Dopaminergic Mechanisms Underlying Behavioral Deficits Following Mild TBI

在美国，每年有近250万人因心脏病而前往急诊室。 创伤性脑损伤（TBI）。其中近75%被诊断为轻度TBI或脑震荡， 几乎有三分之一的患者会发展出长期的行为问题。执行功能 缺陷、抑郁和焦虑等情绪障碍、情感障碍和物质使用 疾病是轻度TBI患者的一些更常见的主诉。青春期男孩和女孩（高中） 和大学年龄）与老年（成人）患者相比更严重地受到脑震荡的影响。新出现的数据 还表明，女孩和妇女有两倍的可能性维持轻度TBI，有不同的和更严重的 症状和需要更长的时间来恢复比男性同行。我们开发了一种温和的 TBI在青少年（5周龄）大鼠中的作用，并已证明，尽管在成年大鼠中轴突损伤的程度相似， 在创伤后早期，只有雌性大鼠表现出认知缺陷。重要的是，随着这些动物的年龄增长， 进入成年后，他们开始发展抑郁样的行为，这只表现在发情期， 发情周期这种短暂的无助和快感缺乏的现象是经前 一些女性经历的焦虑症。我们的初步数据表明，激活 使用化学发生方法或D2受体激动剂的中皮质边缘多巴胺回路逆转了这种情况 在受伤动物中观察到的抑郁样行为。D2受体的活性随时间的变化而变化。 发情周期，在发情期间发生的激素激增之后立即发生最低活性 发情前期使用雌激素和孕激素受体拮抗剂阻断这种激增能够减少 类似抑郁的行为这项建议的工作假设是，轻度TBI的青春期女性， 结果发展为多巴胺能减退状态，其特征在于 腹侧被盖区（VTA）的多巴胺神经元和内侧核D2受体的表达 前额叶皮层（PFC）。具体目的是检测雌激素受体β亚型是否为雌激素受体β亚型。 D2受体表达减少的关键介质（目的1），是否激活D2受体内 内侧PFC的激活促进抑郁样行为的逆转（目的2），以及是否激活内侧PFC的激活 腹侧被盖区的DA能神经元投射到内侧前额叶皮层将逆转抑郁样行为。激素受体 拮抗剂将全身施用，D2受体激动剂和retroAAV 2将直接输注到 仅由设计药物激活的内侧PFC和Gq-设计受体将表达于 使用AAV载体的VTA。这些实验的数据将为性别特异性提供机制基础。 青少年期轻度TBI后的行为缺陷。

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.