Mechanisms and significance of programmed cell death in hypothalamic CRH neurons

下丘脑CRH神经元程序性细胞死亡的机制及意义

基本信息

批准号：
10566449
负责人：
YUCHIN Albert Pan
金额：
$ 40万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566449
关键词：
Address Affect Animals Anxiety Apoptosis Brain CRISPR/Cas technology Cell Count Cell Death Cells Corticotropin Corticotropin-Releasing Hormone Development Disease Down Syndrome Cell Adhesion Molecule Excitatory Synapse Functional disorder Future Genetic Glucocorticoid Receptor Glucocorticoids Growth Health Hormones Hydrocortisone Hypothalamic structure Image Impairment Knowledge Measures Mediating Mental Depression Mental disorders Modeling Molecular Monitor Mutate NRCAM gene Neurons Neurosecretory Systems Optics Pathway interactions Pattern Pituitary Gland Play Population Regulation Retina Risk Rodent Role Stress Synapses System Testing Zebrafish acute stress analog biological adaptation to stress cell type early life stress experimental study gain of function hypothalamic-pituitary-adrenal axis interest mutant neural neural circuit neuron loss neuronal excitability neuronal survival novel therapeutics postsynaptic neurons presynaptic neurons stress related disorder stressor synaptogenesis tool

项目摘要

PROJECT SUMMARY/ABSTRACT Corticotropin-releasing hormone (CRH) expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response. CRH neurons integrate stress-related neural inputs and, as part of the hypothalamic-pituitary-adrenal (HPA) axis, induce the release of ACTH and, ultimately, glucocorticoids (cortisol). The development of CRH neurons is of great biomedical interest, as developmental vulnerabilities of CRH neurons contribute to stress-associated disorders such as anxiety and depression. It is, therefore, critical to identify the molecular and cellular mechanisms mediating the development of CRH neurons and determine how developmental changes affect stress response. Using zebrafish, which are genetically accessible and optically translucent, we found that DSCAML1 deficiency impaired the developmental cell death of CRH neurons and caused hyperactivation of the HPI axis (the zebrafish analog of the HPA axis). Given that DSCAML1 is known to mediate intercellular interactions, we hypothesize that proximity-based and synaptic interactions in CRH neurons trigger developmental cell death, which tunes the activity of the neuroendocrine stress response system. To test this, we propose the following aims. In Aim 1, we will test whether proximity-based interactions promote cell death in CRH neurons. Using the live imaging strength of the zebrafish model, we will examine whether interactions between adjacent CRH neurons promote cell death and determine how varying levels of DSCAML1 modulate the extent of cell loss. In Aim 2, we will test whether synaptic interactions affect CRH neuron cell death. Synaptic activity plays an instructive role in neuronal survival. Given DSCAML1’s known functions in synaptogenesis, we will investigate whether CRH neuron survival is dependent on neuronal activity and how DSCAML1-mediated synaptogenesis controls the excitability of CRH neurons. In Aim 3, we will test how DSCAML1 acts within CRH neurons to trigger cell death and establish HPI-axis activity. Using CRH neuron-specific mutants, we will determine how DSCAML1 functions within CRH neurons and whether DSCAML1’s function in other cell types also contributes to HPI-axis development. In Aim 4, we will test the hypothesis that CRH neuron number tunes HPI-axis activity. While the significance of cell death is widely recognized, the functional impact of CRH neuron cell death has not been explored. We will use genetic tools to increase or decrease CRH neuron number and determine the causal relationship between cell number and HPI-axis activity. Together, these aims will shed light on how intercellular interactions influence CRH neuron cell death and provide a molecular framework for future molecular studies.

项目概要/摘要下丘脑中表达促肾上腺皮质激素释放激素 (CRH) 的神经元是 CRH 神经元整合应激相关的神经输入，并作为神经内分泌应激反应的一部分。下丘脑-垂体-肾上腺 (HPA) 轴，诱导 ACTH 的释放，并最终诱导糖皮质激素的释放（皮质醇） CRH 神经元的发育具有重大的生物医学意义，因为 CRH 神经元的发育脆弱性。因此，CRH 神经元会导致焦虑和抑郁等压力相关疾病。确定介导 CRH 神经元发育的分子和细胞机制并确定使用斑马鱼来研究发育变化如何影响应激反应。光学半透明，我们发现 DCAML1 缺陷损害了 CRH 的发育细胞死亡神经元并导致 HPI 轴（HPA 轴的斑马鱼类似物）过度激活。 DCAML1 已知可介导细胞间相互作用，我们捕获了基于邻近性和突触的相互作用 CRH 神经元的相互作用触发发育细胞死亡，从而调节神经内分泌的活动为了测试这一点，我们在目标 1 中提出了以下目标：基于邻近性的相互作用促进 CRH 神经元的细胞死亡。在斑马鱼模型中，我们将检查相邻 CRH 神经元之间的相互作用是否会促进细胞死亡和确定不同水平的 DCAML1 如何调节细胞损失的程度在目标 2 中，我们将测试是否。突触相互作用影响 CRH 神经元细胞死亡突触活动在神经元中起着指导作用。鉴于 DCAML1 在突触发生中的已知功能，我们将研究 CRH 神经元是否具有生存能力。生存取决于神经元活动以及 DCAML1 介导的突触发生如何控制 CRH 神经元的兴奋性在目标 3 中，我们将测试 DCAML1 如何在 CRH 神经元内发挥作用来触发细胞。使用 CRH 神经元特异性突变体来确定 DCAML1 的死亡并建立 HPI 轴活性。 CRH 神经元内的功能以及 DCAML1 在其他细胞类型中的功能是否也有助于 HPI 轴在目标 4 中，我们将测试 CRH 神经元数量调节 HPI 轴活动的假设。虽然细胞死亡的重要性已被广泛认识，但 CRH 神经元细胞死亡的功能影响我们将使用遗传工具来增加或减少 CRH 神经元数量并确定细胞数量和 HPI 轴活动之间的因果关系将共同阐明这些目标是如何产生的。细胞间相互作用影响 CRH 神经元细胞死亡并为未来提供分子框架分子研究。