Cortical modulation of brainstem circuits

描述(申请人提供)：感觉处理的经典理论认为大脑是一个被动的、受刺激驱动的装置。较新的观点认为，感知是一种积极的、高度选择性的操作，在这种操作中，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，它直接影响头和颈部感觉的第一个处理站。尽管皮质三叉神经通路在解剖学上很突出，但人们对其功能知之甚少。在这里，我们将重点放在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，皮质三叉神经的输入通过抑制三叉神经核中神经元的反应来调节痛觉。三叉神经脊束核尾侧核(SpVc)在痛觉加工中起关键作用，主要接受初级(SI)和次级(SII)躯体感觉皮质以及岛叶皮质的皮质输入。目的利用麻醉大鼠的单单位记录：(1)确定皮质三叉神经传入是否抑制SpVc投射神经元的活动；(2)比较SI、SII和岛叶皮质传入的作用。令人兴奋的初步发现表明，SII强烈抑制而SI兴奋SpVc投射神经元。目的利用我们最近发展的光遗传学方法研究皮质三叉神经细胞功能的细胞基础。在光遗传学方法中，光敏感的阳离子通道视紫红质在皮质三叉神经细胞及其轴突终末表达。这种新的方法允许选择性地激活SpVc中的皮质三叉神经突触。在体外脑片上的膜片钳记录将比较皮层三叉神经突触输入到SpVc的投射神经元和局部环路神经元的特性。这将剖析兴奋性皮质三叉神经传入在SpVc中转化为有效的前馈抑制的电路和突触机制。在目标III中，我们直接测试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，该范式测量了对热刺激的反应，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来自三个皮质区域的皮质三叉神经输入是如何调节痛觉的。解开这些调节影响的突触机制将为改进持续性疼痛的药物治疗提供必要的信息。最后，通过明确特定皮质区域在疼痛调制中的作用，这些结果将推动目前使用皮质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.