Peptide Receptor Systems

肽受体系统

基本信息

批准号：
7969322
负责人：
Ted B Usdin
金额：
$ 152.23万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7969322
关键词：
Acute Affect Affective Animals Anxiety Area Association Learning Behavior Behavioral Biochemical Biological Assay Blood Circulation Brain Brain region Cell Nucleus Cells Chemicals Cues Data Depressed mood Disease Drug usage Emotional Emotions Evaluation Exhibits Extinction (Psychology)Fiber Freezing Fright Gene-Modified Genes Glutamate Receptor Glutamate Transporter Glutamates Goals Hormones Human Hypothalamic Hormones Hypothalamic structure Infusion procedures Intervention Investigation Knockout Mice Laboratories Lead Learning Lighting Location Maps Mental disorders Molecular Target Moods Mouse Strains Mus Nerve Neurons Neuropeptides Neuroregulator Neurosecretory Systems Nociception Pain Parathyroid Hormone Receptor 2 Parathyroid Hormones Pathway interactions Peptide Receptor Peptides Pharmaceutical Preparations Phenotype Physiological Pituitary Gland Pituitary Hormones Population Positioning Attribute Primates Process Psychotropic Drugs Public Health Rattus Receptor Signaling Regulation Reporting Rodent Role Shock Signal Transduction Site Stress Suggestion Symptoms System Testing Thalamic structure Therapeutic Effect Work behavior test chronic pain classical conditioning design effective therapy environmental change fast-acting neurotransmitter gene function hormone regulation human PTH protein insight neurotransmitter release nonhuman primate novel null mutation object recognition pain behavior paraventricular nucleus receptor receptor density receptor expression release factor response restraint stressor therapeutic target tuberoinfundibular peptide 39

项目摘要

A current major focus of the laboratory is investigation of the physiological functions of the neuropeptide Tuberoinfundibular Peptide of 39 residues (TIP39) and its receptor the Parathyroid Hormone 2 (PTH2) receptor, which were discovered in this laboratory several years ago. TIP39 is synthesized by two discrete groups of neurons that project to areas involved in emotional function. These areas contain a matching distribution of the PTH2 receptor, and neurons in these regions project to the areas containing TIP39 neurons. Thus the system is ideally positioned to coordinate and modulate functions relevant to mental disorders. Our experimental work is performed in rodents, but to evaluate its relevance to human behavior we compared the neuroanatomical distribution of TIP39 and PTH2 receptor expression in humans and non-human primates with the distribution in rodents. During this reporting period we completed a study of the neuroanatomical distribution of the PTH2 receptor and TIP39 that showed that they are extremely similar to each other in human and non-human primates, and to the distributions that we have previously reported in rat and mouse. This suggests that it should be possible to extrapolate from what we learn about this system in rodents to humans. In primates as well as rodents TIP39 containing fibers and PTH2 receptor synthesizing neurons are concentrated in brain regions involved in emotion and hormonal regulation. There is a high TIP39/PTH2 receptor density in the area of the hypothalamic paraventricular nucleus, which is a major regulator of pituitary hormone release. A high degree of colocalization between the PTH2 receptor and a vesicular glutamate transporter indicates that PTH2 receptors are present on glutamatergic neurons. PTH2 receptor containing glutamatergic nerve terminals are adjacent to cells containing each of the major pituitary regulating hormones in this region, suggesting that TIP39 may regulate pituitary function by modulating release of the neurotransmitter glutamate. We tested this idea by infusing TIP39 into the hypothalamic paraventricular nucleus in the presence and absence of drugs that block ionotropic glutamate receptors. We found that TIP39 activated a large number of hypothalamic neurons and that this activation was dependent on the activation of ionotropic glutamate receptors. The infusion of TIP39 also affected the levels of several hormones in the bloodstream. Thus TIP39 appears to be an endogenous regulator of neuroendocrine function, acting by modulating the excitation of cells containing hypothalamic hormone releasing factors. Previously, we found using established behavioral tests such as the open-field, dark-light emergence, shock-probe burying and elevated plus maze under varied lighting or following restraint, that mice with null mutation of the gene encoding TIP39 (TIP39-KO) have increased anxiety-like behavior when stressed. We also found that they exhibit greater fear-like behavior in a Pavlovian conditioning paradigm. The increased fear-like behavior (freezing behavior in the test) appeared to result from increased learning or increased significance of cues and not to a change in extinction of a learned association. We are continuing our investigation of the phenotype of TIP39-KO mice and have developed mice with a null mutation and mice with a conditional null mutation of the gene encoding the PTH2 receptor. We have begun using a more ethologically relevant novel object recognition paradigm to investigate the role of TIP39 signaling. Current evidence supports the suggestion that TIP39 signaling normally modulates behavioral responses to stress. TIP39 and the PTH2 receptor are also present in several brain areas that are part of pain processing pathways. Previous data, using acute administration of synthetic TIP39, supported the suggestion that TIP39/PTH2 receptor signaling modulates pain information. Surprisingly, we found little difference in pain behavior assays in knockout mice. We recently developed a PTH2 receptor antagonist. We used this antagonist to reexamine the potential involvement of TIP39 signaling in pain. Using intrathecal and intracerebroventricular administration we find robust effects in nociceptive assays, and comparing the effects of the antagonist in wild-type and knockout mice clearly shows that the effects are due to block of TIP39 signaling. Greater potency of the antagonist following intracerebral infusion than intrathecal administration, and TIP39 and PTH2 receptor expression in brain areas involved in affective aspects of pain processing such as midline thalamic and amygdalar nuclei suggest that TIP39 signaling is involved in emotional aspects of pain processing. Our interpretation of these data is that TIP39 may normally function to modulate several mood-related functions. We speculate that dysregulation of TIP39 or genes like TIP39 could increase the vulnerability to psychiatric disorders and that endogenous regulation of TIP39 signaling may limit dysfunctional responses that could lead to mood or anxiety-related disease. Chronic pain, anxiety, and depressed mood individually present major public health problems and they also contribute to the burden of many other diseases. Increased understanding of the neuromodulatory systems that affect these symptoms will ultimately lead to better intervention strategies.

该实验室的当前主要重点是研究39个残基（TIP39）的神经肽结核肽肽的生理功能及其受体甲状旁腺激素2（PTH2）受体，这些受体是在该实验室几年前发现的。 TIP39由两个离散的神经元组合成，这些神经元将投影到情感功能所涉及的领域。这些区域包含PTH2受体的匹配分布，以及这些区域中的神经元向包含TIP39神经元的区域投影。因此，该系统的定位是协调和调节与精神障碍相关的功能。我们的实验工作是在啮齿动物中进行的，但是为了评估其与人类行为的相关性，我们比较了人类和非人类灵长类动物中TIP39和PTH2受体表达的神经解剖学分布与啮齿动物中的分布。在此报告期间，我们完成了PTH2受体和TIP39神经解剖学分布的研究，该研究表明它们在人类和非人类灵长类动物以及我们先前在大鼠和小鼠中报告的分布中彼此非常相似。这表明应该可以从我们在啮齿动物中学到的系统向人类中学到的东西推断出来。在灵长类动物和啮齿动物中，含有纤维和PTH2受体合成神经元的TIP39集中在与情绪和激素调节有关的大脑区域中。下丘脑旁脑核的区域中有很高的TIP39/PTH2受体密度，这是垂体激素释放的主要调节剂。 PTH2受体和囊泡谷氨酸转运蛋白之间的高度共定位表明PTH2受体存在于谷氨酸能神经元上。含有谷氨酸能神经末端的PTH2受体与该区域中包含每种主要垂体调节激素的细胞相邻，这表明TIP39可以通过调节神经递质谷氨酸的释放来调节垂体功能。我们通过在存在和不存在阻断离子型谷氨酸受体的药物的情况下将TIP39注入下丘脑旁室核中测试了这一想法。我们发现TIP39激活了大量下丘脑神经元，并且这种激活取决于离子型谷氨酸受体的激活。 TIP39的输注还影响了血液中几种激素的水平。因此，TIP39似乎是神经内分泌功能的内源性调节剂，其作用是通过调节含有下丘脑激素释放因子的细胞的激发。以前，我们发现使用既定的行为测试，例如开放型，黑光出现，掩埋冲击探针和升高的迷宫，在不同的照明或后续约束下进行，而在压力时，基因编码TIP39（TIP39-KO）的基因编码TIP39（TIP39-KO）的无效小鼠在压力时会增加焦虑症状。我们还发现，它们在帕夫洛维亚的调节范式中表现出更大的恐惧行为。恐惧样行为的增加（测试中的冻结行为）似乎是由于学习的增加或提示的意义增加而导致的，而不是导致学习关联的灭绝变化。我们正在继续研究TIP39-KO小鼠的表型，并开发了具有无效突变的小鼠，并且具有编码PTH2受体的基因的条件无效突变。我们已经开始使用更具伦理学相关的新颖对象识别范例来研究TIP39信号的作用。当前的证据支持以下建议：TIP39信号通常调节对压力的行为反应。 TIP39和PTH2受体也存在于几个大脑区域，这些区域是疼痛处理途径的一部分。先前的数据使用急性给药合成TIP39，支持了TIP39/PTH2受体信号传导调节疼痛信息的建议。令人惊讶的是，我们发现敲除小鼠的疼痛行为分析几乎没有差异。我们最近开发了PTH2受体拮抗剂。我们使用该拮抗剂重新检查了TIP39信号传导疼痛的潜在参与。使用鞘内和脑室内给药，我们发现在伤害性测定中有鲁棒的效果，并比较拮抗剂在野生型和敲除小鼠中的影响清楚地表明，这些作用是由于TIP39信号传导的阻滞而产生的。脑内输注后拮抗剂的效力比鞘内给药更大，而在疼痛处理的情感方面，诸如中线丘脑和杏仁核核的脑区域中的TIP39和PTH2受体表达表明TIP39信号与疼痛处理的情绪方面有关。我们对这些数据的解释是，TIP39通常可以调制几个与情绪相关的功能。我们推测，TIP39或TIP39之类的基因的失调可能会增加对精神疾病的脆弱性，并且TIP39信号传导的内源性调节可能会限制可能导致情绪或焦虑有关的疾病的功能失调的反应。慢性疼痛，焦虑和沮丧的情绪单独提出了重大的公共健康问题，它们也会导致许多其他疾病的负担。对影响这些症状的神经调节系统的更多了解最终会导致更好的干预策略。