Investigation of cerebello-thalamic circuits for the treatment of headache

对治疗偏头痛和创伤后头痛(PTH)的新方法的需求显著未得到满足 遭受创伤性脑损伤(TBI)的退伍军人。这项提议的主要目的是调节 小脑-丘脑回路治疗偏头痛和甲状旁腺激素。头痛会降低生活质量，并可能与 使感官异常失效，包括畏光和疼痛。据估计，仅偏头痛就影响了18%的 女性和6%的男性(总共12%)。然而，这种患病率在退伍军人中更高(总体为50%)， 曾在伊拉克和阿富汗服役，并经历过脑外伤和/或创伤后应激障碍。到目前为止， 近一半患有偏头痛或甲状旁腺素的患者在目前的治疗中得不到任何有益的结果 治疗。 这项提议将检验这样一个假设，即抑制小脑-丘脑回路可用于治疗偏头痛。 在老鼠身上有类似的行为。在第一个目标中，计划是抑制丘脑后区和顶核 用于治疗头痛状态的小鼠。为了模拟头痛，我们将使用降钙素 基因相关肽(CGRP)(一种足以诱发偏头痛的神经肽)和脑损伤 模型涉及轻微的闭合头部撞击。我们将在三种可翻译的行为范式中测试小鼠 测量避光、触摸过敏症和做鬼脸。我们将调节丘脑后部区域和 用抑制性配体激活设计者的化学发生策略研究小脑顶核 受体。我们的初步数据表明，刺激这两个大脑区域足以诱导 小鼠的偏头痛样行为。成功完成这一目标将为DIRECT提供可翻译的目标 治疗头痛障碍的大脑调制。在这项提议的第二个目标中，我们将使用血液-氧气- 水平相关功能磁共振成像(BOLD FMRI)识别血管下游靶点 偏头痛或创伤后头痛状态下的丘脑后部和小脑。我们会 给小鼠注射降钙素基因相关肽后进行成像 (PACAP)(一种也被报道会导致患者偏头痛的多肽)，或轻度脑外伤。我们还将 光遗传刺激丘脑后区和小脑顶核绘制功能图 大脑下游靶点的连通性变化。目标是识别更多的大脑目标，这些目标 更易于进行调制。 这项研究的意义在于这些临床前研究有可能转化为临床。有大的 对于患有头痛障碍的退伍军人群体来说，对新疗法的需求至关重要。本研究 有可能为治疗偏头痛和甲状旁腺激素提供新的治疗方法的路线图。

There is a significant unmet need for new approaches to treat migraine and post-traumatic headache (PTH) in Veterans who have suffered traumatic brain injury (TBI). The major aim of this proposal is to modulate cerebello-thalamic circuits to treat migraine and PTH. Headache reduces quality of life and can coincide with disabling sensory abnormalities including photophobia and pain. Migraine alone is estimated to affect 18% of women and 6% of men (12% overall). However, this prevalence is even greater in Veterans (50% overall) who have served in Iraq and Afghanistan and have experienced TBI and/or post-traumatic stress disorder. To date, nearly half of patients who have either migraine or PTH receive no beneficial outcomes with current treatments. This proposal will test the hypothesis that inhibition of cerebello-thalamic circuits can be used to treat migraine- like behaviors in mice. In the first aim, the plan is to inhibit the posterior thalamic area and the fastigial nucleus of the cerebellum to treat mice that are in a headache-like state. To model headache, we will use calcitonin gene-related peptide (CGRP) (a neuropeptide that is necessary and sufficient to induce migraine) and a TBI model involving mild closed head impact. We will test mice in three translatable behavior paradigms that measure light aversion, touch hypersensitivity and grimace. We will modulate the posterior thalamic area and fastigial nuclei of the cerebellum using a chemogenetic strategy with an inhibitory ligand-activated designer receptor. Our preliminary data indicate that stimulation of those two brain regions is sufficient to induce migraine-like behaviors in mice. Successful completion of this aim will provide translatable targets for direct brain modulation to treat headache disorders. In the second aim of this proposal, we will use blood-oxygen- level-dependent functional magnetic resonance imaging (BOLD fMRI) to identify downstream targets of the posterior thalamic area and cerebellum during a migraine-like or post-traumatic headache-like state. We will perform imaging in mice after they are given CGRP, pituitary adenylate cyclase-activating polypeptide (PACAP) (a peptide that is also reported to cause migraine in patients), or mild TBI. We will also optogenetically stimulate the posterior thalamic area and cerebellum fastigial nucleus to map functional connectivity changes of downstream targets in the brain. The goal is to identify additional brain targets that are more accessible for modulation. The significance of this study is the potential translation of these pre-clinical studies to the clinic. With large populations of Veterans suffering from headache disorders the need for new therapeutics is critical. This study has the potential to provide a road map for new therapeutic approachs to treating migraine and PTH.