Dopaminergic Mechanisms Underlying Behavioral Deficits Following Mild TBI

在美国，每年有近250万人前往急诊室就诊，原因是 遭受创伤性脑损伤(TBI)。在这些患者中，近75%的人被诊断为轻度脑外伤或脑震荡， 这些患者中几乎有三分之一会继续发展成长期的行为问题。执行职能 缺陷、情绪障碍，如抑郁和焦虑、情感障碍和物质使用 精神障碍是轻度脑外伤患者更常见的主诉之一。青春期男孩和女孩(高中 与年龄较大的(成人)患者相比，脑震荡的影响更严重。新兴数据 还表明，女孩和妇女患轻度脑外伤的可能性是女性的两倍，不同的和更严重的 与男性相比，她们的症状和恢复时间更长。我们已经开发出一种温和的模型 在青春期(5周大)大鼠的脑损伤中发现，尽管有相似程度的轴突损伤 创伤后早期只有雌性大鼠表现出认知缺陷。重要的是，随着这些动物年龄的增长 成年后，他们开始产生类似抑郁的行为，这种行为只在发情期表现出来。 发情周期。这种一过性无助和快感缺乏的现象是经前症状。 一些女性经历的烦躁不安的障碍。我们的初步数据表明，激活 使用D2受体激动剂或化学发生途径的中皮质边缘多巴胺环路逆转 在受伤的动物身上观察到的类似抑郁的行为。D2受体的活性随发育阶段的不同而变化 动情周期中，最低的活动发生在激素激增之后，在 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青春期女性的轻度脑损伤 大鼠导致低多巴胺能状态的发展，其特征是 腹侧被盖区的多巴胺能神经元与内侧D2受体的表达 前额叶皮质(PFC)具体目的是测试雌激素受体β同型是否是 关键介体D2受体表达减少(AIM 1)，是否激活D2受体内 内侧前额叶促进抑郁样行为的逆转(目标2)，以及是否激活 VTA中投射到内侧PFC的DA神经元将逆转抑郁样行为。激素受体 拮抗剂将全身给药，D2受体激动剂和逆转录AAV2将直接注入 由特制药物独有激活的内侧PFC和GQ-Designer受体将在 使用AAV载体的VTA。这些实验的数据将为性别区分提供机制基础 轻度脑外伤后的行为缺陷在青春期持续存在。

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.