From stress to anhedonia: examining inflammation and altered glutamate function as distinct or common etiological pathways

快感缺失是一种常见的转诊断症状，经常无法对可用的心理社会和 药物治疗，并与残疾和自杀风险有关。开发新的治疗方法 因为快感缺失的实质性异质性而受到阻碍。为了解决这个问题，NIMH 研究领域标准（RDoC）方法强调了识别电路特定子域的必要性 功能性损伤。快感缺失症状的一个潜在途径是通过神经生物学变化 与长时间暴露于应激有关（“应激诱导的快感缺失”），其特征是神经系统功能降低， 奖励相关区域的激活，如内侧前额叶皮层（mPFC）和腹侧纹状体，以及 在行为上，由于未能追求奖励和预期积极或有益结果的能力下降， (i.e.悲观偏见）。虽然压力升高可能导致快感缺乏的具体机制是 尚未完全理解，两个候选机制是升高的炎性细胞因子和改变的 神经元功能。已知应激源会增加谷氨酸，特别是在mPFC中，导致 许多负面影响，包括兴奋性毒性、树突收缩和棘突触减少 密度的应激源也被证明可以激活免疫反应，提高促炎细胞因子 肿瘤坏死因子（TNF）α、白细胞介素-6（IL-6）和IL-1b。重要的是，越来越多的工作 表明炎症的升高和谷氨酸功能的改变可能是相关的。当前的目标 因此，我们建议探索炎症和血管生成的独立和叠加作用， 在压力诱发的快感缺失中对悲观预期的体验起作用。我们建议雇用 40名健康对照者外周炎症标志物和MRS谷氨酸的血浆分析 无快感缺失组和60名快感缺失组，按外周炎症水平分层。目标1 我们将分析感知压力、炎症和生态瞬间之间的关联， 悲观预期评估（EMA）。在目标2中，我们将使用急性应激操作 和磁共振波谱检查mPFC谷氨酸在急性应激反应中的变化， 感知压力、对压力的情绪反应和悲观预期之间的关联。 最后，在目标3中，我们将研究对压力的兴奋性反应是否与以下方面的个体差异有关： 炎症，并将测试炎症和谷氨酸对应激的反应的一系列调解模型， 悲观的预期。这项工作将提供深入了解神经生物学机制， 压力引起的快感缺失，其结果将用于为未来使用靶向治疗的工作提供信息。

Anhedonia is a common transdiagnostic symptom that frequently fails to respond to available psychosocial and pharmacological treatments and has been linked to disability and suicidal risk. Development of new treatments for anhedonia has been hindered by its substantial heterogeneity. To address this problem, the NIMH Research Domain Criteria (RDoC) approach has emphasized the need to identify circuit-specific sub-domains of functional impairment. One potential pathway to anhedonic symptoms is through neurobiological changes associated with prolonged exposure to stress (“stress-induced anhedonia”), characterized neurally by reduced activation in reward-related regions such as the medial prefrontal cortex (mPFC) and ventral striatum, and behaviorally by a failure to pursue rewards and reduced ability to anticipate positive or rewarding outcomes (i.e. pessimistic biases). While the specific mechanisms by which elevated stress may lead to anhedonia are not fully understood, two candidate mechanisms are elevated inflammatory cytokines and altered glutamatergic functioning. Stressors are known to increase glutamate, particularly in mPFC, leading to numerous negative effects including excito-toxicity, shrinkage of dendrites, and reduction of spine synapse density. Stressors have also been shown to activate immune responses, elevating proinflammatory cytokine tumor necrosis factor (TNF) alpha, interleukin-6 (IL-6), and IL-1b. Critically, a growing body of work has suggested that elevated inflammation and altered glutamate functioning may be linked. The goal of the current proposal is therefore to explore the independent and additive contributions of inflammation and glutamatergic functioning to the experience of pessimistic expectations in stress-induced anhedonia. We propose to employ plasma analysis of peripheral inflammatory markers and MRS glutamate in 40 healthy control participants without anhedonia and 60 participants with anhedonia stratified by level of peripheral inflammation. In Aim 1 we will analyze associations between perceived stress, inflammation, and an ecological momentary assessment (EMA) measure of pessimistic expectations. In Aim 2, we will use an acute stress manipulation and MR spectroscopy to examine changes in mPFC glutamate in response to acute stress, examining associations between perceived stress, glutamatergic response to stress, and pessimistic expectations. Finally, in Aim 3 we will examine whether glutamatergic response to stress is related to individual differences in inflammation and will test a serial mediation model of inflammation and glutamate response to stress on pessimistic expectations. This work will provide insight into the neurobiological mechanisms that underlie stress-induced anhedonia and the results will be used to inform future work using targeted treatments.