Cortical modulation of brainstem circuits

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装置。最近的观点认为感知是一种积极的和高度选择性的操作，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，它直接影响头部和颈部感觉的第一个处理站。尽管它的解剖学突出很少知道的功能皮质三叉神经通路。在这里，我们专注于它在调节有害输入的作用。基于强有力的初步研究结果，我们的中心假设是，皮质三叉神经的输入调制疼痛感知抑制三叉神经核神经元的反应。三叉神经脊束尾侧核（SpVc）在疼痛处理中起着关键作用，主要接受来自初级（SI）和第二（SII）躯体感觉皮层以及岛叶皮层的皮层输入。目的在麻醉大鼠上用单单位记录法研究：（1）三叉皮质传入是否抑制SpVc投射神经元的活动;（2）比较SI、SII和岛叶皮质传入的作用。令人兴奋的初步研究结果表明，SII强烈抑制，而SI兴奋SpVc投射神经元。目的II将利用我们最近发展的光遗传学方法研究皮质三叉神经功能的细胞基础，其中光敏阳离子通道，通道视紫红质，在皮质三叉神经元及其轴突终末的表达。这种新方法允许选择性激活SpVc中的皮质三叉神经突触。膜片钳记录在体外切片将比较属性的皮质三叉神经突触输入的投射和局部电路神经元在SpVc。这将剖析兴奋性皮质三叉神经输入在SpVc中转化为有效的前馈抑制的回路和突触机制。在目的III中，我们直接测试的假设，皮质三叉神经输入调节行为反应伤害性输入。为此，我们采用了一种新的操作性行为范式，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层区域的皮质三叉神经输入如何调节疼痛感知。揭示这些调节作用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，通过精确定位特定皮层区域在疼痛调制中的作用，这些结果将推进目前使用皮层刺激缓解疼痛的治疗方法。

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.