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Early life adversity as a modifier of recovery after traumatic brain injury to the developing brain.

早年的逆境对于发育中的大脑的创伤性脑损伤后的恢复有一定的调节作用。

基本信息

批准号：
10621373
负责人：
Kaila N Parker
金额：
$ 3.96万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621373
关键词：
3-nitrotyrosine Acute Acute Brain Injuries Adolescence Adult Age Antioxidants Area Biological Blood - brain barrier anatomy Brain Brain Injuries C-reactive protein CASP3 gene Caring Cause of Death Cell Death Cell Lineage Cerebral cortex Child Childhood Injury Clinical Research Cognition Cognitive deficits Development Dextrans Elderly Enzyme-Linked Immunosorbent Assay Epigenetic Process Euthanasia Extravasation Female Flow Cytometry Fluorescein-5-isothiocyanate Foundations Genetic HMGB1 gene Health Hippocampus Histology IL1R1 gene ITGAM gene Immune Immune system In Situ Nick-End Labeling Infiltration Inflammation Inflammatory Injections Injury Interleukin-1 beta Interleukin-6 Ipsilateral Learning Leukocytes Life Link Malondialdehyde Maternal Behavior Measures Memory Mental Health Microglia Modeling Monitor Mus Myelin Myelin Basic Proteins Myelogenous Nature Neurobiology Neurologic Deficit Neurons Neutrophil Infiltration Outcome Oxidation-Reduction Oxidative Stress PTPRC gene Pathogenesis Pathway interactions Phenotype Pre-Clinical Model Proteins Recovery Research Risk Rodent Secondary to Serum Social Behavior Stimulus Stress Stressful Event Study models TNF gene Testing Tissues Toddler Toxic effect Traumatic Brain Injury Traumatic Brain Injury recovery Traumatic injury Tumor Necrosis Factor-Beta United States Western Blotting age related aged anxiety-like behavior anxiety-related behavior behavior measurement biological adaptation to stress blood-brain barrier disruption brain tissue cell injury childhood adversity cognitive function critical period cytokine disability early experience early life adversity falls functional outcomes genetic approach glial activation improved injured insight long term recovery male monocyte neglect neuroinflammation neuron loss neutrophil novel object recognition pharmacologic physical conditioning postnatal psychosocial stressors pup receptor recruit response social social deficits

项目摘要

Project Summary These studies will determine if early life adversity (ELA) impacts recovery after traumatic injury to the developing brain. ELA refers to a broad spectrum of stressful events, including maternal neglect, and there is substantial evidence implicating ELA in later life poorer mental and physical health. A current model links ELA to “biological embedding”, whereby allostatic neurobiological pathways promote the enduring effects of ELA. Here I will focus on two of these ELA pathways, the immune system and redox state, as modifiers of recovery after an early age traumatic brain injury (TBI). I will study ELA, resulting from fragmented maternal care during a critical period of brain development [(postnatal day (P) 2-9], in combination with a well-established model of focal injury to the cerebral cortex in mice at postnatal day p21, an age that approximates the toddler-aged child. We and others have demonstrated that the brain at p21 is particularly vulnerable to oxidative stress and shows a unique sensitivity to inflammatory cytokines, corresponding to a more pronounced disruption of the blood-brain barrier (BBB) and leukocyte recruitment, compared to the injured adult brain. Based on these collective findings, I hypothesize that ELA enhances neuroinflammation, BBB disruption, and oxidative stress in the acutely injured brain and promotes long-term cognitive and social deficits. To test this hypothesis, Specific Aim 1 will determine if ELA has an additive or synergistic effect on inflammation when combined with TBI. Flow cytometry will be used to profile circulating and brain-infiltrated myeloid lineage cells and pro-inflammatory cytokines will be measured by ELISAs in serum and brain homogenates. Specific Aim 2 will determine if ELA supports acute secondary pathogenesis after TBI. Western immunoblots will be used to detect oxidative stress, BBB disruption, and cell damage. Complimentary histology will assess cell injury, microglial activation, and barrier leakage to FITC-tagged dextrans. Specific Aim 3 will determine if ELA disrupts long-term functional and structural recovery after TBI. I will assess anxiety-like behaviors, learning and memory, and social behaviors at adulthood. Lastly, stereology will be used to quantify cortical and hippocampal volumes and neurons in CA1, CA2, and CA3. Together, these studies offer the first insights into how ELA may influence secondary damage and recovery after an early age TBI. Such findings offer a foundation for developing strategies that are uniquely tailored to those brain-injured children who have experienced ELA.

项目总结