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Dissecting and modifying temporal dynamics underlying major depressive disorder

剖析和修改重度抑郁症背后的时间动态

基本信息

批准号：
10004169
负责人：
Kafui Dzirasa
金额：
$ 71.33万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004169
关键词：
Address Amygdaloid structure Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavior Control Behavioral Brain Brain Diseases Brain region Cells Chronic Code Cognition Cognitive Collection Communities Coupling Data Development Disease Disease model Emotional Emotions Etiology Exhibits Frequencies Functional disorder Gene Expression Genetic Health Hippocampus (Brain)Human Impairment Individual Link Location Machine Learning Major Depressive Disorder Measures Mediating Memory Mental Depression Mental disorders Methods Modeling Molecular Monitor Mood Disorders Mus Neurons Nucleus Accumbens Outcome Play Pre-Clinical Model Prefrontal Cortex Research Rodent Rodent Model Role Schizophrenia Signal Transduction Site Social Behavior Social Functioning Stress Techniques Testing Thalamic structure Therapeutic Intervention Time Validation Ventral Tegmental Area Viral Work autism spectrum disorder base cell type cognitive function depression model depressive symptoms emotional functioning human imaging imaging study in vivo millisecond mouse model multidisciplinary network models neuromechanism novel novel therapeutics optogenetics preclinical study relating to nervous system reward processing social defeat spatiotemporal tool

项目摘要

Title: Dissecting and modifying temporal dynamics underlying major depressive disorder Multiple human imaging studies have described aberrant spatiotemporal dynamics in specific brain networks across subjects with major depressive disorder. Furthermore, rodent studies have identified dysfunctional synchrony across cortical limbic circuits in genetic and stress- induced models of major depressive disorder. Nevertheless, it remains to be clarified whether these observed changes in neural dynamics play a causal role or simply reflect (i.e., correlate with) the behavioral-state observed in major depressive disorder. Several major challenges to addressing this question exist. 1) The brain synchronizes dynamics across multiple timescales. Rodent studies classically monitor dynamics at the millisecond time scale (reflecting circuits), and human studies typically monitor brain dynamics at the seconds time scale (reflect circuit and network level activity). 2) Rodent studies are generally limited in their ability to monitor large-scale activity from many brain regions concurrently, while human imaging studies observe activity across the whole brain. 3) To our knowledge, few approaches/models integrate changes in cell-type specific gene expression implicated in depression to changes in circuit and network- specific brain dynamics. 4) Techniques which directly manipulate brain dynamics (neural synchrony and cross-frequency coupling) have yet to be largely implemented throughout the rodent research community. To address these challenges, we propose to perform multi-circuit in vivo neural recordings in the two widely used rodent models of depression. We will then utilize machine learning to determine the spatiotemporal dynamic alterations that are shared between the two models. Next, we will test whether cellular molecular manipulations implicated in major depressive disorder are sufficient to induce the same spatiotemporal dynamic alterations. Finally, we will verify that these spatiotemporal dynamics are causal by directly inducing and suppressing them and measuring their impact on behavior. This strategy will yield an unprecedented understanding of how altered dynamics within specific brain circuits contribute to depression.

标题：剖析和修改重性抑郁症的时间动力学基础多项人类成像研究已经描述了特定的异常时空动态重度抑郁症受试者的大脑网络。此外，啮齿动物研究已经发现了在遗传和压力下大脑皮层边缘回路的同步功能障碍- 重度抑郁症的诱导模型。然而，仍有待澄清的是，这些观察到的神经动力学变化起因果作用或简单地反映（即，相关与）在重度抑郁症中观察到的行为状态。若干重大挑战，解决这个问题的方法是存在的。1)大脑在多个时间尺度上保持动态。啮齿动物研究通常在毫秒时间尺度上监测动态（反射电路），并且人类研究通常以秒时间尺度（反射电路）监测大脑动力学以及网络级活动）。2)啮齿类动物的研究通常在监测能力方面受到限制，大规模的活动，从许多大脑区域同时进行，而人类成像研究观察到，整个大脑的活动。3)据我们所知，很少有办法/模式纳入变革，在细胞类型特异性基因表达中，抑郁症与回路和网络的变化有关，特定的大脑动力学4)直接操纵大脑动力学的技术（神经同步和交叉频率耦合）还没有在整个啮齿动物研究社区。为了应对这些挑战，我们建议在在两种广泛使用的抑郁症啮齿动物模型中的体内神经记录。我们将利用机器学习，以确定共享的时空动态变化，两个模型。下一步，我们将测试是否涉及细胞分子操纵的主要抑郁症足以引起相同的时空动态变化。最后，我们将通过直接归纳和抑制它们并测量它们对行为的影响。这一战略将产生对特定脑回路内改变的动力学如何有助于萧条