Peripheral Inflammation and Stress Drive Ventral Striatal Maladaptations

周围炎症和压力导致腹侧纹状体适应不良

• 批准号: 10828485
• 负责人: James A Bibb
• 金额: $ 49.47万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-11 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10828485
• 关键词: Address; Adult; Affect; Anxiety; Basal Ganglia; Behavior; Behavioral; Biochemical; Brain; Brain region; Cell physiology; Chemical Models; Chronic; Clinical; Corpus striatum structure; Critical Pathways; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DRD2 gene; Data; Dopamine; Dopamine D1 Receptor; Dynorphins; Exposure to; Female; Fiber; Functional disorder; Goals; Health; Immune; Immune system; Impairment; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Inflammatory Response; Intervention; Knock-out; Link; Mediating; Mental Depression; Mental Health; Mental disorders; Modeling; Molecular; Mood Disorders; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Peripheral; Phosphorylation; Photometry; Process; Research; Rewards; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stress; Structure; Suicide; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Transgenic Organisms; Ventral Striatum; Visceral; adducin; behavioral response; biological adaptation to stress; brain circuitry; burden of illness; cell type; chemically induced colitis; comorbidity; disability; experience; gastrointestinal; gastrointestinal function; in vivo; inhibitor; innovation; kappa opioid receptors; male; mortality; multiple omics; neurobehavior; neurobehavioral; neurobiological mechanism; neurochemistry; neuronal excitability; neurophysiology; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; novel therapeutic intervention; pharmacologic; psychological symptom; sex; stressor; systemic inflammatory response; targeted treatment; tool

PERIPHERAL INFLAMMATION AND STRESS DRIVE VENTRAL STRIATAL MALADAPTATIONS PROJECT SUMMARY Mental illnesses such as depression and anxiety are a major disease burden linked to suicide and mortality. It is well known that exposure to stress can precipitate neuropsychiatric complications. The immune system also has a large influence on psychological symptoms and chronic conditions like inflammatory bowel disease dramatically increase risk of depression and anxiety. Surprisingly, little is known of the brain circuitry-specific mechanisms that drive this comorbidity. Our goal is to address this need by studying how systemic inflammation and stress cause maladaptations in reward/aversion circuitry of the ventral striatum (nucleus accumbens, NAc). In preliminary studies, we found that gastrointestinal (GI) inflammation, as a pervasive form of systemic inflammation, modulates stress-response behavior, and dysregulates NAc synaptic plasticity and excitability of D1 dopamine (DA) receptor (D1R) expressing medium spiny neurons (MSNs). Multi- omic exploration of the mechanistic basis for these effects implicated a novel dynorphin (DYN)-kappa opioid receptor (kOR)-Cdk5/p35-b adducin (ADD2) signaling cascade in the NAc which we hypothesize mediates these maladaptations. Based on these findings we propose to study the effects of peripheral inflammation, stress, and their interactions on neurobehavioral functions (Aim 1), and NAc synaptic plasticity, cell type-specific excitability, and DA neurotransmission (Aim 2). The novel kOR-Cdk5/p35-ADD2 pathway we have identified provides a mechanism by which maladaptive changes in DA neurotransmission can actuate alterations in DA-cAMP-PKA signaling and alter structural plasticity. We will study the mechanisms by which this pathway functions and its contribution to the effects of inflammation and stress on structural plasticity (Aim 3). Innovative components of this proposal include the study of inflammation/stress interactions, NAc cell type-specific interrogation of the role of kOR-Cdk5/p35-ADD2 signaling in mediating these effects, in vivo fiber photometry to study DA dynamics, and a novel systemic Cdk5 inhibitor as a targeted therapeutic approach. This research connects a strong field of striatal signal transduction to a major clinical problem. The impact will be to provide a detailed picture of the mechanistic basis for systemic inflammation-mental illness comorbidity and possible new approaches for therapeutic intervention.

周围炎症和压力导致腹侧纹状体适应不良 项目摘要 抑郁症和焦虑症等精神疾病是与以下疾病相关的主要疾病负担： 自杀和死亡率。众所周知，压力会导致神经精神并发症。这 免疫系统对心理症状和炎症等慢性疾病也有很大影响 肠道疾病会显着增加抑郁和焦虑的风险。令人惊讶的是，人们对大脑知之甚少 驱动这种合并症的电路特定机制。我们的目标是通过研究如何满足这一需求 全身炎症和压力导致腹侧纹状体奖赏/厌恶回路适应不良 （伏隔核，NAc）。在初步研究中，我们发现胃肠道（GI）炎症作为一种 全身性炎症的普遍形式，调节应激反应行为，并调节 NAc 突触 表达中型多棘神经元 (MSN) 的 D1 多巴胺 (DA) 受体 (D1R) 的可塑性和兴奋性。多- 对这些效应机制基础的组学探索涉及一种新型强啡肽 (DYN)-kappa 阿片类药物 NAc 中的受体 (kOR)-Cdk5/p35-b 内收蛋白 (ADD2) 信号级联，我们假设介导这些 适应不良。基于这些发现，我们建议研究外周炎症、压力和 它们对神经行为功能（目标 1）和 NAc 突触可塑性、细胞类型特异性兴奋性的相互作用， 和 DA 神经传递（目标 2）。我们发现的新型 kOR-Cdk5/p35-ADD2 途径提供了 DA 神经传递的适应不良变化可引起 DA-cAMP-PKA 改变的机制 信号传导并改变结构可塑性。我们将研究该通路发挥作用的机制及其作用 炎症和压力对结构可塑性影响的贡献（目标 3）。的创新组件 该提案包括炎症/应激相互作用的研究、NAc 细胞类型特异性作用的研究 kOR-Cdk5/p35-ADD2 信号传导在介导这些效应中的作用，体内光纤光度法研究 DA 动力学，以及 一种新型全身性 Cdk5 抑制剂作为靶向治疗方法。这项研究连接了一个强大的领域 纹状体信号转导是临床的一个主要问题。影响将是提供详细的情况 全身炎症-精神疾病共病的机制基础和可能的新方法 治疗干预。