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。此外，它在患有焦虑症的人中过度活跃。因此，人们普遍认为，许多焦虑症至少部分是由通常介导恐惧或防御行为的杏仁核过程失调引起的。因此，对杏仁核兴奋性控制机制的研究可能为焦虑症的治疗开辟新的途径。这项提议的目的正是通过研究丘脑中线（MTh）核团对杏仁核的影响来实现这一目标。以往关于丘脑对杏仁核影响的研究主要集中在后丘脑，特别是内侧膝状体内侧部的输入。然而，一些追踪研究表明，MTh核也有助于大量的投射到基底外侧（BLA）和中央（CeA）杏仁核。然而，除了解剖学数据，很少有人知道这些强大的神经递质输入的作用。这里提出的工作旨在阐明MTh输入对杏仁核的影响。为此，我们将首先使用解剖学（目标#1）和生理学（目标#2）方法确定杏仁核中MTh输入的靶点和突触后机制。事实上，BLA和CeA都含有多种细胞类型，表达不同的肽/受体，并与彼此和外部传入形成对比连接。因此，在目标#1中，我们将结合联合收割机顺行追踪与免疫细胞化学的各种神经元标记物，以确定目标的MTh轴突终末在杏仁核在光镜和电镜水平。在这些结果的基础上，目标#2将在体外结合联合收割机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细胞对杏仁核依赖性功能的影响。事实上，最近的研究表明，在MTh核中注入蝇蕈醇后，杏仁核依赖性学习和先天恐惧的表达急剧减少。然而，目前尚不清楚这些蝇蕈醇的发现是否是由于抑制附近的丘脑细胞（例如，中背核），或MTh核的其他靶点（例如，前额叶皮层）的障碍，这些靶点投射到杏仁核。将采用两种不同的方法来解决这个问题。首先，在目标3中，我们将在习得性和先天性恐惧的表达过程中同时进行MTh和杏仁核细胞的细胞外记录。接下来，在目标#4中，我们将使用双重病毒策略，允许我们表达盐视紫红质或通道视紫红质，但仅在投射到杏仁核的MTh细胞中。然后，我们将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的任务，探测学习或先天恐惧的行为。总之，这里提出的实验将揭示MTh神经元如何调节杏仁核的兴奋性在表达学习和先天的恐惧。这一知识将铺平道路的药理学干预，旨在调节中线丘脑细胞的活性，利用他们的受体表达的不寻常的配置文件。