Traumatic Brain Injury, Stress, and Headache

创伤性脑损伤合并应激反应的患者最常见的症状是复发性创伤后头痛(PTH)。虽然35-60%的轻度颅脑损伤患者会经历头痛，再加上强烈的压力源，但在这类患者中，头痛的比例上升到85%。甲状旁腺激素与偏头痛有许多共同的特征，包括面部疼痛、先兆和对感觉刺激的敏感性，这表明这两种情况可能是通过重叠的机制发展起来的。现在越来越多的证据表明，偏头痛，以及潜在的甲状旁腺素，可能是由导致硬脑膜传入神经元激活/敏化的硬脑膜引起的。虽然我们之前已经证明了应激单独对硬脑膜传入兴奋性和硬脑膜免疫细胞密度的影响，但如果不是偏头痛，那么应激可能会加剧这些事件，将硬脑膜环境从抑制性转变为兴奋性，从而驱动PTH。因此，这项建议将使用一个临床相关的动物模型来确定免疫分子和肾上腺素能受体是否参与了由脑创伤和应激引起的甲状旁腺激素的增强。首先，我将测试与头痛相关的行为、面部触觉异常疼痛和做鬼脸，并对患有应激性脑损伤的动物的硬脑膜传入的自发和诱发的钙瞬变进行活体记录。其次，我将评估脑外伤和应激动物的硬脑膜传入兴奋性是否发生改变。最后，我将测量脑外伤和应激动物硬脑膜免疫细胞的密度和表型，以及它们表达的细胞因子。这些实验的结果将提供硬脑膜传入和硬脑膜免疫细胞环境对维持甲状旁腺激素有贡献的信息。在拟议的实验中，我将使用一系列的行为分析和活体显微镜，结合膜片钳电生理学、流式细胞术和细胞因子的表达。因此，拟议实验的成功完成将提供有关对钙调节至关重要的蛋白质功能的新信息，为治疗炎症性疼痛提供新的治疗方法，并为建立独立科学家的职业生涯提供坚实的实验基础。

The symptom most commonly experienced with patients with traumatic brain injury combined with and stress is recurrent post-­traumatic headache (PTH). While 35-­60% of patients with mild TBI experience headache, in combination with an intense stressor, the rate of headache in this patient population rises to 85%. PTH shares many features with migraine, including facial allodynia, aura, and sensitivity to sensory stimuli, suggesting that these two conditions may develop through overlapping mechanisms. A growing body of evidence now implicates that migraine, and potentially PTH, may arise from the dura that leads to activation/sensitization of dural afferent neurons. While we have previously demonstrated the effect of stress alone on dural afferent excitability and dural immune cell density, it is likely that TBI with stress potentiates these events, shifting the dural environment from inhibitory to excitatory to drive PTH, if not migraine. Therefore, this proposal will employ a clinically – relevant animal model to determine if immune molecules and adrenergic receptors are involved in the potentiation of PTH that results from TBI and stress. First, I will test headache-­linked behaviors, facial tactile allodynia and grimacing, paired with in vivo recordings of spontaneous and evoked calcium transients in dural afferents in animals with TBI with stress. Second, I will assess if dural afferent excitability is altered in animals with TBI and stress. Finally, I will measure the density and phenotype of dural immune cells and the cytokines they express in animals with TBI and stress. Results from these experiments will provide information in which dural afferents and the milieu of dural immune cells contribute to the maintenance of PTH. In the proposed experiments, I will employ an array of behavioral assays and in vivo microscopy paired with patch clamp electrophysiology and flow cytometry and cytokine expression. Thus, the successful completion of the proposed experiments will provide novel information regarding the function of a protein critical for Ca2+ regulation, suggest novel therapeutic approaches for the treatment of inflammatory pain, and provide a solid experimental foundation upon which to build a career as an independent scientist.