Lateral Habenula in Stress and Resilience

外侧缰核的压力和弹性

• 批准号: 9275023
• 负责人: John F Neumaier
• 金额: $ 38.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275023
• 关键词: Affect; Anhedonia; Animal Model; Animals; Antidepressive Agents; Anxiety; Behavior; Behavioral; Bilateral; Brain region; CAV2 gene; Case Study; Cell Nucleus; Cells; Clozapine; Coupled; Deep Brain Stimulation; Depressed mood; Development; Emotional; Emotions; Epitopes; Fluoxetine; Future; Gene Expression; Genes; Genetic Translation; Glutamates; Goals; Habenula; Health; Human; Individual; Injectable; Lateral; Lead; Learning; Lesion; Life; Ligands; Medial; Mediating; Mental Depression; Messenger RNA; Methods; Modeling; Molecular Target; Moods; Motivation; Neurons; Odors; Output; Oxides; Pathway interactions; Pattern; Phenotype; Pilot Projects; Play; Polyribosomes; Production; Rattus; Refractory; Research; Rewards; Ribosomal Proteins; Role; Saccharin; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Stimulus; Stress; Structure; Swimming; Symptoms; Syndrome; Testing; Tissues; Transgenes; Translations; Validation; Ventral Tegmental Area; Viral Vector; Work; Yang; adeno-associated viral vector; antidepressant effect; designer receptors exclusively activated by designer drugs; dorsal raphe nucleus; early experience; effective therapy; emotional behavior; experimental study; gene product; hedonic; improved; intersectionality; neurochemistry; novel; pleasure; preclinical study; preference; psychologic; public health relevance; receptor; resilience; response; social; stress disorder; stress related disorder; stress resilience; transcriptome sequencing; transgene expression; treatment-resistant depression; vector

 DESCRIPTION (provided by applicant): Currently available antidepressants work well for only a subset of individuals with depression and other stress-related disorders. Therefore, identifying new targets for treating depression is an urgent health imperative. The Lateral Habenula (LHb) is a small, bilateral structure that appears to play a critical role as a relay node connecting several key brain regions that are involved in mood control such as the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTG). The detailed neurochemistry of the LHb is poorly understood. We know that LHb plays a critical role in mediating negative or aversive emotional states relating to mood, reward, and motivation. Pilot studies in humans and animal models suggest that the LHb may be an important target for treating refractory depression. For example, we found that the expression and activation of hM4Di, a Gi-coupled inhibitory DREADD, in LHb produced an antidepressant effect in the forced swim test model of antidepressant action. The primary technical strategy for this project will be the use of intersectional transgene expression in rats using two types of viral vectors: AAV-DIO-transgene vectors (injected into LHb) and CAV2-Cre vectors (injected into one of the projection target regions-DRN, VTA or RMTG). Together these vectors produce transgene expression only in neurons of the desired pathway. This strategy will be used to manipulate the activity of these discrete pathways (with DREADDs) as well as to interrogate mRNA translation in each (with RiboTag). Aim 1 will test which of these LHb pathways is responsible for modulating immobility in the forced swim test. We predict that modulating the LHb to DRN pathway will alter immobility, and that activating the Gi-coupled DREADD with the ligand clozapine-N-oxide will reduce immobility whereas activating the Gs-coupled DREADD will exacerbate immobility. Aim 2 will assess the contribution of these pathways to different domains of stress-related emotional states such as anhedonia (saccharin preference), anxiety (open field), and emotional learning (conditioned place aversion) using DREADDs that activate or inhibit these pathways selectively. Aim 3 will assess how LHb pathways alter the emergence of behavioral vulnerability or resilience in response to repeated social defeat stress. Aim 4 will use RiboTag, an epitope-tagged ribosomal protein, to selectively immunopurify the polyribosomes from the transduced pathways followed by RNAseq and validation of significantly different mRNAs. This will allow us to evaluate the gene expression phenotypes of neurons in each pathway, and to investigate how LHb neurons respond to stress exposure as well as antidepressant treatment. It will be a powerful method for identifying regulatory networks and potential nodes of control that can promote resilience to stress. Together, these experiments will provide a great deal of new information about the functional organization of LHb, its role in animal models of stress, and may help to identify new molecular targets in LHb that can leveraged in the treatment of stress disorders.

 描述（由适用提供）：目前可用的抗抑郁药仅适用于一部分患有抑郁症和其他与压力有关的疾病的人。因此，确定治疗抑郁症的新目标是紧急健康的必要条件。外侧Habenula（LHB）是一种小的双边结构，似乎在中继节点起着关键作用 连接了与情绪控制有关的几个关键大脑区域，例如背侧raphe核（DRN），通风区（VTA）和rosstromedial肿瘤核心（RMTG）。 LHB的详细神经化学知之甚少。我们知道，LHB在介导与情绪，回报和动机有关的负面或厌恶情绪状态中起着关键作用。对人类和动物模型的试点研究表明，LHB可能是治疗难治性抑郁症的重要目标。例如，我们发现在LHB中，HM4Di（一种gi耦合的抑制性无知）的表达和激活在抗抑郁作用的强制游泳测试模型中产生了抗抑郁作用。该项目的主要技术策略将是使用两种类型的病毒矢量在大鼠中使用交叉转化表达：AAV-Dio-dio-transgene载体（注入LHB）和CAV2-CRE矢量（注入了投影靶标的区域之一，将其注入了一个，VTA或RMTG）。这些载体一起仅在所需途径的神经元中产生转化表达。该策略将用于操纵这些离散途径（带有恐惧）的活性，并在每个（带有Ribotag）中询问mRNA翻译。 AIM 1将测试这些LHB途径中的哪个负责调节强制游泳测试中的固定性。我们预测，将LHB调节为DRN途径将改变固定性，并且激活GI耦合的Dreadd与配体氯氮平-N-氧化物将降低固定性，而激活GS耦合的Dreadd Will Will Will Will Will Will Will会加重固定性。 AIM 2将评估这些途径对与压力相关的情绪状态的不同领域的贡献，例如Anhedonia（糖精蛋白偏好），焦虑症（开放式）和情绪学习（有条件的地位），使用Dreadds AIM 3 AIM 3将评估LHB途径如何改变行为脆弱性或对反复的社交击败压力的响应的出现。 AIM 4将使用表位标记的核糖体蛋白Ribotag选择性地免疫性地从转移的途径中进行多核糖体，然后是RNASEQ，并验证明显不同的mRNA。这将使我们能够评估每种途径中神经元的基因表达表型，并研究LHB神经元如何应对胁迫暴露以及抗抑郁治疗的反应。这将是确定可以促进压力弹性的控制网络和潜在控制节点的强大方法。总之，这些实验将提供有关LHB功能组织的大量新信息，其在压力动物模型中的作用，并可能有助于确定LHB中可以利用应力障碍治疗的新分子靶标。