Inflammatory signalling in the pain pathway: age-dependent differences in the response of neuronal ensembles to pain promoting molecules

脊髓背角作为中枢神经系统的一部分，是一个复杂的神经元网络，其作用是对周围神经系统传递给它的传入感觉信息进行反应和处理。这是一个分层的(层状)结构，很像大脑皮层，每一层都接受不同的感觉输入。每层神经元也是高度异质性的，一些是向大脑传递信息的中间神经元，另一些是在大脑中从一个位置传递信息到另一个位置的中间神经元。最近，我们已经表明，与成年相比，早期生命中的系统免疫系统对炎性刺激的反应不同。我们和其他人已经证明，儿童和新生儿在早期生活中对疼痛的感知和处理方式是不同的。这是由于包括大脑和脊髓在内的整个身体都发生了正常的成熟变化。最近，其他研究小组表明，炎症能够在大脑的某些部分留下持久的“记忆”，即使在最初的挑战解决后，这些记忆也可以在以后的生活中重新激活，以推动进一步的炎症。我们还表明，中枢神经系统的免疫细胞，即小胶质细胞，在早期生命中对损伤和感染的反应也不同，它们分泌的分子，即所谓的“炎症汤”，对这些挑战的反应是不同的。该项目将使用我们在疼痛神经生物学方面的世界领先专业知识和我们独特的技术工具来评估生命过程中不同时间点的特定炎症信号如何影响疼痛处理。我们将使用体内和体外相结合的方法来观察脊髓网络对炎症汤的特定成分的反应，当它们应用于脊髓或大脑中处理和反应疼痛的部分时。我们将看看早期生活事件如何影响这些大脑中心对炎症的反应，并通过识别这些过程在不同年龄的差异，确定适合年龄的治疗方法来治疗和管理疼痛。疼痛是一种神经现象，影响所有年龄的人的生活，不分性别或种族。它损害了人们的生活，导致社交退缩、焦虑和抑郁。体验疼痛的核心是卫生署，而这项计划将为了解这些复杂网络如何运作，并最终导致行为反应和疼痛体验开辟新的道路，长远目标是确定可以操纵的神经元或信号通路的数量，以减轻人和动物的疼痛。

The dorsal horn (DH) of the spinal cord, as part of the central nervous system, is a complex network of neurons whose purpose is to respond and process afferent sensory information conveyed to it from the peripheral nervous system. The DH is a layered (laminated) structure, much like the cerebral cortex, with each lamina receiving different sensory inputs. Neurons in each lamina are also highly heterogenous, some are interneurons conveying information to the brain, others are interneurons relaying information from site to site within the DH. Recently we have shown that the systemic immune system responds differently to inflammatory stimuli in early life compared to adulthood. It has been shown, by us and others, that pain in early life is detected and processed differently by children and neonates. This is due to normal maturational changes which take place throughout the body including the brain and spinal cord. More recently other groups have shown that inflammation is able to leave a lasting "memory" in parts of the brain which can be reactivated later in life to drive further inflammation even when the initial challenge has resolved. We have also shown that the immune cells of the CNS, microglia, also respond to damage and infection differently in early life and that the molecules they secrete, the so called "inflammatory soup", in response to these challenges is different. This project will use our world-leading expertise in pain neurobiology and our unique technological tools to assess how pain processing is effected by specific inflammatory signalling at different points in the life-course. We will use a combination of in vivo and ex-vivo approaches to see how spinal networks respond to specific components of the inflammatory soup when they are applied to the spinal cord or parts of the brain which process and respond to pain. We will see how early life events can impact on the response of these brain centres to inflammation and by identifying differences in these processes in different ages identify targets for age appropriate therapies to treat and manage pain.Pain is a neurological phenomenon that affects the lives of people of all ages and regardless of sex or ethnicity. It blights the lives of people leading to social withdrawal, anxiety and depression. Central to the experience of pain is the DH and this project will break new ground in understanding how these complex networks function and ultimately lead to behavioural responses and the experienced of pain, with the long-term aim of identifying populations of neurons or signalling pathways that can be manipulated to relieve pain in people and animals.