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

 描述（由申请人提供）：重度抑郁症是最常见的精神疾病之一，影响着全世界数百万人。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%会产生耐药性。因此，需要抗抑郁药的新靶点。越来越多的证据表明抑郁症相关的海马电路变化的重要作用。例如，抑郁的人类和抑郁的动物模型具有较小的海马，以及减少的活动依赖性基因和过程，如海马齿状回（DG）神经发生。值得注意的是，抗抑郁药物和非药物治疗，如电休克治疗改善这些变化。从这些工作中，一个发现新型抗抑郁药的新框架已经出现：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--如脑深部电刺激（DBS）--可以逆转抑郁症相关症状和神经病理学，特别是海马体。引人注目的是，在抑郁症的背景下，DBS仅针对非海马脑区。DBS的主要海马输入-内嗅皮层（Ent）通过穿孔路径（PP）-已被证明在其他情况下的生理学上有益：它增强了人类的记忆和记忆和DG神经发生在实验室动物。然而，它仍然是未知的，如果刺激PP将产生抗抑郁样行为。对于这个探索性和发展性的R21项目，我们将测试的假设，控制激活PP DG是抗抑郁。这一假设来自我们的初步数据，显示：a）应激和抑郁与TRIP 8 B（HCN通道的脑特异性辅助亚基）的更高PP水平相关; B）TRIP 8 B的种系敲除-其是抗抑郁的-增加DG神经发生;和c）PP去抑制（通过TRIP 8 B的敲低来去抑制Ent神经元兴奋性）增加DG神经发生并且是抗抑郁的。我们还提供了d）我们可以通过PP活化化学发生刺激DG的可行性数据。基于这些数据，我们将：目标1：确定是否基于分子的PP去抑制促进抗抑郁行为使用病毒介导的KD的TRIP 8b在PP和抑郁症相关的认知行为电池;和目标2：确定是否PP活性的化学遗传刺激驱动抗抑郁行为使用DREADDs（设计师受体独家激活的设计师药物）介导神经元活动和行为。虽然这里提出的目标涉及相当大的风险，但考虑到大量的试点数据和已发表的PP刺激改善海马认知功能的能力，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，并具有集中的行为成果，使其成为R21机制的理想选择。即使假设是不正确的，实验设计确保收集的数据将推进我们对影响和认知的大脑回路的认识。

 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.