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.

外围炎症和应力驱动腹侧纹状体疾病 项目摘要的精神疾病（例如抑郁和焦虑）是与之相关的主要疾病负担 自杀和死亡率。众所周知，承受压力会导致神经精神并发症。这 免疫系统对心理症状和慢性疾病（如炎症）也有很大的影响 肠道疾病大大增加了抑郁和焦虑的风险。令人惊讶的是，对大脑知之甚少 驱动这种合并症的特定电路机制。我们的目标是通过研究如何满足这一需求 全身性炎症和压力会导致腹侧纹状体的奖励/厌恶电路不良 （伏隔核，NAC）。在初步研究中，我们发现胃肠道（GI）炎症是一种 全身炎症的普遍形式，调节应力反应行为并使NAC突触失调失调 表达中刺神经元（MSN）的D1多巴胺（DA）受体（D1R）的可塑性和兴奋性。多- 这些效果的机械基础的OMIC探索暗示了一种新型的Dynorphin（Dyn）-Kappa阿片类药物 NAC中的受体（kor）-cdk5/p35-b adducin（add2）信号级联 适应不良。根据这些发现，我们建议研究周围炎症，压力和 它们在神经行为功能（AIM 1）和NAC突触可塑性，细胞类型特异性兴奋性上的相互作用， 和DA神经传递（AIM 2）。我们确定的新型Kor-CDK5/p35-ADD2途径提供了一个 DA神经传递中适应不良的变化的机制可以在DA-CAMP-PKA中进行变化 信号传导和改变结构可塑性。我们将研究该途径功能及其其功能的机制 炎症和压力对结构可塑性的影响的贡献（AIM 3）。创新组件 该建议包括研究炎症/应力相互作用，NAC细胞类型特异性询问 在介导这些作用时，在体内纤维光度法中，用于研究DA动力学和 一种新型的系统性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 纹状体信号转导向主要的临床问题。影响是提供有关 全身性炎症性疾病合并症的机理基础和可能的新方法 治疗干预。