Cortical modulation of brainstem circuits

脑干回路的皮质调节

• 批准号: 8578075
• 负责人: ASAF KELLER
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578075
• 关键词: Area; Attention; Axon; Behavioral; Behavioral Paradigm; Brain; Brain Stem; Cations; Cerebral cortex; Cognition; Conscious; Data; Development; Devices; Down-Regulation; Emotions; Esthesia; Future; Goals; Head and neck structure; In Vitro; Light; Measures; Neurons; Nociception; Nociceptive Stimulus; Output; Pain; Pain management; Pathway interactions; Perception; Persistent pain; Play; Presynaptic Terminals; Process; Property; Rattus; Research; Resistance; Role; Sensory; Sensory Process; Shapes; Signal Transduction; Slice; Somatosensory Cortex; Specific qualifier value; Spinal Cord; Stimulus; Structure; Structure of trigeminal nerve spinal tract nucleus; Synapses; System; Techniques; Testing; Thalamic structure; Time; Trigeminal Neuralgia; Trigeminal Nuclei; base; chronic pain; conventional therapy; density; design; feeding; improved; inhibitory neuron; neural circuit; nociceptive response; novel strategies; operation; optogenetics; patch clamp; response; theories

DESCRIPTION (provided by applicant): Classical theories of sensory processing view the brain as a passive, stimulus-driven device. More recent views see perception as an active and highly selective operation in which top-down influences strongly shape the bottom-up information flow. An important component of top-down regulation is the corticotrigeminal tract, which directly impacts the very first processing station for sensations from the head and neck. Despite its anatomical prominence very little is known about the functions of the corticotrigeminal pathway. Here we focus on its role in modulating noxious inputs. Based on strong preliminary findings, our central hypothesis is that corticotrigeminal inputs modulate pain perception by suppressing responses of neurons in the trigeminal nuclei. The caudal spinal trigeminal nucleus (SpVc), which plays a pivotal role in pain processing, receives cortical inputs primarily from primary (SI) and second (SII) somatosensory cortex, and the insular cortex. Aim I will use single unit recordings in anesthetized rats to: (1) determine whether corticotrigeminal inputs suppress the activity of SpVc projection neurons, and (2) compare the roles of inputs from SI, SII and insular cortex. Exciting preliminary findings indicate that SII strongly suppresses while SI excites SpVc projection neurons. Aim II will investigate the cellular bases of corticotrigeminal function using our recently developed optogenetic approach in which the light sensitive cation channel, channelrhodopsin, is expressed in corticotrigeminal neurons and their axon terminals. This novel approach allows selective activation of corticotrigeminal synapses in SpVc. Patch clamp recordings in in vitro slices will compare the properties of corticotrigeminal synaptic inputs to projection and local circuit neurons in SpVc. This will dissect the circuit and synaptic mechanisms by which excitatory corticotrigeminal inputs are transformed into potent feed- forward inhibition in SpVc. In Aim III we directly test the hypothesis that corticotrigeminal inputs regulate behavioral responses to nociceptive inputs. For this we have adapted a new operant behavioral paradigm that measures responses to thermal stimuli, and the effects of manipulating corticotrigeminal activity on these behavioral responses. These studies will disclose, for the first time, how corticotrigeminal inputs from each of the three cortical areas regulate pain perception. Unraveling the synaptic mechanisms of these modulatory influences will provide information needed to improve pharmacologic therapies for persistent pain. Finally, by pinpointing the roles of specific cortical regions in pain modulation, these results will advance current treatments that use cortical stimulation for pain relief.

描述（由申请人提供）：感觉处理的经典理论将大脑视为被动刺激驱动的设备。最新的观点将感知视为一种主动且高度选择性的操作，其中自上而下会影响自下而上的信息流。自上而下调控的一个重要组成部分是皮质三次仪式，这直接影响了头部和颈部感觉的第一个加工站。尽管其解剖学突出程度很少，但对皮质三次途径的功能知之甚少。在这里，我们关注它在调节有害输入中的作用。基于强烈的初步发现，我们的中心假设是皮质三次输入通过抑制三叉神经核中神经元的反应来调节疼痛感知。在疼痛加工中起关键作用的尾脊柱三叉神经核（SPVC），主要来自原发性（SI）和第二（SII）体体皮质和下部皮质的皮质输入。目的我将使用麻醉大鼠中的单个单位记录来：（1）确定皮质三次输入是否抑制了SPVC投影神经元的活性，（2）比较Si，Sii和Insular Cortex的输入的作用。令人兴奋的初步发现表明，SII强烈抑制，而SI激发了SPVC投影神经元。 AIM II将使用我们最近开发的光遗传学方法研究皮质三次功能的细胞碱基，其中光敏感阳离子通道通道旋转蛋白在皮质三膜神经元及其轴突末端表达。这种新颖的方法允许选择性激活SPVC中的皮质三次突触。斑块夹在体外切片中的记录将比较皮质三次突触输入的特性与SPVC中的投影和局部电路神经元。这将剖析兴奋性皮质三次输入的电路和突触机制，转化为SPVC中有效的进料 - 向前抑制。在AIM III中，我们直接检验了以下假设：皮质三次输入调节对伤害性输入的行为反应。为此，我们改编了一种新的操作行为范式，该行为范式衡量了对热刺激的反应，以及操纵皮质三次活性对这些行为反应的影响。这些研究将首次披露三个皮质区域中每个区域的皮质三次输入如何调节疼痛感知。阐明这些调节影响的突触机制将提供改善药理学疗法的信息，以减轻持续性疼痛。最后，通过确定特定皮质区域在疼痛调节中的作用，这些结果将推动当前使用皮质刺激缓解疼痛的治疗方法。