Peptide Receptor Systems

肽受体系统

• 批准号: 8939952
• 负责人: Ted B Usdin
• 金额: $ 102.43万
• 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/8939952
• 关键词: Acute; Acute Pain; Address; Adrenal Glands; Adult; Affect; Affective; Amygdaloid structure; Animal Model; Animals; Anxiety; Area; Arousal; Aversive Stimulus; Behavior; Behavioral; Biochemical; Brain; Brain Stem; Brain region; Cell Nucleus; Cognitive; Collaborations; Data; Dimensions; Drug usage; Emotional; Emotions; Environment; Excision; Exhibits; Freezing; Fright; Future; Gene Deletion; Gene-Modified; Genetic; Glucocorticoids; Glutamates; Goals; Half-Life; Hippocampus (Brain); Hormones; Human; Hypersensitivity; Hypothalamic structure; Immediate-Early Genes; Intervention; Intralaminar Nuclear Group; Investigation; Knowledge; Laboratories; Lead; Ligands; Link; Location; Maintenance; Maps; Maternal Behavior; Measures; Memory; Mental Depression; Mental disorders; Modeling; Molecular Target; Mood Disorders; Moods; Mus; Nerve; Neuroendocrine Cell; Neuromodulator; Neurons; Neuropathy; Neuropeptides; Neurosecretory Systems; Nociception; Pain; Pain Disorder; Pain management; Parathyroid Hormone Receptor 2; Pathway interactions; Peptide Receptor; Performance; Pharmaceutical Preparations; Pharmacogenetics; Physiologic Thermoregulation; Physiological; Plastics; Play; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Preclinical Drug Evaluation; Process; Prolactin; Proliferating Cell Nuclear Antigen; Psychotropic Drugs; Regulation; Rodent; Role; Sensory; Shock; Signal Transduction; Site; Spinal Cord; Stimulus; Stress; Structure of nucleus infundibularis hypothalami; Swimming; Symptoms; System; Tactile; Temperature; Testing; Thalamic structure; Time; Treatment Efficacy; adult neurogenesis; allodynia; behavior change; behavior test; chronic pain; density; design; environmental change; fast-acting neurotransmitter; gene function; hormone regulation; insight; locus ceruleus structure; mouse model; neurochemistry; neurogenesis; noradrenergic; novel; null mutation; object recognition; painful neuropathy; paraventricular nucleus; performance tests; preoptic nucleus; presynaptic; prevent; pup; receptor; research study; resilience; response; sciatic nerve; sensory stimulus; stressor; therapeutic target; tuberoinfundibular peptide 39

Investigation of the physiological functions of the neuropeptide Tuberoinfundibular Peptide of 39 residues (TIP39) and its receptor, the Parathyroid Hormone Receptor 2 (PTH2R) has been a recent focus of the section. These molecules were discovered in this laboratory several years ago. In previous project years we mapped their neuroanatomical distributions. TIP39 is synthesized in 3 discrete groups of neurons, 2 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 PTH2Rs, 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 the anatomical mapping of TIP39 and the PTH2R laboratory projects turned to investigation of hypotheses derived from their distribution. The hypothalamus contains a relatively high density of PTH2R and TIP39 containing terminals. In previous project years we found that TIP39 modulates activation of neurons in the hypothalamic paraventricular nucleus, which controls several neuroendocrine functions, including release of glucocorticoid stress hormones from the adrenal gland. TIP39 does this by acting on the terminals of neurons within the paraventricular nucleus that release the classic fast-acting transmitter glutamate. Thus TIP39 modulates excitatory inputs to neuroendocrine cells. We also found that TIP39 signaling in the hypothalamic median preoptic nucleus contributes to thermoregulation. An appropriate homeostatic response to cold exposure required TIP39 signaling, while maintenance of a normal baseline temperature in an environment to which mice were adapted did not. These studies lead to the general model proposing that TIP39 action on presynaptic PTH2Rs on some populations of glutamatergic neurons may be necessary for robust and sufficient excitatory transmitter release under particular high demand conditions. Previously we found that mice with genetic deletion of the genes encoding TIP39 (TIP39-KO) or null mutation of the PTH2R (PTH2R-KO) have a greater increase in anxiety-like behavior under stressful testing conditions than mice with normal TIP39 function. We also found that under conditions of novelty-induced arousal but not when acclimated to the testing environment mice that lack TIP39 signaling, because of either ligand or receptor loss or acute receptor blockade, have impaired performance in behavioral tests that depend on memory function. Using a mouse model of post-traumatic stress disorder we obtained evidence that TIP39 signaling modulates long-term emotional memory. In this model animals are exposed to a single aversive stimulus, after which fear memory is evaluated by measuring the time spent motionless (freezing, a rodent fear-like response) when the animals are re-exposed to the context in which the stimulus was delivered. While the absence of TIP39 signaling did not cause a detectable change in fear memory one week after the shock, both TIP39-KO and PTH2R-KO mice exhibited greater fear-like behavior than wild-type littermates two weeks following the shock. During this review period we found that the increased behavioral response lasts at least two months. Using a pharmacogenetic approach to transiently inhibit their function we found that PTH2R expressing neurons play a critical role at the time of the initial aversive stimulus. Thus our data suggest that TIP39 signaling may normally limit the detrimental effects of environmental stress on emotional state. Dysfunctional responses to stress are widely thought to contribute to depression, implying that this neuropeptide system plays a role in normal resilience. Pain and depression are frequently associated. However, the extent to which pain affects mood or to which mood affects pain is not clear. Interactions within overlapping brain regions that are critically involved in the affective dimensions of pain and other emotional responses are likely to contribute to the links between chronic pain and mood disorders, but there is little relevant data. We previously found that TIP39 modulates acute pain sensitivity, acting primarily within the brain to affect the processing of nociceptive sensory information. We then found that TIP39 signaling has a large effect on the control of nociceptive sensitivity in models of chronic pain. This effect of TIP39 appeared to involve modulation of function of the locus coeruleus (LC), a brainstem nucleus that contains noradrenergic neurons with a modulatory influence in much of the CNS. In combination with other observations this suggests that TIP39 may be one of the modulators involved in the relationship between sensory stimuli and mood. A next step in this line of investigation is to evaluate the effects of TIP39 or other neuromodulators on mood and anxiety related behavior in pain models. Difficulty distinguishing between effects of ongoing aversive sensory input and its long-term consequences is a significant roadblock for the design and implementation of these experiments. To overcome this limitation the section developed a paradigm to investigate and compare cellular and behavioral changes during and after reversing a mouse model of neuropathic pain. Tactile allodynia produced by placing a plastic cuff around the sciatic nerve resolved within several days when the cuff was removed. In contrast, changes in elevated O-maze, forced-swim, Y-maze spontaneous alternation and novel-object recognition test performance that developed after nerve cuff placement remained for at least three weeks after nerve cuffs were removed. The cellular changes underlying depression are unclear, but one contemporary hypothesis suggests that low levels of adult neurogenesis play a role. Adult hippocampal neurogenesis is inhibited in chronic pain models suggesting that changes in neurogenesis may be involved in depression associated with chronic pain. We therefore evaluated hippocampal neurogenesis in the reversible neuropathic model. Expression of proliferating cell nuclear antigen and doublecortin, which are synthesized by neurons that are in a state of proliferation or differentiation respectively, was suppressed after nerve cuff placement and remained suppressed three weeks after cuff removal. We observed that expression of FosB, an immediate early gene with a relatively long half-life, remained elevated in the basolateral amygdala of mice with resolved nociception and persisting behavioral effects, while it declined to baseline levels in the spinal cord and central amygdalar nucleus. Observations made using the reversible nerve cuff paradigm suggest that different processes control tactile hypersensitivity and the behavioral changes and impaired neurogenesis that are associated with neuropathic allodynia. Future studies will address the relevance of plasticity in the basolateral amygdalar nucleus and changes in hippocampal neurogenesis to the effects of pain on mood and behavior changes. The newly developed paradigm provides an approach for the identification of mechanisms that link pain and other conditions, as well as for screening drugs to prevent or alleviate depression associated with poorly controlled pain. The section has an ongoing collaboration with Dr. Arpad Dobolyi to investigate the contribution of TIP39 signaling to maternal behavior. During this review period we obtained evidence that TIP39 signaling in a projection from the thalamic posterior intralaminar nucleus to the hypothalamic arcuate nucleus is an important part of a pathway by which pup suckling leads to prolactin secretion.

研究了39个残基（TIP39）及其受体甲状旁腺激素受体2（PTH2R）的神经肽结核肽肽的生理功能的研究。这些分子是几年前在这个实验室中发现的。在过去的项目中，我们绘制了他们的神经解剖分布。 TIP39是在3个离散的神经元组中合成的，在丘脑的尾端有2个，一个在脑干中合成。 TIP39将神经元的合成项目投影到与情绪功能调节有关的几个大脑区域。这些区域包含PTH2RS的匹配分布，这些区域中的神经元将其投影到包含TIP39神经元的区域。因此，该系统的定位是协调和调节与精神障碍相关的功能。 在TIP39和PTH2R实验室项目的解剖学映射之后，转向调查从其分布中得出的假设。下丘脑包含含有末端的PTH2R和TIP39的密度相对较高。在过去的项目中，我们发现TIP39调节下丘脑旁脑室中神经元的激活，该核控制着多种神经内分泌功能，包括从肾上腺中释放糖皮质激素应激激素。 TIP39通过作用于释放经典快速发射器谷氨酸的室核内神经元的末端来做到这一点。因此，TIP39调节神经内分泌细胞的兴奋性输入。我们还发现，下丘脑中值前核中的TIP39信号传导有助于体温调节。对冷暴露的适当稳态反应需要提示39信号传导，而在适应小鼠的环境中维持正常基线温度则没有。这些研究导致一般模型提出TIP39对某些谷氨酸能神经元的突触前PTH2R的作用对于在特定的高需求条件下鲁棒和足够的兴奋性发射器释放可能是必需的。 以前，我们发现，与正常TIP39功能的小鼠相比，在压力测试条件下，具有遗传缺失的小鼠（tip39-ko）或PTH2R（PTH2R-KO）的无效的PTH2R（PTH2R-KO）无效突变的小鼠具有更大的焦虑样行为行为。我们还发现，在新颖性引起的唤醒条件下，但在适应缺乏TIP39信号传导的测试环境小鼠时，由于配体或受体丧失或急性受体阻滞，在取决于记忆功能的行为测试中的性能受损。使用创伤后应激障碍的小鼠模型，我们获得了TIP39信号传导调节长期情绪记忆的证据。在该模型中，动物暴露于单个厌恶刺激中，此后通过测量动物将动物的时间不断地暴露于传递刺激的情况下，通过测量一动不动的时间（冻结，类似啮齿动物的恐惧反应）来评估恐惧记忆。虽然TIP39信号传导的缺失并没有引起恐惧记忆发生后一周的恐惧记忆的可检测变化，但TIP39-KO和PTH2R-KO小鼠均表现出比野生型窝式同窝夫人在冲击后两周都表现出更大的恐惧行为。在此审查期间，我们发现行为反应的增加至少持续两个月。使用药物遗传学方法瞬时抑制其功能，我们发现表达神经元的PTH2R在初始厌恶刺激时起着至关重要的作用。因此，我们的数据表明，TIP39信号通常可能会限制环境压力对情绪状态的有害影响。人们普遍认为对压力的功能失调会导致抑郁症，这意味着该神经肽系统在正常的弹性中起着作用。 疼痛和抑郁经常相关。但是，疼痛影响情绪或情绪影响疼痛的程度尚不清楚。重叠的大脑区域内的相互作用与疼痛和其他情绪反应的情感维度有关，可能会导致慢性疼痛与情绪障碍之间的联系，但几乎没有相关数据。我们先前发现，TIP39调节急性疼痛敏感性，主要作用在大脑内部，以影响伤害感受感官信息的处理。然后，我们发现TIP39信号对慢性疼痛模型中伤害感受敏感性的控制具有很大的影响。 TIP39的这种效果似乎涉及对基因座（LC）功能的调节，该基因座（LC）是一种脑干核，其中包含甲肾上腺素能神经元在许多CNS中具有调节作用。结合其他观察结果，这表明TIP39可能是参与感觉刺激与情绪之间关系的调节剂之一。 这一调查的下一步是评估TIP39或其他神经调节剂对疼痛模型中情绪和焦虑相关行为的影响。难以区分持续的厌恶感官输入的影响及其长期后果是这些实验设计和实施的重要障碍。为了克服这一局限性，该部分开发了一个范式，以调查和比较逆转神经性疼痛小鼠模型期间和之后的细胞和行为变化。触觉异常性异常症是通过将袖子在去除袖口的几天内在坐骨神经周围放置在坐骨神经周围而产生的。相反，O-Maze，强迫速度，Y迷宫自发的交替和新型对象识别测试表现的变化在神经袖口放置后发育至少三周后，去除神经袖口后至少三周。 抑郁症的基础变化尚不清楚，但是一个当代的假设表明，较低水平的成年神经发生起作用。在慢性疼痛模型中抑制了成年海马神经发生，这表明神经发生的变化可能与慢性疼痛相关的抑郁症涉及。因此，我们评估了可逆神经性模型中的海马神经发生。神经袖口放置后，抑制了分别处于增殖或分化状态的神经元合成的神经元合成的增殖细胞核抗原和双铁蛋白的表达，并在袖口去除后三周被抑制。我们观察到，FOSB的表达是一种具有相对较长半衰期的早期基因，在小鼠的基底外侧杏仁核中保持升高，具有分辨的伤害感受和持续的行为效应，而脊髓和中央amygdalar nucleus却拒绝底线。 使用可逆的神经袖口范式进行的观察结果表明，不同的过程控制触觉超敏反应以及与神经性异常性异常性异常相关的行为变化和神经发生受损。未来的研究将解决可塑性在基底外侧杏仁核中的相关性，以及海马神经发生与疼痛对情绪和行为变化的影响的变化。新开发的范式提供了一种方法来识别将疼痛和其他疾病联系起来的机制，以及筛查药物以预防或减轻与无法控制的疼痛相关的抑郁症。 该部分与Arpad Dobolyi博士进行了持续的合作，以研究TIP39信号对孕产妇行为的贡献。在此审查期间，我们获得了证据表明，在丘脑后后部核的投影中，tip39信号传导到下丘脑弧形核心核是幼犬哺乳的途径的重要组成部分。