Dopaminergic mechanisms underlying behavioral deficits following mild TBI

轻度 TBI 后行为缺陷的多巴胺能机制

基本信息

批准号：
9981088
负责人：
Ramesh Raghupathi
金额：
$ 36.17万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9981088
关键词：
Adolescence Adolescent Adult Affect Age Agonist Anhedonia Animal Testing Animals Anxiety Attenuated Behavior Behavioral Brain Concussion Brain Injuries Chronic Cognitive deficits Data Development Diagnosis Dopamine Dopamine D2 Receptor Elderly Emergency department visit Emotional Disturbance Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Estrous Cycle Estrus Executive Dysfunction Exhibits Female Female Adolescents Genetic Headache Hormone Receptor Hormones Injury Lead Male Adolescents Measures Medial Mediating Mediator of activation protein Medical Membrane Mental Depression Microdialysis Modeling Mood Disorders Mus Neurons Patients Pharmacology Phase Phenols Phenotype Prefrontal Cortex Problem behavior Proestrus Progesterone Receptors Protein Isoforms Proteins Quinpirole Rattus Receptor Activation Reporting Risk Selective Estrogen Receptor Modulators Signal Transduction Sports Substance Use Disorder Substance abuse problem Sucrose Suggestion Surface Symptoms Synapses Tamoxifen Testing Time Traumatic Brain Injury Tyrosine 3-Monooxygenase United States Ventral Tegmental Area Virus Woman adeno-associated viral vector axon injury boys college depressive behavior depressive symptoms design designer receptors exclusively activated by designer drugs dopaminergic neuron experience experimental study extracellular forced swim test girls high school injured male mild traumatic brain injury preclinical study preference premenstrual dysphoric disorder promoter receptor binding receptor expression resilience sex targeted treatment treatment strategy vector young adult

项目摘要

Almost 2.5 million people visit the emergency room each year in the United States as a consequence of sustaining a traumatic brain injury (TBI). Of these almost 75% are diagnosed with a mild TBI or a concussion, and almost a third of these patients go on to develop long-term behavioral problems. Executive function deficits, emotional disturbances such as depression and anxiety, affective disorders and substance use disorders are some of more common complaints of mild TBI patients. Adolescent boys and girls (high school and college-age) are more severely affected by concussions compared to older (adult) patients. Emerging data also suggest that girls and women are twice as likely to sustain a mild TBI, have different and more severe symptoms and take longer to recover from than their male counterparts. We have developed a model of mild TBI in the adolescent (5-week-old) rat and have demonstrated that despite similar extents of axonal injury in the early post-traumatic period only the female rats exhibit cognitive deficits. Importantly, as these animals age into adulthood, they begin to develop depression-like behavior, which manifests only in the estrus phase of the estrous cycle. This phenomenon of transient helplessness and anhedonia are hallmarks of premenstrual dysphoric disorder that some women experience. Our preliminary data demonstrate that activating the mesocorticolimbic dopamine circuit using chemogenetic approaches or agonist of the D2 receptor reversed the depressive-like behavior observed in injured animals. The activity of the D2 receptor varies with phases of the estrous cycle with the lowest activity occurring immediately after the hormone surge that occurs during proestrus. Blocking this surge using estrogen and progesterone receptor antagonists was able to reduce depressive-like behavior. The working hypothesis of this proposal is that mild TBI in the adolescent female rat results in the development of a hypodopaminergic state characterized by a decrease in the activity of the dopamine neurons in the ventral tegmental area (VTA) and the expression of D2 receptors in the medial prefrontal cortex (PFC). The specific aims are designed to test whether the estrogen receptor β isotype is the key mediator of the decrease in D2 receptor expression (Aim 1), whether the activation of D2 receptors within the medial PFC facilitate the reversal of the depressive-like behavior (Aim 2), and whether the activation of the DA neurons in the VTA projecting to the medial PFC will reverse depressive-like behavior. Hormone receptor antagonists will be systemically administered, D2 receptor agonist and retroAAV2 will be infused directly into the medial PFC, and Gq-designer receptors exclusively activated by designer drugs will be expressed in the VTA using an AAV vector. The data from these experiments will provide the mechanistic basis for sex-specific behavioral deficits following mild TBI sustained in adolescence.

在美国，每年有近 250 万人因以下原因前往急诊室就诊：遭受创伤性脑损伤 (TBI)，其中近 75% 被诊断患有轻度 TBI 或脑震荡，几乎三分之一的患者会出现长期的行为问题。缺陷、情绪障碍（例如抑郁和焦虑）、情感障碍和药物滥用轻度 TBI 患者（高中生）最常见的症状是精神障碍。与老年（成人）患者相比，老年（成人）患者受到脑震荡的影响更严重。还表明，女孩和妇女遭受轻度 TBI 的可能性是女性的两倍，她们有不同且更严重的症状与男性相比，我们开发了一种轻度症状的模型。对青春期（5 周龄）大鼠进行 TBI 试验并证明，尽管轴突损伤程度相似重要的是，随着这些动物的衰老，在创伤后早期，只有雌性大鼠表现出认知缺陷。进入成年期，它们开始出现类似抑郁的行为，这种行为仅在发情期表现出来。这种短暂的无助和快感缺乏的现象是经前的标志。我们的初步数据表明，一些女性会经历焦虑症。使用化学遗传学方法或 D2 受体激动剂的中皮质边缘多巴胺回路逆转了在受伤动物中观察到的抑郁样行为 D2 受体的活性随损伤的阶段而变化。发情周期中，激素激增后立即出现最低活动。使用雌激素和孕激素受体拮抗剂阻止发情前期的激增能够减少。该提案的工作假设是青春期女性患有轻度 TBI。大鼠导致多巴胺能低下状态的发展，其特征是多巴胺能活性降低腹侧被盖区 (VTA) 的多巴胺神经元和内侧被盖区 D2 受体的表达前额皮质（PFC）的具体目的是测试雌激素受体β同种型。 D2 受体表达减少的关键介质（目标 1），D2 受体的激活是否在内侧 PFC 有助于逆转抑郁样行为（目标 2），以及是否激活 VTA 中的 DA 神经元投射到内侧 PFC 将逆转激素受体的行为。拮抗剂将全身给药，D2受体激动剂和retroAAV2将直接注入内侧 PFC 和仅由设计药物激活的 Gq 设计受体将在使用 AAV 载体的 VTA 实验数据将为性别特异性提供机制基础。轻度创伤性脑损伤（TBI）导致青春期持续的行为缺陷。