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: 10274675
• 负责人: James A Bibb
• 金额: $ 50.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274675
• 关键词: Address; Adult; Affect; Anxiety; Basal Ganglia; Behavior; Behavioral; Biochemical; Brain; Brain region; Cell physiology; Chemical Models; Chemicals; Chronic; Clinical; Colitis; 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; Lead; Link; Mediating; Mental Depression; Mental Health; Mental disorders; Modeling; Molecular; Mood Disorders; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Peripheral; Pharmacology; Phosphorylation; Photometry; Process; Research; Rewards; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stress; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Transgenic Organisms; Ventral Striatum; Visceral; adducin; base; behavioral response; biological adaptation to stress; brain circuitry; burden of illness; cell type; comorbidity; disability; experience; gastrointestinal; gastrointestinal function; in vivo; inhibitor/antagonist; innovation; kappa opioid receptors; male; multiple omics; neurobehavior; neurobehavioral; neurobiological mechanism; neurochemistry; neurophysiology; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; novel therapeutic intervention; psychological symptom; receptor; sex; stressor; suicide mortality; 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.

外周炎症和应激驱动纹状体腹侧核变性 项目摘要抑郁症和焦虑症等精神疾病是主要的疾病负担，与 自杀和死亡。众所周知，暴露在压力之下会引发神经精神并发症。这个 免疫系统对心理症状和慢性疾病(如炎症)也有很大影响 肠道疾病极大地增加了抑郁和焦虑的风险。令人惊讶的是，人们对大脑知之甚少 驱动这种共病的特定电路机制。我们的目标是通过研究如何满足这种需求 全身性炎症和应激导致腹侧纹状体奖赏/厌恶回路的不适应 (伏核，NAC)。在初步研究中，我们发现胃肠道(GI)炎症作为一种 弥漫形式的全身性炎症，调节应激反应行为，并失调NAC突触 表达中棘神经元的多巴胺受体(D1R)的可塑性和兴奋性。多个- 这些作用的机制基础的组学探索暗示了一种新的强啡肽(Dyn)-kappa阿片类药物 受体(KOR)-CDK5/p35-b内收蛋白(ADD2)信号在NAC中级联，我们假设它介导这些 适应不良。基于这些发现，我们建议研究外周炎症、应激和 它们对神经行为功能的相互作用(目标1)，以及NAC突触可塑性，细胞类型特异性兴奋性， 和多巴胺神经递质(目标2)。我们发现的新的Kor-CDK5/p35-ADD2通路提供了一种 DA神经传递的不良适应改变可激活DA-cAMP-PKA改变的机制 发出信号并改变结构的可塑性。我们将研究这一途径的作用机制和它的 促进炎症和应力对结构可塑性的影响(目标3)。创新的组件 这项建议包括研究炎症/应激的相互作用，询问NAC细胞类型的具体作用 Kor-CDK5/p35-ADD2信号在介导这些效应中的作用，体内纤维光度法研究DA动力学，以及 一种新的全身性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 纹状体信号转导成为临床的一大难题。其影响将是提供一幅关于 全身性炎症-精神疾病共病的机制基础及可能的治疗新途径 治疗性干预。