Prefrontal circuitry and pain

 描述(申请人提供)疼痛不仅仅是一种由周围神经系统处理的感觉。疼痛通过多个皮质和皮质下网络参与中枢神经系统。神经性疼痛是一种慢性疼痛，由躯体感觉神经系统受损引起，可导致生活中生理、心理和行为方面的有害变化。神经病理性疼痛改变了人类内侧前额叶皮质(MPFC)的结构、化学成分和连接。重要的是，组成mPFC的回路在处理我们日常经验中的情感成分方面是必不可少的，因此，与疼痛的情感成分或不愉快有关。对于正常情况下mPFC和神经病理性疼痛动物模型中疼痛相关回路的功能，缺乏全面的了解。因此，这一建议试图了解皮质内(局部)和皮质下(远程)突触输入到主要的mPFC神经元群体的组织和功能，并针对关键的皮质下疼痛结构：中脑导水管周围灰质(PAG)。PAG是初级痛觉调节网络中的一个纽带，对内源性镇痛和自主神经痛反应至关重要。我们的目标是1)阐明mPFC内皮质-PAG神经元的局部和远程回路；2)评估神经病理性疼痛改变皮质-PAG回路的神经元件的具体机制。为了实现这些目标，我们将开发一种多方面的方法，包括逆行标记、电生理学、电路映射、光遗传学和行为技术。这项拟议研究的基本原理是，确定神经病理性疼痛改变大脑认知和情绪网络(特别是mPFC-PAG)中的电路功能的神经机制将产生关于疼痛情感维度的关键知识。这样的理解可以为治疗干预带来新的策略。我们的发现将有助于对神经病理性疼痛如何改变在疼痛的感知和情感相关性中至关重要的特定皮质网络的细胞和电路机制提供新的重要见解。

 DESCRIPTION (provided by applicant) Pain is more than a sensation processed by the peripheral nervous system. Pain engages the central nervous system via multiple cortical and subcortical networks. Neuropathic pain is a chronic pain resulting from damage to the somatosensory nervous system which can cause detrimental changes to physiological, psychological, and behavioral aspects of life. Neuropathic pain alters the structure, chemistry, and connectivity of medial prefrontal cortex (mPFC) in humans. Importantly, circuits comprising the mPFC are essential in processing emotional components of our everyday experiences, and therefore, are implicated in the affective component, or unpleasantness, of pain. A comprehensive understanding is lacking regarding the functionality of pain- relevant circuitry in the mPFC under normal conditions and in animal models of neuropathic pain. Therefore, this proposal seeks to understand the organization and function of both intracortical (local) and subcortical (long-range) synaptic inputs to a major population of mPFC neurons with specific targeting to a key subcortical pain structure: the periaqueductal gray (PAG). The PAG is a link in the primary pain-modulating network essential for endogenous analgesia and autonomic response to pain. Our objectives are 1) to elucidate the local and long-range circuitry of cortico-PAG neurons in the mPFC and 2) to assess the specific mechanisms by which the neural elements of cortico-PAG circuitry are altered by neuropathic pain. To accomplish these goals, we will develop a multifaceted approach involving retrograde labeling, electrophysiology, circuit mapping, optogenetic and behavioral techniques. The rationale for the proposed research is that identifying the neural mechanisms through which neuropathic pain alters circuit function in cognitive and emotional networks of the brain (specifically mPFC-PAG) will produce critical knowledge regarding the affective dimension of pain. Such an understanding can lead to novel strategies for therapeutic intervention. Our findings will contribute new and important insights into cellular and circuit mechanisms for how neuropathic pain alters specific cortical networks essential in the perception and emotional relevance of pain.