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

快感缺乏是一种常见的跨诊断症状，通常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 因为快感缺乏症一直受到其实质上的异质性的阻碍。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 有功能障碍。导致非享乐症症状的一个潜在途径是通过神经生物学改变。 与长期暴露于压力(“应激性快感缺乏症”)有关，神经性特征是 奖赏相关区域的激活，如内侧前额叶皮质(MPFC)和腹侧纹状体 在行为上表现为不追求回报和预期积极或奖励结果的能力降低 (即悲观的偏见)。虽然增加压力可能导致快感缺失的具体机制是 目前还不完全了解，两种可能的机制是炎性细胞因子升高和改变 谷氨酸能起作用。众所周知，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、树突萎缩和脊突突触减少 密度。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、白介素6(IL-6)和IL-1b。关键的是，越来越多的作品已经 提示炎症升高和谷氨酸功能改变可能是有联系的。当前的目标是 因此，建议探索炎症和谷氨酸能的独立和相加的贡献 对应激性快感缺乏症的悲观预期起作用。我们建议聘用 40例健康体检者外周血炎性标志物及谷氨酸MRS分析 无快感缺乏症和60名有快感缺乏症的参与者按外周炎症水平分层。在目标1中 我们将分析感知到的压力、炎症和生态瞬间之间的联系 评估(EMA)衡量悲观预期的指标。在目标2中，我们将使用急性应激处理 和磁共振波谱检查mPFC谷氨酸在急性应激反应中的变化，检查 感受到的压力、谷氨酸对压力的反应和悲观预期之间的联系。 最后，在目标3中，我们将研究谷氨酸对压力的反应是否与个体差异有关。 并将测试炎症和谷氨酸对应激反应的一系列中介模型 悲观的预期。这项工作将提供对神经生物学机制的洞察。 结果将被用来指导未来使用靶向治疗的工作。

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.