Peptide Receptor Systems

肽受体系统

• 批准号: 8342114
• 负责人: Ted B Usdin
• 金额: $ 110.11万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 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/8342114
• 关键词: Acclimatization; Acute; Adrenal Glands; Affect; Animals; Anxiety; Area; Arousal; Behavior; Behavioral; Biochemical; Birth; Brain; Brain Stem; Brain region; Chemicals; Cognitive; Collaborations; Corticosterone; Data; Disease model; Drug usage; Emotional; Emotions; Environment; Event; Exhibits; Female; Freezing; Fright; Functional disorder; Future; Gene Deletion; Gene Mutation; Gene-Modified; Genes; Genetic; Genotype; Glucocorticoids; Glutamates; Goals; Hormonal; Hormones; Human; Hungary; Hypothalamic structure; Intervention; Investigation; Laboratories; Ligands; Location; Maps; Maternal Behavior; Measures; Mediator of activation protein; Memory; Memory impairment; Mental disorders; Milk; Molecular Target; Mood Disorders; Moods; Mouse Strains; Mus; Neuroendocrine Cell; Neurons; Neuropeptides; Neuroregulator; Neurosecretory Systems; Pain; Parathyroid Hormone Receptor 2; Parathyroid gland; Partner in relationship; Pathway interactions; Patients; Peptide Receptor; Peptides; Performance; Pharmaceutical Preparations; Physiological; Pituitary Hormones; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Production; Prolactin; Psychotropic Drugs; Rattus; Regulation; Reporting; Rodent; Role; Sensory; Shock; Short-Term Memory; Signal Transduction; Site; Stress; Symptoms; System; Testing; Thalamic structure; Time; Treatment Efficacy; Universities; Weight; Weight Gain; Wild Type Mouse; chronic depression; chronic pain; cognitive function; design; environmental change; fast-acting neurotransmitter; foot; gene function; hormone regulation; insight; male; mouse model; neurochemistry; novel; null mutation; object recognition; paraventricular nucleus; postnatal; prenatal; pup; receptor; research study; response; sex; sexual dimorphism; social; stressor; therapeutic target; tuberoinfundibular peptide 39; vpr Genes

Summary: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. These molecules were discovered in this laboratory several years ago. In previous years of this project we mapped the neuroanatomical distributions of TIP39 and the PTH2 receptor. TIP39 is synthesized by three discrete groups of neurons, two at the caudal border of the thalamus and one in the brainstem. TIP39 synthesizing neurons project to several brain areas that are involved in the regulation of 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. Following this anatomical mapping, laboratory projects turned to investigation of hypotheses derived from the distribution of TIP39 and the PTH2R. We found recently that TIP39 modulates activation of neurons in the paraventricular nucleus of the hypothalamus, which controls several neuroendocrine functions, including release of glucocorticoid stress hormone from the adrenal gland. TIP39 increased the stress hormone corticosterone. TIP39 does this by acting on the terminals of neurons within the paraventricular nucleus that release the classic fast-acting transmitter glutamate, thus it modulates excitatory inputs to neuroendocrine cells. We also found that TIP39 modulates pain sensitivity, acting primarily within the brain to affect the processing of painful sensory information. The brain areas where TIP39 appears to modulate pain are also implicated in affective disorders, so a hypothesis we plan to examine in the future is that TIP39 signaling is involved in the strong relationship between chronic pain and depression. In previous years of the project we found that mice with genetic deletion of the gene encoding TIP39 (TIP39-KO) have increased anxiety-like behavior that depends upon the stress created by the testing conditions. Under conditions of minimal stress loss of TIP39 had little effect, while under increased stress animals without TIP39 exhibited significantly greater anxiety-like behavior than mice with normal TIP39 function. During this reporting period we investigated the role of TIP39 in modulating the effects of stress on cognitive function. We tested TIP39-KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2-R), in tasks of short-term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y-maze test) under conditions of novelty-induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling because of either ligand or receptor loss showed memory impairment, under conditions of novelty-induced arousal but not when acclimated to the testing environment. We also found that acute intracerebral administration of a PTH2R antagonist we developed reproduced the effect of the genetic mutations, indicating that these deficits resulted from loss of TIP39 signaling at the time of the experiment. Thus our data suggest that TIP39 signaling may normally limit the detrimental effects of environmental stress on cognitive performance. Patients with a number of mental health disorders exhibit much greater dysfunction in a novel environment and under stress than under familiar conditions. We previously found that the neuroanatomical distributions of TIP39 and the PTH2-R are almost identical in humans and rodents, so this suggests that TIP39 signaling may be involved in limiting deleterious effects of stress in humans. During this reporting period we also began looking at the effects of TIP39 signaling on long-term emotional memory. We used a mouse model of post-traumatic stress disorder in which the animals are exposed to a single traumatic event (electric foot-shock) after which fear memory is evaluated by re-exposing them to the context of the traumatic event and measuring the time spent motionless (freezing, a rodent fear-like response). The lack of TIP39 signaling did not cause a detectable change in fear memory one week after the shock. However, both mice lacking the peptide gene as well as mice with null mutation in the PTH2-R gene exhibited greater fear-like behavior than wild-type mice two weeks following the shock. This suggests that, similar to its role in short-term cognitive performance, TIP39 normally limits the long-term detrimental effects of fear or stress. Mice without TIP39 signaling also exhibited increased anxiety-like behavior two weeks following the shock, a behavior also consistent with a post-traumatic stress disorder model. Most of our studies have been performed in male animals, although we did find a significant sexual dimorphism in the postnatal expression of TIP39 in rats. There is a significant post-pubertal decline in TIP39 in male rats and a significantly smaller decline in females, suggesting involvement in sex specific functions. In the previous reporting period we found that TIP39 modulates release of the pituitary hormone prolactin in male mice. Prolactin is a major mediator of maternal functions, including milk production. We have now begun examining the role of TIP39 signaling in female-specific functions. In a continuing collaboration with Dr. Arpad Dobolyi of Semmelweis University in Hungary, we found that TIP39 levels are significantly increased in lactating females, that pup suckling activates the neurons that synthesize TIP39, and that acute block of TIP39 signaling inhibits the stimulation of prolactin release normally caused by pup suckling. In a study comparing wild-type and PTH2R-KO mouse dams we found no significant differences in their maternal behaviors, but the pups of PTH2R-KO dams gained weight significantly more slowly than the pups of WT dams in the postnatal period. By mating wild-type males with KO females and KO males with WT females all pups had identical genotypes. Pup weights were the same at birth, indicating that postnatal and not prenatal factors affected the weight gain, which is consistent with TIP39 modulation of the sensitivity of prolactin release to pup suckling. Together with previous data this suggests that TIP39 helps to control which or how effectively hypothalamic excitatory pathways control neuroendocrine function, contributing to an appropriate hormonal response to changing conditions.

摘要：实验室目前的主要工作重点是研究39个残基的神经肽结节漏斗肽（TIP39）及其受体甲状旁腺激素2（PTH2）受体的生理功能。这些分子是几年前在这个实验室发现的。在该项目的前几年，我们绘制了 TIP39 和 PTH2 受体的神经解剖学分布图。 TIP39 由三组独立的神经元合成，其中两组位于丘脑尾部边缘，一组位于脑干。 TIP39 合成神经元投射到涉及情绪功能调节的多个大脑区域。这些区域包含匹配的 PTH2 受体分布，这些区域中的神经元投射到包含 TIP39 神经元的区域。因此，该系统非常适合协调和调节与精神障碍相关的功能。根据该解剖图，实验室项目转而研究源自 TIP39 和 PTH2R 分布的假设。 我们最近发现，TIP39 调节下丘脑室旁核神经元的激活，控制多种神经内分泌功能，包括肾上腺释放糖皮质激素应激激素。 TIP39 增加应激激素皮质酮。 TIP39 通过作用于室旁核内的神经元末端来实现这一点，释放经典的快速作用递质谷氨酸，从而调节神经内分泌细胞的兴奋性输入。 我们还发现 TIP39 调节疼痛敏感性，主要在大脑内发挥作用，影响疼痛感觉信息的处理。 TIP39 似乎调节疼痛的大脑区域也与情感障碍有关，因此我们计划在未来研究的一个假设是，TIP39 信号传导与慢性疼痛和抑郁之间的密切关系有关。 在该项目的前几年中，我们发现 TIP39 编码基因（TIP39-KO）基因缺失的小鼠的焦虑样行为有所增加，这取决于测试条件产生的压力。 在最小应激条件下，TIP39 缺失几乎没有影响，而在应激增加时，没有 TIP39 的动物比具有正常 TIP39 功能的小鼠表现出明显更大的焦虑样行为。 在本报告期内，我们研究了 TIP39 在调节压力对认知功能的影响中的作用。我们测试了 TIP39-KO 小鼠和其受体甲状旁腺激素 2 受体 (PTH2-R) 零突变小鼠的短期陈述性记忆和社会记忆任务（分别为物体识别和社会识别测试）以及工作任务。在新奇引起的唤醒或适应测试条件的条件下的记忆（Y 迷宫测试）。由于配体或受体丢失而缺乏 TIP39 信号的小鼠在新奇事物引起的兴奋条件下表现出记忆障碍，但在适应测试环境时则不然。 我们还发现，我们开发的 PTH2R 拮抗剂的急性脑内给药再现了基因突变的效果，表明这些缺陷是由于实验时 TIP39 信号传导的丢失造成的。因此，我们的数据表明，TIP39 信号传导通常可以限制环境压力对认知表现的不利影响。患有多种精神疾病的患者在新的环境和压力下比在熟悉的条件下表现出更大的功能障碍。 我们之前发现 TIP39 和 PTH2-R 在人类和啮齿动物中的神经解剖学分布几乎相同，因此这表明 TIP39 信号传导可能参与限制压力对人类的有害影响。 在本报告期间，我们还开始研究 TIP39 信号传导对长期情绪记忆的影响。 我们使用了创伤后应激障碍的小鼠模型，其中动物暴露于单一创伤事件（电击足部），之后通过将它们重新暴露于创伤事件的背景并测量时间来评估恐惧记忆一动不动（冻结，类似啮齿类动物的恐惧反应）。 电击一周后，TIP39 信号传导的缺失并未导致恐惧记忆发生可检测到的变化。然而，在电击两周后，缺乏肽基因的小鼠以及 PTH2-R 基因无效突变的小鼠都比野生型小鼠表现出更强的恐惧样行为。 这表明，与它在短期认知表现中的作用类似，TIP39 通常会限制恐惧或压力的长期有害影响。 没有 TIP39 信号传导的小鼠在电击两周后也表现出焦虑样行为增加，这种行为也与创伤后应激障碍模型一致。 我们的大部分研究都是在雄性动物中进行的，尽管我们确实发现大鼠出生后 TIP39 表达存在显着的性别二态性。 雄性大鼠青春期后 TIP39 显着下降，雌性大鼠下降幅度明显较小，表明与性别特异性功能有关。在之前的报告中，我们发现 TIP39 调节雄性小鼠垂体激素催乳素的释放。 催乳素是母体功能（包括产奶量）的主要调节因子。我们现在开始研究 TIP39 信号传导在女性特异性功能中的作用。在与匈牙利 Semmelweis 大学的 Arpad Dobolyi 博士的持续合作中，我们发现哺乳期雌性中 TIP39 水平显着升高，幼崽哺乳会激活合成 TIP39 的神经元，并且 TIP39 信号传导的急性阻断会抑制催乳素释放的刺激通常是由幼犬吃奶引起的。 在一项比较野生型和 PTH2R-KO 母鼠的研究中，我们发现它们的母性行为没有显着差异，但 PTH2R-KO 母鼠的幼鼠在出生后的体重增长速度明显慢于 WT 母鼠。 通过将野生型雄性与 KO 雌性以及 KO 雄性与 WT 雌性交配，所有幼崽都具有相同的基因型。 幼仔出生时体重相同，表明产后而非产前因素影响体重增加，这与 TIP39 对催乳素释放对幼仔哺乳敏感性的调节一致。 结合之前的数据，这表明 TIP39 有助于控制下丘脑兴奋性通路控制神经内分泌功能的方式或方式，从而有助于对不断变化的条件做出适当的激素反应。