Peptide Receptor Systems

肽受体系统

基本信息

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
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/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

项目摘要

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.

39 个残基的神经肽结节漏斗肽 (TIP39) 及其受体甲状旁腺激素受体 2 (PTH2R) 的生理功能研究一直是该部分最近的焦点。这些分子是几年前在这个实验室发现的。在之前的项目中，我们绘制了它们的神经解剖学分布。 TIP39 在 3 组独立的神经元中合成，其中 2 组在丘脑尾缘，一组在脑干。 TIP39 合成神经元投射到涉及情绪功能调节的多个大脑区域。这些区域包含匹配分布的 PTH2R，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。在绘制 TIP39 和 PTH2R 的解剖图之后，实验室项目转向研究从它们的分布中得出的假设。下丘脑含有相对高密度的含有 PTH2R 和 TIP39 的末端。在之前的项目中，我们发现 TIP39 调节下丘脑室旁核神经元的激活，该核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 通过作用于室旁核内的神经元末端来释放经典的快速作用递质谷氨酸来实现这一点。因此，TIP39 调节神经内分泌细胞的兴奋性输入。我们还发现下丘脑正中视前核中的 TIP39 信号传导有助于体温调节。对寒冷暴露的适当稳态反应需要 TIP39 信号传导，而在小鼠适应的环境中维持正常基线温度则不需要。这些研究得出的一般模型提出，TIP39 对某些谷氨酸能神经元群体的突触前 PTH2R 的作用可能是在特定高需求条件下强健且足够的兴奋性递质释放所必需的。此前我们发现，TIP39编码基因基因缺失（TIP39-KO）或PTH2R无效突变（PTH2R-KO）的小鼠在压力测试条件下比TIP39功能正常的小鼠焦虑样行为增加更多。我们还发现，在新奇事物引起的兴奋条件下，但在适应测试环境时，缺乏 TIP39 信号传导的小鼠，由于配体或受体丢失或急性受体阻断，在依赖于记忆功能的行为测试中表现受损。使用创伤后应激障碍小鼠模型，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，动物受到单一厌恶刺激，之后通过测量当动物重新暴露于刺激所传递的环境时静止不动（冻结，啮齿类动物的恐惧样反应）的时间来评估恐惧记忆。虽然TIP39信号传导的缺失并没有在电击后一周引起恐惧记忆的可检测变化，但TIP39-KO和PTH2R-KO小鼠在电击后两周比野生型同窝小鼠表现出更强的恐惧样行为。在此审查期间，我们发现增加的行为反应至少持续两个月。使用药物遗传学方法暂时抑制其功能，我们发现表达 PTH2R 的神经元在最初的厌恶刺激时发挥着关键作用。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，这意味着这种神经肽系统在正常的恢复能力中发挥着作用。疼痛和抑郁经常相关。然而，疼痛对情绪的影响程度或情绪对疼痛的影响程度尚不清楚。与疼痛和其他情绪反应的情感维度密切相关的重叠大脑区域内的相互作用可能有助于慢性疼痛和情绪障碍之间的联系，但相关数据很少。我们之前发现 TIP39 调节急性疼痛敏感性，主要在大脑内发挥作用，影响伤害性感觉信息的处理。然后我们发现 TIP39 信号传导对慢性疼痛模型中伤害感受敏感性的控制有很大影响。 TIP39 的这种作用似乎涉及蓝斑 (LC) 功能的调节，蓝斑是一种脑干核，含有去甲肾上腺素能神经元，对中枢神经系统的大部分区域具有调节影响。与其他观察结果相结合，这表明 TIP39 可能是参与感觉刺激和情绪之间关系的调节剂之一。该研究的下一步是评估 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性感官输入的影响及其长期后果是这些实验设计和实施的一个重大障碍。为了克服这一限制，该部门开发了一种范例来研究和比较逆转小鼠神经性疼痛模型期间和之后的细胞和行为变化。在坐骨神经周围放置塑料袖带所产生的触觉异常性疼痛在取下袖带后几天内就会消失。相比之下，放置神经袖带后出现的高架 O 迷宫、强迫游泳、Y 迷宫自发交替和新物体识别测试表现的变化在神经袖带移除后仍保留至少三周。抑郁症背后的细胞变化尚不清楚，但一项当代假设表明，低水平的成人神经发生发挥了作用。成人海马神经发生在慢性疼痛模型中受到抑制，表明神经发生的变化可能与慢性疼痛相关的抑郁症有关。因此，我们在可逆神经病变模型中评估了海马神经发生。分别由处于增殖或分化状态的神经元合成的增殖细胞核抗原和双皮质素的表达在神经套囊放置后受到抑制，并且在神经套囊移除后三周仍然受到抑制。我们观察到，FosB（一种具有相对较长半衰期的早期基因）的表达在疼痛感受得到缓解和持续行为影响的小鼠的基底外侧杏仁核中保持升高，而在脊髓和中央杏仁核中则下降至基线水平。使用可逆神经袖带范式进行的观察表明，不同的过程控制着与神经性异常性疼痛相关的触觉超敏性和行为改变以及神经发生受损。未来的研究将探讨基底外侧杏仁核的可塑性和海马神经发生的变化与疼痛对情绪和行为变化的影响的相关性。新开发的范例提供了一种方法，用于识别疼痛与其他病症之间的联系机制，以及筛选药物以预防或减轻与疼痛控制不良相关的抑郁症。该部门正在与 Arpad Dobolyi 博士合作，研究 TIP39 信号传导对母亲行为的影响。在本综述期间，我们获得的证据表明，从丘脑后层板内核到下丘脑弓状核的投射中的 TIP39 信号传导是幼崽哺乳导致催乳素分泌途径的重要组成部分。