Peripheral Inflammation and Stress Drive Ventral Striatal Maladaptations

外周炎症和应激驱动腹主动脉畸形 抑郁症和焦虑症等精神疾病是一种主要的疾病负担， 自杀和死亡。众所周知，暴露于压力下会导致神经精神并发症。的 免疫系统对心理症状和慢性疾病如炎症也有很大影响 肠道疾病会显著增加抑郁和焦虑的风险。令人惊讶的是， 电路特定的机制，驱动这一comormance。我们的目标是通过研究如何满足这一需求 全身性炎症和应激导致腹侧纹状体的奖赏/厌恶回路适应不良 （核小体，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，并使NAc突触 D1多巴胺（DA）受体（D1 R）表达中型棘神经元（MSN）的可塑性和兴奋性。多重 对这些作用的机制基础的组学探索涉及一种新的强啡肽（DYN）-κ阿片样物质 我们假设NAc中的kOR-Cdk 5/p35-B内收蛋白（ADD 2）信号级联介导了这些信号通路。 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， 和DA神经传递（Aim 2）。我们已经鉴定的新的kOR-Cdk 5/p35-ADD 2通路提供了一个新的途径。 DA神经传递中的适应不良变化可驱动DA-cAMP-PKA改变的机制 并改变结构可塑性。我们将研究这一途径的功能机制及其在 炎症和应激对结构可塑性的影响（目的3）。创新组件 这一建议包括炎症/应激相互作用的研究，NAc细胞类型特异性的作用的询问， kOR-Cdk 5/p35-ADD 2信号转导介导这些作用，体内纤维光度法研究DA动力学， 作为靶向治疗方法的新型全身性Cdk 5抑制剂。这项研究连接了一个强大的领域， 纹状体信号转导的一个主要临床问题。其影响将是提供一个详细的图片， 全身性炎症-精神疾病共病的机制基础和治疗的可能新途径 治疗干预

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.