Midline thalamic control of the amygdala

丘脑中线控制杏仁核

• 批准号: 9091646
• 负责人: DENIS PARE
• 金额: $ 38.75万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091646
• 关键词: Address; Affect; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Automobile Driving; Axon; Behavior; Behavioral; Binding Proteins; Brain; Brain Stem; Cells; Data; Dependovirus; Electrons; Emotions; Food; Freezing; Fright; Functional Imaging; Geniculate body structure; Glutamates; Halorhodopsins; Health; Human; In Vitro; Infusion procedures; Insula of Reil; Interneurons; Intervention; Knowledge; Label; Learning; Left; Light; Mammals; Medial; Medial Dorsal Nucleus; Mediating; Memory; Methods; Microscopic; Midline Thalamic Nuclei; Muscimol; Neurons; Outcome; Output; Parvalbumins; Peptide Receptor; Peptides; Phenotype; Physiological; Play; Prefrontal Cortex; Presynaptic Terminals; Process; Publishing; Rattus; Reporter; Reporting; Research; Role; Safety; Signal Transduction; Slice; Somatostatin; Source; Structure; Techniques; Testing; Thalamic structure; Viral; Work; arm; biocytin; cell type; conditioned fear; differential expression; emotion regulation; experience; extracellular; immunocytochemistry; novel strategies; optogenetics; patch clamp; postsynaptic; programs; receptor expression; research study; response; selective expression; sensory input; treatment of anxiety disorders

 DESCRIPTION (provided by applicant): The amygdala plays a critical role in the genesis of defensive behaviors. Moreover, it is hyperactive in humans afflicted with anxiety disorders. Thus, it is commonly believed that many anxiety disorders result, at least in part, from a dysregulation of amygdala processes normally mediating fear or defensive behaviors. Accordingly, research on the mechanisms controlling amygdala excitability might open new approaches for the treatment of anxiety disorders. This proposal aims to do just that, by studying the influence of midline thalamic (MTh) nuclei on the amygdala. Prior studies on thalamic influences over the amygdala have focused on inputs arising from the posterior thalamus, particularly from the medial portion of the medial geniculate nucleus. Yet, a number of tracing studies have revealed that MTh nuclei also contribute massive projections to the basolateral (BLA) and central (CeA) amygdala. However, other than anatomical data, little is known about the role of these strong glutamatergic inputs. The work proposed here aims to shed light on the influence of MTh inputs to the amygdala. To this end, we will first identify the targets and postsynaptic mechanisms of MTh inputs in the amygdala using anatomical (Aim #1) and physiological (Aim #2) methods. Indeed, BLA and CeA both contain multiple cell types that express different peptides/receptors and form contrasting connections with each other and extrinsic afferents. Therefore, in Aim #1, we will combine anterograde tracing with immunocytochemistry for various neuronal markers to identify the targets of MTh axon terminals in the amygdala at the light and electron microscopic levels. Building on these results, Aim #2 will combine optogenetic and patch clamp recording techniques in vitro to study the impact of MTh inputs on amygdala cells. Armed with this information, the last two aims will examine the influence of MTh cells on amygdala-dependent functions. Indeed, recent studies have revealed that following muscimol infusions in MTh nuclei, the expression of amygdala-dependent learned and innate fear is drastically reduced. However, it is unclear whether these muscimol findings result from the inhibition of nearby thalamic cells (e.g. mediodorsal nucleus), or the disfacilitaton of other targets of MTh nuclei (e.g. prefrontal cortex), that project to the amygdala. Two differen approaches will be used to address this question. First, in Aim #3, we will perform simultaneous extracellular recordings of MTh and amygdala cells during the expression of learned and innate fear. Next, In Aim #4, we will use a dual viral strategy allowing us to express halorhodopsin or channelrhodopsin, but only in MTh cells that project to the amygdala. We will then optogenetically inhibit or excite amygdala-projecting MTh cells and examine how this affects behavior on amygdala-dependent tasks that probe learned or innate fear. Together, the experiments proposed here will reveal how MTh neurons regulate the excitability of the amygdala during the expression of learned and innate fear. This knowledge will pave the way for pharmacological interventions aiming to regulate the activity of midline thalamic cells by taking advantage of their unusual profile of receptor expression.

 描述（由申请人提供）：杏仁核在防御行为的发生中起着关键作用，而且，它在患有焦虑症的人类中过度活跃，因此，人们普遍认为许多焦虑症至少部分是由其引起的。杏仁核过程的失调通常会介导恐惧或防御行为，因此，对控制杏仁核兴奋性的机制的研究可能会为治疗焦虑症开辟新的方法。通过研究中线丘脑（MTh）核对杏仁核的影响，先前关于丘脑对杏仁核影响的研究主要集中在来自后丘脑的输入，特别是来自内侧膝状核的内侧部分。研究表明，MTh 核还对基底外侧杏仁核 (BLA) 和中央杏仁核 (CeA) 做出大量投射。然而，除了解剖数据之外，我们对这些强谷氨酸输入的作用知之甚少，这里提出的工作旨在阐明 MTh 输入对杏仁核的影响。为此，我们将首先使用杏仁核中 MTh 输入的目标和突触后机制。解剖学（目标#1）和生理学（目标#2）方法实际上，BLA 和 CeA 都包含表达不同肽/受体并与每种细胞形成对比连接的多种细胞类型。因此，在目标#1中，我们将结合顺行追踪与免疫细胞化学来检测各种神经元标记，以在光和电子显微镜水平上识别杏仁核中MTh轴突末端的靶标，目标#2。将在体外结合光遗传学和膜片钳记录技术来研究 MTh 输入对杏仁核细胞的影响。有了这些信息，最后两个目标将检查 MTh 输入的影响。事实上，最近的研究表明，在 MTh 细胞核中注入蝇蕈醇后，杏仁核依赖性习得性恐惧和先天性恐惧的表达显着降低。附近的丘脑细胞（例如背内侧核），或 MTh 核团其他目标（例如前额皮质）的障碍，这些细胞投射到首先，在目标 #3 中，我们将在表达习得性恐惧和先天恐惧时同时进行 MTh 和杏仁核细胞的细胞外记录。双重病毒策略使我们能够表达盐视紫红质或通道视紫红质，但仅限于投射到杏仁核的 MTh 细胞，然后我们将通过光遗传学抑制或兴奋。杏仁核投射 MTh 细胞，并研究这如何影响杏仁核依赖性任务的行为，这些任务探究习得性或先天性恐惧，这里提出的实验将揭示 MTh 神经元在习得性和先天性恐惧表达过程中如何调节杏仁核的兴奋性。这些知识将为药物干预铺平道路，旨在通过利用中线丘脑细胞不寻常的受体表达特征来调节其活性。