Molecular and chemogenetic control of dentate gyrus inputs: a novel approach to combat depression-like behavior

齿状回输入的分子和化学遗传学控制：对抗抑郁样行为的新方法

• 批准号: 9358934
• 负责人: AMELIA J EISCH
• 金额: $ 21万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-13 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358934
• 关键词: Ablation; Affect; Animal Model; Animals; Antidepressive Agents; Applications Grants; Behavior; Behavioral Symptoms; Brain; Brain region; Cognition; Cognitive; Data; Deep Brain Stimulation; Depressed mood; Development; Disinhibition; Drug resistance; Electric Stimulation; Electroconvulsive Therapy; Ensure; Experimental Designs; Exploratory/Developmental Grant; Health; Hippocampus (Brain); Human; Knock-out; Knowledge; Laboratories; Laboratory Animals; Lead; Link; Literature; Magnetism; Major Depressive Disorder; Mediating; Memory; Mental Depression; Mental disorders; Molecular; Neurons; Nucleus Accumbens; Outcome; Perforant Pathway; Performance; Pharmaceutical Preparations; Pharmacotherapy; Processed Genes; Publishing; Relapse; Repression; Research Personnel; Risk; Role; Staging; Stress; Swimming; Symptoms; Testing; Viral; Work; antidepressant effect; base; behavioral outcome; brain dysfunction; clinically relevant; cognitive function; combat; dentate gyrus; depressed patient; depressive symptoms; designer receptors exclusively activated by designer drugs; entorhinal cortex; improved; knock-down; neural circuit; neurogenesis; neuronal excitability; neuropathology; novel; novel strategies; relating to nervous system; social; theories; tool

 DESCRIPTION (provided by applicant): Major Depressive Disorder is one of the most common psychiatric disorders, affecting millions of people worldwide. Antidepressant drugs are widely used, but 50% of depressed patients receiving these medications will relapse, and 30% are drug resistant. Thus, new targets for antidepressants are needed. Converging evidence indicates an important role for depression-associated changes in hippocampal circuitry. For example, depressed humans and animal models of depression have smaller hippocampi, and decreased activity-dependent genes and processes, like hippocampal dentate gyrus (DG) neurogenesis. Notably, antidepressant drugs and non-pharmacological treatments like electroconvulsive treatment ameliorate these changes. From such work, a new framework for discovery of novel antidepressants has emerged: find treatments that "recalibrate" depression-linked dysfunctional neural circuits and behavior. Indeed, other approaches to "stimulate" neural circuits - such as deep brain stimulation (DBS) - can reverse depression-related symptoms and neuropathology, particularly in the hippocampus. Strikingly, in the context of depression, DBS has only been targeted to non-hippocampal brain regions. DBS of the main hippocampal input - the entorhinal cortex (Ent) via the perforant path (PP) - has proven physiologically beneficial in other contexts: it enhances memory in humans and memory and DG neurogenesis in laboratory animals. However, it remains unknown if stimulation of the PP will produce antidepressant-like behaviors. For this exploratory and developmental R21 project, we will test the hypothesis that controlled activation of PP to DG is antidepressive. This hypothesis emerges from our pilot data showing: a) stress and depression are linked to greater PP levels of TRIP8b, a brain-specific auxiliary subunit of HCN channels; b) germline knockout of TRIP8b - which is antidepressive - increases DG neurogenesis; and c) PP disinhibition (de-repression of Ent neuronal excitability via knockdown of TRIP8b) increases DG neurogenesis and is antidepressive. We also provide d) feasibility data that we can chemogenetically-stimulate DG via PP activation. Based on these data, we will: Aim 1: Determine whether molecular-based PP disinhibition promotes antidepressive behavior using viral-mediated KD of TRIP8b in the PP and a battery of depression-linked and cognitive behaviors; and Aim 2: Determine whether chemogenetic stimulation of PP activity drives antidepressive behavior using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to mediate neuronal activity and behavior. While the aims proposed here involve considerable risk, they are logical and highly feasible given the large amount of pilot data and the published ability of PP stimulation to improve hippocampal cognitive function. This project is in an early and conceptual stage, and has focused, behavioral outcomes, making it ideal for the R21 mechanism. Even if the hypothesis is incorrect, the experimental design ensures that the collected data will advance our knowledge of brain circuits contributing to affect and cognition.

 描述(申请人提供)：严重抑郁障碍是最常见的精神疾病之一，影响全球数百万人。抗抑郁药物被广泛使用，但接受这些药物治疗的抑郁症患者中有50%会复发，30%具有抗药性。因此，需要抗抑郁药物的新靶点。越来越多的证据表明，抑郁相关的海马神经元改变起着重要作用。例如，抑郁的人类和抑郁动物模型的海马区较小，活动依赖的基因和过程减少，如海马齿状回(DG)的神经发生。值得注意的是，抗抑郁药物和非药物治疗，如电惊厥治疗，可以改善这些变化。从这些工作中，发现新的抗抑郁药物的新框架已经出现：找到“重新校准”与抑郁症相关的功能失调的神经回路和行为的治疗方法。事实上，其他“刺激”神经回路的方法--如脑深部刺激(DBS)--可以逆转抑郁症相关的症状和神经病理，尤其是在海马区。引人注目的是，在抑郁症的背景下，DBS只针对非海马区的大脑区域。海马体的主要输入--通过穿孔通路(PP)的内嗅皮层(Ent)--的DBS已被证明在其他方面有生理上的好处：它增强了人类的记忆和实验室动物的记忆和DG神经发生。然而，刺激PP是否会产生抗抑郁药样行为仍不清楚。对于这个探索性和发展性的R21项目，我们将检验PP对DG的受控激活是抗抑郁的假设。这一假说来自我们的试点数据，表明：a)压力和抑郁与更高的PP水平有关，TRIP8b是HCN通道的大脑特异性辅助亚单位；b)胚系敲除TRIP8b-抗抑郁-增加DG神经发生；以及c)PP去抑制(通过敲除TRIP8b降低Ent神经元的兴奋性)增加DG神经发生，具有抗抑郁作用。我们还提供了我们可以通过PP激活来化学刺激DG的可行性数据。基于这些数据，我们将：目标1：确定基于分子的PP去抑制是否通过病毒介导的PP中TRIP8b的KD以及一系列与抑郁相关的和认知行为来促进抗抑郁行为；以及目标2：确定是否通过使用DREADDS(设计者受体，设计者药物独有地激活)来调节神经元的活动和行为来确定PP活动的化学发生刺激是否驱动抗抑郁行为。虽然这里提出的目标包含相当大的风险，但考虑到大量的先导数据和已发表的PP刺激改善海马体认知功能的能力，它们是合乎逻辑的和高度可行的。该项目处于早期和概念阶段，并已有重点的行为结果，使其成为R21机制的理想选择。即使假设是不正确的，实验设计也确保收集的数据将促进我们对大脑回路的了解，这些回路有助于情感和认知。