Inflammation Effects on Corticostriatal Connectivity and Reward: Role of Dopamine

项目摘要 这项拟议中的研究将确定急性服用多巴胺前体左旋多巴是否会 逆转炎症对奖赏回路内功能连接的影响以及快感缺乏， 重度抑郁症（MDD）患者的精神发育迟滞。炎症的生物标志物，如 作为炎性细胞因子和急性期蛋白质，如C反应蛋白（CRP）， 情绪障碍患者的比例很大。此外，施用细胞因子或细胞因子 实验室动物和人类的诱导物与抑郁症状有关，包括快感缺乏， 抑郁症的核心症状，反映了奖励处理受损。既往神经影像学发现 表明炎性细胞因子部分通过影响纹状体细胞， 多巴胺例如，炎症刺激已被证明会减少腹侧皮层的神经激活， 纹状体享乐奖励和减少纹状体多巴胺释放与减少基于努力 奖励的动机。此外，我们最近发表的MDD患者数据表明， 炎症增加（通过血浆CRP和炎性细胞因子测量）与 腹侧和背侧纹状体到腹内侧前额叶皮质回路的功能连接性降低， 而这又分别与快感缺乏和精神发育迟缓有关。有趣的是，我们 初步数据表明，多巴胺前体左旋多巴的急性给药可以逆转这些变化。 炎症增加患者皮质纹状体连接的改变。这些发现表明 炎症相关的中脑边缘多巴胺减少可能会导致奖励相关的连接减少， 皮质纹状体回路导致快感缺乏和精神发育迟滞的症状，这是常见的， 许多精神疾病，并且通常对标准疗法的治疗有抵抗力。因此 拟议的研究将测试以下假设：1）多巴胺前体左旋多巴的给药将 在炎症程度高而非低的抑郁症患者中， 和2）左旋多巴将减少快感缺乏和精神发育迟滞的症状（使用客观评价）。 以及动机和运动速度的临床测量）与奖励内的连接性增加相关- 相关脑区为了验证这些假设，我们将使用静息状态和基于任务的功能性MRI，任务- 阳性和阴性效价的RDoC结构的基础和临床评估，以及药理学 使用左旋多巴的攻击策略。这项拟议中的研究将确定多巴胺在以下影响中的作用： 炎症对奖赏回路和相关行为的影响。此外，拟议的研究将阐明可靠的 成像生物标志物，其将允许确定新的治疗药物的脑中的靶标接合， 调节多巴胺通路以逆转炎症对动机和运动的影响的策略 神经精神障碍包括抑郁症患者的功能。

PROJECT SUMMARY The proposed research will determine whether acute administration of the dopamine precursor levodopa will reverse the impact of inflammation on functional connectivity within reward circuitry as well as anhedonia and psychomotor retardation in patients with major depressive disorder (MDD). Biomarkers of inflammation, such as inflammatory cytokines and acute-phase proteins like C-reactive protein (CRP), are reliably elevated in a significant proportion of patients with mood disorders. Furthermore, administration of cytokines or cytokine inducers to laboratory animals and humans is associated with depressive symptoms including anhedonia, a core symptom of depression that reflects impaired reward processing. Previous neuroimaging findings demonstrate that inflammatory cytokines produce behavioral changes in part through effects on striatal dopamine. For example, inflammatory stimuli have been shown to decrease neural activation of the ventral striatum to hedonic reward and to decrease striatal dopamine release in association with reduced effort-based motivation for reward. Moreover, our recently published data in patients with MDD have demonstrated a relationship between increased inflammation (as measured by plasma CRP and inflammatory cytokines) and decreased functional connectivity within ventral and dorsal striatal to ventromedial prefrontal cortical circuitry, which was in turn associated with anhedonia and psychomotor slowing, respectively. Interestingly, our preliminary data suggest that acute administration of the dopamine precursor, levodopa, can reverse these alterations in corticostriatal connectivity in patients with increased inflammation. These findings indicate that inflammation-related decreases in mesolimbic dopamine may cause reduced connectivity within reward-related corticostriatal circuitry leading to symptoms of anhedonia and psychomotor retardation, which are common to a number of psychiatric disorders and are often resistant to treatment with standard therapies. Thus, the proposed research will test the hypotheses that 1) administration of the dopamine precursor levodopa will increase connectivity in reward-related brain regions in depressed patients with high but not low inflammation, and 2) levodopa will decrease symptoms of anhedonia and psychomotor retardation (assessed using objective and clinical measures of motivation and motor speed) in association with increased connectivity within reward- related brain regions. To test these hypotheses, we will use resting state and task-based functional MRI, task- based and clinical assessments of RDoC constructs of positive and negative valence, and a pharmacological challenge strategy using levodopa. The proposed research will establish the role of dopamine in the effects of inflammation on reward circuitry and related behavior. In addition, the proposed studies will elucidate reliable imaging biomarkers that will allow determination of target engagement in the brain of novel therapeutic strategies that modulate dopamine pathways to reverse the effects of inflammation on motivation and motor function in patients with neuropsychiatric disorders including depression.