Inflammation Effects on Corticostriatal Connectivity and Reward: Role of Dopamine

项目总结 这项拟议的研究将确定急性给药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通性的影响以及快感缺乏和 严重抑郁障碍患者的精神运动发育迟缓。炎症的生物标志物，如 作为炎性细胞因子和急性时相蛋白，如C反应蛋白(CRP)，在 有很大比例的患者患有情绪障碍。此外，给予细胞因子或细胞因子 对实验动物和人类的诱导剂与抑郁症状有关，包括快感缺乏，一种 抑郁的核心症状，反映奖赏过程受损。既往神经影像表现 证明炎性细胞因子在一定程度上通过影响纹状体而引起行为改变 多巴胺。例如，炎症刺激已被证明可以降低腹侧神经的激活。 纹状体对享乐性奖赏和减少纹状体多巴胺释放与基于减少努力的关系 奖励的动机。此外，我们最近公布的MDD患者数据显示， 炎症增加(以血浆C反应蛋白和炎性细胞因子测定)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， 这反过来又分别与快感缺失和精神运动减慢有关。有趣的是，我们的 初步数据表明，急性给予多巴胺前体左旋多巴可以逆转这种情况。 炎症增加患者的皮质纹状体连接性改变。这些发现表明， 炎症相关的中脑边缘多巴胺的减少可能导致奖赏相关的连接性降低 皮质纹状体回路导致快感缺失和精神运动迟缓的症状，这些症状在 许多精神疾病，而且往往对标准疗法治疗有抵抗力。因此， 拟议中的研究将检验这样的假设：1)注射多巴胺前体左旋多巴将 在炎症程度高但不低的抑郁症患者中，增加与奖励相关的大脑区域的连接， 2)左旋多巴可以减少快感减退和精神运动发育迟缓的症状(客观评估 以及动力和运动速度的临床测量)与奖励内增加的连接性相关- 相关的大脑区域。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磁共振，任务- RDoC正价和负价结构的基础和临床评估，以及一种药理学 使用左旋多巴的挑战策略。这项拟议的研究将确定多巴胺在 奖赏回路和相关行为上的炎症。此外，拟议的研究将阐明可靠的 成像生物标记物将允许确定新的治疗方法的大脑中的靶参与 调节多巴胺通路以逆转炎症对动力和运动的影响的策略 包括抑郁症在内的神经精神障碍患者的功能。

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.