皮层细胞进行光遗传学操作，以评估 SZ 振荡生物标志物之间的偶然联系。这些研究将产生用于解释人类测量的关键生物力学信息，帮助它们从生物标志物到临床检测的成熟。 ii）关于这些测量和它们标记的精神病状态（例如 SZ）如何与神经活动的新兴模式及其相关的网络级动态相关的潜在新颖见解此外，拟议的工作将直接建立在我关于感觉生物标记的研究生工作的基础上。通过识别这些措施的皮质基质并将我的专业知识扩展到视觉领域、动物研究、双光子光学成像和光遗传学光刺激，我可以对精神病性障碍进行研究。这次培训将使我能够对 SZ 基因小鼠模型进行后续研究。并进一步探索微电路动力学破坏、视觉以外的感觉方式以及基于这些生物测定的干预策略的行为/感知后果。