Cortical modulation of brainstem circuits

脑干回路的皮质调节

• 批准号: 8385520
• 负责人: ASAF KELLER
• 金额: $ 36.84万
• 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/8385520
• 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的、刺激驱动的装置。最近的观点将感知视为一种主动且高度选择性的操作，其中自上而下的影响强烈地塑造了自下而上的信息流。自上而下调节的一个重要组成部分是皮质三叉神经束，它直接影响头颈部感觉的第一个处理站。尽管其解剖学意义重大，但人们对皮质三叉神经通路的功能知之甚少。在这里，我们重点关注它在调节有害输入方面的作用。基于强有力的初步发现，我们的中心假设是皮质三叉神经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。三叉神经尾部脊髓核 (SpVc) 在疼痛处理中发挥着关键作用，主要接收来自初级 (SI) 和第二 (SII) 体感皮层以及岛叶皮层的皮层输入。目标我将使用麻醉大鼠的单单位记录来：（1）确定皮质三叉神经输入是否抑制 SpVc 投射神经元的活动，以及（2）比较来自 SI、SII 和岛叶皮层的输入的作用。令人兴奋的初步结果表明，SII 强烈抑制而 SI 兴奋 SpVc 投射神经元。 Aim II 将使用我们最近开发的光遗传学方法研究皮质三叉神经功能的细胞基础，其中光敏感阳离子通道视紫红质在皮质三叉神经元及其轴突末端表达。这种新方法允许选择性激活 SpVc 中的皮质三叉神经突触。体外切片中的膜片钳记录将比较皮质三叉神经突触输入到 SpVc 中投射和局部回路神经元的特性。这将剖析兴奋性皮质三叉神经输入转化为 SpVc 中有效前馈抑制的电路和突触机制。在目标 III 中，我们直接检验了皮质三叉神经输入调节对伤害性输入的行为反应的假设。为此，我们采用了一种新的操作行为范式，用于测量对热刺激的反应，以及操纵皮质三叉神经活动对这些行为反应的影响。这些研究将首次揭示三个皮质区域的皮质三叉神经输入如何调节疼痛感知。揭示这些调节影响的突触机制将为改善持续性疼痛的药物治疗提供所需的信息。最后，通过查明特定皮质区域在疼痛调节中的作用，这些结果将推进目前使用皮质刺激缓解疼痛的治疗方法。