Thalamo-Limbic Circuits in Pain

疼痛中的丘脑边缘回路

基本信息

批准号：
10397151
负责人：
Steve Davidson
金额：
$ 35万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397151
关键词：
Affective Anatomy Animal Model Animals Anterior Anxiety Area Axon Behavior Behavioral Biophysics Brain Cell Nucleus Cells Clinical Cognitive Cues Data Development Dimensions Electrophysiology (science)Emotional Exhibits Foundations Future G-Protein-Coupled Receptors Genes Goals Human In Vitro Individual Injury Insula of Reil Intervention Intractable Pain Knowledge Lead Learning Measures Membrane Mental Depression Metabotropic Glutamate Receptors Modeling Molecular Target Morphology Motivation Mus Neuroanatomy Neurobiology Neurons Nociception Outcome Output Pain Pain Measurement Pain Threshold Pain management Pain-Free Pathway interactions Patients Persistent pain Persons Pharmacology Physiological Prosencephalon Receptor Signaling Regulation Research Rodent Role Sensory Sensory Thresholds Signal Transduction Somatosensory Cortex Spinal Structure Synapses Synaptic plasticity System Techniques Testing Thalamic structure Withdrawal Work behavioral pharmacology chronic pain chronic pain patient cingulate cortex clinical pain coping design and construction experience experimental study hippocampal pyramidal neuron improved in vitro testing in vivo indexing inflammatory pain innovation neural circuit neurophysiology neuroregulation novel optogenetics pain behavior pain model pain processing pain reduction pain relief painful neuropathy patch clamp postsynaptic receptor relating to nervous system success tool

项目摘要

Pain tolerance varies widely among peoples and, depending on external and internal circumstances, varies within an individual from moment to moment. Although the concept of pain tolerance is familiar, the neurobiological substrates that regulate pain tolerance are unknown. Pain tolerance requires motivational, emotional, and cognitive processing in addition to the sensory dimension of the pain experience. Achieving an understanding the specific neurons and circuits in the brain that regulate pain tolerance may to lead to breakthroughs that will enhance the capacity of patients to cope with intractable pain. This project utilizes innovative techniques to both assess pain tolerance behavior in animals, and to dissect the neural circuits thought to regulate pain tolerance. We have discovered that a subtype of pyramidal neuron in limbic cortical areas including the anterior cingulate cortex and insula becomes hyperexcitable during periods of lowered pain tolerance produced by injury. These neurons express GRM2, the gene encoding group II metabotropic glutamate receptors, which is a potential molecular target to control pain tolerance in clinical settings. The goals of this project are: 1) To identify the thalamo-limbic pathways that regulate pain tolerance; 2) To determine the role of GRM2 limbic cortical neurons in pain tolerance and nociceptive-withdrawal behaviors, and, 3) to determine whether pain tolerance can be modulated by pharmacological manipulation of group II metabotropic glutamate receptors. Optogenetic and pharmacological experiments will be performed in vivo in mouse to learn whether pain tolerance can be modulated independently of standard nociceptive-withdrawal thresholds. Modulation of neural activity in models of inflammatory and neuropathic pain will be tested to determine whether injury-induced changes to pain tolerance can be reversed. Neuro-anatomical and neurophysiological approaches in vitro will be used to generate new information on the plasticity of the thalamo-cortical circuits hypothesized to regulate pain tolerance and the membrane biophysics of GRM2 neurons. These experiments will be performed using animal models of persistent pain to determine whether function and anatomy of thalamo-cortical synapses and GRM2 neurons are altered by pain to provide mechanistic understanding for behavioral changes in pain tolerance. Pharmacological modulation of group II mGluR signaling will be tested in vitro to determine the potential for these receptors to be used in future clinical interventions. Completion of this project will generate new knowledge on the neural systems involved in the supraspinal processing of pain, including pain tolerance, and potentially catalyze an innovative shift in strategy for pain relief to enhance coping ability in chronic pain patients through neuromodulation.

疼痛耐受性在民族之间差异很大，并且根据外部和内部环境的不同一时之间的个人。虽然疼痛的概念很熟悉，但调节疼痛耐受性的神经生物学底物尚不清楚。疼痛耐受需要激励性，除了疼痛体验的感觉维度外，情绪和认知处理。实现了解调节疼痛耐受性的大脑中特定的神经元和电路可能导致突破将增强患者应对顽固性疼痛的能力。这个项目利用既可以评估动物的疼痛耐受性行为，又要剖析神经回路的创新技术被认为可以调节疼痛耐受性。我们发现边缘皮质中的锥体神经元亚型在疼痛降低时期受伤产生的公差。这些神经元表达GRM2，编码II组的基因代谢型谷氨酸受体，这是控制临床环境中疼痛耐受性的潜在分子靶标。这该项目的目标是：1）确定调节疼痛耐受性的丘脑limbic途径； 2）到确定GRM2边缘皮质神经元在疼痛耐受性和伤害性脱水行为中的作用， 3）确定是否可以通过对II组的药理学操纵来调节疼痛耐受性代谢性谷氨酸受体。光遗传学和药理学实验将在体内进行鼠标以了解是否可以独立于标准伤害性 - withDrawal来调节疼痛耐受性阈值。在炎症和神经性疼痛模型中神经活动的调节将测试确定是否可以逆转受伤引起的疼痛耐受性的变化。神经 - 动物学和体外神经生理方法将用于生成有关可塑性的新信息假设可以调节疼痛耐受性和GRM2的膜生物物理学的丘脑皮层电路神经元。这些实验将使用持续疼痛的动物模型进行，以确定是否是否丘脑皮质突触和GRM2神经元的功能和解剖学因疼痛而改变以提供对疼痛耐受性行为变化的机械理解。 II组的药理调节 MGLUR信号传导将在体外测试，以确定这些受体在未来临床中使用的潜力干预措施。该项目的完成将产生有关涉及的神经系统的新知识疼痛上脊柱上的处理，包括疼痛的耐受性，并可能催化策略的创新转变缓解疼痛以通过神经调节来增强慢性疼痛患者的应对能力。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single-nucleus transcriptomic analysis of human dorsal root ganglion neurons.

DOI：
10.7554/elife.71752
发表时间：
2021-11-26
期刊：
eLife
影响因子：
7.7
作者：
Nguyen MQ;von Buchholtz LJ;Reker AN;Ryba NJ;Davidson S
通讯作者：
Davidson S

The Operant Plantar Thermal Assay: A Novel Device for Assessing Thermal Pain Tolerance in Mice.

操作性足底热测定：一种评估小鼠热痛耐受性的新型装置。

DOI：
10.1523/eneuro.0210-19.2020
发表时间：
2020
期刊：
eNeuro
影响因子：
3.4
作者：
Reker,AshlieN;Chen,Sisi;Etter,Katherine;Burger,Taylor;Caudill,Makayla;Davidson,Steve
通讯作者：
Davidson,Steve

Chemogenetic modulation of posterior insula CaMKIIa neurons alters pain and thermoregulation.