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（由适用提供）：杏仁核在防御行为的起源中起关键作用。此外，它在患有焦虑症的人类中过度活跃。这通常认为，至少部分是由于通常介导恐惧或防御行为的杏仁核过程的失调而导致许多焦虑症。根据，对控制杏仁核令人兴奋的机制的研究可能为治疗焦虑症的新方法开辟了新方法。该提议旨在通过研究中线丘脑（MTH）核对杏仁核的影响来做到这一点。先前关于丘脑对杏仁核的影响的研究集中在丘脑后丘脑引起的投入上，尤其是媒体介质部分。然而，许多追踪研究表明，MTH核也为Basolatoral（BLA）和Central（CEA）杏仁核贡献了巨大的项目。但是，除了解剖学数据外，对这些强谷氨酸能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，我们首先使用解剖学（AIM＃1）和物理（AIM＃2）方法来确定杏仁核中MTH输入的目标和突触后机制。实际上，BLA和CEA都包含多种表达不同肽/受体的细胞类型，并彼此形成对比的连接和外部传入。因此，在AIM＃1中，我们将对各种神经元标记的免疫细胞化学进行顺行追踪，以在光和电子显微镜水平下鉴定杏仁核中MTH轴突末端的靶标。在这些结果的基础上，AIM＃2将在体外结合光遗传学和贴片夹记录技术，以研究MTH输入对杏仁核细胞的影响。持有这些信息，最后两个目标将检查MTH细胞对杏仁核依赖性功能的影响。实际上，最近的研究表明，在MTH核中麝香酚的输注后，杏仁核依赖的学习和先天恐惧的表达大大减少了。但是，尚不清楚这些肌抗酚的发现是抑制近丘脑细胞（例如培养基核），还是其他核的其他靶标（例如，前额叶皮层）的disfacilitaton，该靶标会向杏仁核。将使用两种不同的方法来解决这个问题。首先，在AIM＃3中，我们将在学习和先天恐惧的表达期间同时对MTH和Amygdala细胞进行细胞外记录。接下来，在AIM＃4中，我们将使用双重病毒策略，使我们能够表达甲状腺素或通道旋转蛋白，但仅在投射到杏仁核的MTH细胞中。然后，我们将光学上抑制或激发杏仁核预测的MTH细胞，并检查这如何影响探测或天生恐惧的杏仁核依赖性任务的行为。共同提出的实验将揭示MTH神经元如何调节杏仁核的兴奋，这是在学识渊博和天生的恐惧表达过程中如何调节杏仁核的。这些知识将为药物干预措施铺平道路，旨在通过利用其异常的受体表达概况来调节中线丘脑细胞的活性。