Dopaminergic mechanisms underlying behavioral deficits following mild TBI

轻度 TBI 后行为缺陷的多巴胺能机制

• 批准号: 10320649
• 负责人: Ramesh Raghupathi
• 金额: $ 0.78万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320649
• 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; contact sports; 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

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.

由于 维持创伤性脑损伤（TBI）。在这些近75％的人中，被诊断出患有轻度TBI或咨询 这些患者中几乎有三分之一继续出现长期行为问题。执行功能 缺陷，情绪障碍，例如抑郁和动画，情感障碍和吸毒 疾病是轻度TBI患者的一些更常见的抱怨。青春期男孩和女孩（高中 与年龄较大（成人）患者相比，咨询的影响更大。新兴数据 还表明，女孩和妇女维持温和的TBI的可能性是不同，更严重的可能性 症状比男性需要更长的时间才能恢复。我们已经开发了中期的模型 TBI在青少年（5周大）的大鼠中，已经证明了渴望在 创伤后早期，只有雌性大鼠暴露了认知缺陷。重要的是，随着这些动物的年龄 成年后，他们开始发展类似抑郁症的行为，这仅在 这种短暂的无助和狂欢的现象是经前线的标志 一些女性经历的烦躁不安。我们的初步数据表明，激活 使用化学生物发生方法或D2受体的激动剂逆转了中皮质糖多巴胺的回路 在受伤的动物中观察到的抑郁样行为。 D2受体品种的活性 发酵周期的活动最低，在发生霍斯纳刺激后立即发生 前弹性。使用雌激素和孕酮受体拮抗剂阻止这种激增，能够减少 类似抑郁的行为。该提议的工作假设是青春期女性的轻度TBI 大鼠导致发育的低载胺能状态的发展，其特征是降低 腹侧盖区域（VTA）中的多巴胺神经元和培养基中D2受体的表达 前额叶皮层（PFC）。具体目的旨在测试雌激素受体β同种型是否是 D2受体表达降低的关键介体（AIM 1），是否激活D2受体 内侧PFC最喜欢的类似抑郁症行为的逆转（AIM 2），以及是否激活 VTA向内侧PFC投射的DA神经元将逆转抑郁样的行为。激素接收器 拮抗剂将被系统施用，D2受体激动剂和Retroaav2将直接注入 内侧PFC和GQ-Designer接收器专门由设计师药物激活 VTA使用AAV矢量。这些实验的数据将为性别特异性提供机械基础 行为定义了青春期中的轻度TBI。