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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

基本信息

批准号：
10404616
负责人：
James A Bibb
金额：
$ 50.48万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404616
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 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 chemically induced colitis comorbidity disability experience gastrointestinal gastrointestinal function in vivo inhibitor 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

项目摘要

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腹侧纹状体畸形适应