Investigation of cerebello-thalamic circuits for the treatment of headache

对于治疗偏头痛和创伤后头痛（PTH）的新方法存在显著未满足的需求， 遭受创伤性脑损伤（TBI）的退伍军人。该提案的主要目的是调节 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， 包括恐惧症和疼痛在内的感觉异常偏头痛单独估计影响18%的 妇女和6%的男子（总体为12%）。然而，这种患病率在退伍军人中甚至更高（总体为50%）， 曾在伊拉克和阿富汗服役，经历过创伤性脑损伤和/或创伤后应激障碍。到目前为止， 近一半患有偏头痛或PTH的患者在目前的治疗中没有获得有益的结果， 治疗。 这项提议将检验抑制小脑-丘脑回路可用于治疗偏头痛的假设， 就像老鼠的行为一样。在第一个目标，计划是抑制后丘脑区和小脑顶核 来治疗处于头痛样状态的小鼠。为了模拟头痛，我们将使用降钙素 基因相关肽（CGRP）（一种神经肽，是必要的，足以诱发偏头痛）和TBI 涉及轻度闭合头部撞击的模型。我们将在三种可转换的行为模式中测试小鼠， 测量光厌恶、触摸过敏和鬼脸。我们将调整后丘脑区域， 小脑顶核的化学发生策略与抑制配体激活的设计师 受体的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。这一目标的成功实现，将为直接翻译提供可译的目标 大脑调节来治疗头痛。在这个建议的第二个目标中，我们将使用血氧- 水平依赖性功能磁共振成像（BOLD fMRI），以确定下游目标的 在偏头痛样或创伤后头痛样状态下，丘脑后区和小脑的活动。我们将 给小鼠注射CGRP，垂体腺苷酸环化酶激活肽， （PACAP）（一种也被报道会引起患者偏头痛的肽）或轻度TBI。我们还将 光遗传学刺激丘脑后区和小脑顶核以映射功能 大脑中下游目标的连接变化。目标是确定更多的大脑目标， 更易于调制。 本研究的意义在于将这些临床前研究转化为临床。大 对于患有头痛疾病的退伍军人群体来说，对新疗法的需求是至关重要的。本研究 有可能为治疗偏头痛和PTH的新治疗方法提供路线图。

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.