Functional characterization of an amygdala to accumbens nociceptive circuit

超过1亿美国人患有慢性疼痛，经历着持续的伤害性感觉和负性 情绪性症状。目前可用的疼痛治疗方法不足以安全有效地缓解这两种疾病 慢性疼痛的感觉和情感特征，部分原因是它们缺乏特异性来调节不同的 神经细胞的类型和突起。虽然诊断成像工具已经将情感上的不快与 慢性疼痛，广泛脑区功能障碍，如杏仁基底外侧核(BLA)和核团 伏隔(NAC)-它们缺乏特异性来识别可能支持这一点的单个功能细胞类型 不适应的可塑性。识别和定位情感伤害性神经回路的关键第一步是 可视化动态的伤害性传递之间的情感-动机的大脑区域在 从急性疼痛过渡到慢性疼痛。拟议项目的研究目标是从功能上描述一种 伤害性BLA至NAC环路在急性和慢性负性情绪激励行为中的作用 伤害性状态。血乳酸功能障碍与慢性疼痛和神经精神障碍有关 通过为内部和外部感觉信息赋价的过程。BLA包含一个 负价神经元的功能亚群对伤害性感觉的情绪厌恶方面是必不可少的 (BLA“0Ci)。抑制BLAnoci神经元减少了对伤害性刺激的情感动机反应。 慢性伤害性状态。BLA神经元将远程轴突发送到许多下游目标，包括NAC， 一种纹状体结构，对驱动食欲和厌恶行为很重要。初步数据显示，布拉诺西 神经元投射到“边缘”NAC壳亚区(NAcSh)。此外，还有一组神经元 对NAcSh(“内角”；NAcSh1H)内伤害性刺激的反应，一束BLAnoci轴突强烈 令人兴奋。然而，尚不清楚BLAnoci神经元是否向NAcSh1H传递情感伤害信息 NAcSh1H神经元也不是驱动与伤害相关的消极情感动机行为所必需的。 目标1将在急性和慢性伤害性感受状态下对BLA“0 Ci到NAcSh1H回路进行功能表征 清醒行为受试者BLAnoci轴突终末的活体钙成像和光发生激活。目标2 将使用钙成像对急慢性伤害性状态下的NAcSh1H神经元活动进行成像和操作 以及对NAcSh1H神经活动的光遗传操作。这些拟议目标的完成将导致 BLA和NAcSh1H之间编码急性和慢性的潜在关键作用回路的特征 伤害性信息。这一提议的结果将有助于情感疼痛神经科学领域更好地 了解神经回路在健康和病理状态下的功能。此外，这项研究可能会告诉我们 关于慢性疼痛的负性情感症状的治疗的未来转化性研究。完成 将实现扩大沃基克女士在系统方面的技术专长的培训目标 并促进了她成为情感疼痛研究领域的领先专家的职业目标。

Over 100 million Americans suffer from chronic pain, experiencing persistent nociceptive sensory and negative affective symptoms. Currently available pain treatments are inadequate at safely and effectively relieving both the sensory and affective features of chronic pain, partly because of their lack of specificity to modulate distinct neural cell-types and processes. While diagnostic imaging tools have correlated the affective unpleasantness of chronic pain with dysfunction across broad brain regions-such as the basolateral amygdala (BLA) and nucleus accumbens (NAc)-they lack specificity to identify individual functional cell types that might underlie this maladaptive plasticity. A key first step towards identifying and targeting affective nociceptive neural circuits is to visualize the dynamics of nociceptive transmissions between affective-motivational brain regions during the transition from acute to chronic pain. The research goal of the proposed project is to functionally characterize a nociceptive BLA to NAc circuit that contributes to negative affective-motivational behavior in acute and chronic nociceptive states. Dysfunction of the BLA has been implicated in chronic pain and neuropsychiatric disorders through the process of assigning valence to internal and external sensory information. The BLA contains a functional subpopulation of negative valence neurons essential for the emotionally aversive aspect of nociception (BLA"0 ci). Inhibition of BLAnoci neurons reduces affective-motivational responses to noxious stimuli in acute and chronic nociceptive states. BLA neurons send long-range axons to many downstream targets, including the NAc, a striatal structure important for driving appetitive and aversive behaviors. Preliminary data suggests that BLAnoci neurons project to the "limbic" NAc Shell subregion (NAcSh). Furthermore, there is a group of neurons highly responsive to noxious stimuli within the NAcSh (the "inner-horn"; NAcSh1H) that a bundle of BLAnoci axons strongly innervate. However, it is unknown if BLAnoci neurons transmit affective nociceptive information to the NAcSh1H nor if NAcSh1H neurons are essential for driving nociception-related negative affective-motivational behaviors. Aim 1 will functionally characterize the BLA"0 ci to NAcSh1H circuit in acute and chronic nociceptive states using in vivo calcium imaging and optogenetic activation of BLAnoci axon terminals in awake behaving subjects. Aim 2 will image and manipulate NAcSh1H neuron activity in acute and chronic nociceptive states using calcium imaging and optogenetic manipulation of NAcSh1H neural activity. Completion of these proposed aims will result in the characterization of a potentially key affective circuit between the BLA and NAcSh1H encoding acute and chronic nociceptive information. The outcome of this proposal will help the field of affective pain neuroscience better understand neural circuit function in healthy and pathological states. Furthermore, this research may inform future translational investigations into treatments for the negative affective symptoms of chronic pain. Completion of this fellowship will achieve the training goals of expanding the technical expertise of Ms. Wojick in systems neuroscience and facilitate her career goal of becoming a leading expert in affective pain research.