Measuring and manipulating stress-responsive neuronal activity to improve post-stroke outcomes

中风是一种严重的缺血性神经血管损伤，在发达国家发病率高， 死亡率和幸存者的长期残疾。对于改进干预措施的开发至关重要的是 新的治疗方法考虑到缺血后卒中(IS)的暂时性，以确定适当的时间窗口 进行干预。下丘脑-垂体-肾上腺(HPA)轴激活，影响神经内分泌 应激反应在IS后超急性期升高，增加促肾上腺皮质激素释放激素 (CRH)和皮质类固醇(CORT)信号。IS前的压力和HPA活性升高与病情恶化有关 结果，亚急性期和慢性期的皮质醇过多是典型的和有害的。这个 海马区为HPA轴提供关键的负反馈调节，继发性脑缺血后损伤。 到海马体是很常见的。脑缺血后对海马区的继发性损伤可能依赖于皮质激素 信号；这可能会建立一个前馈环路，从而使中风后应激增强 信号会自我传播，进一步促进兴奋性毒性和神经退化。 越来越多的证据表明，靶向CRH信号可以减少IS后的发病率和 死亡率；这包括高级抗CRH抗体治疗和CRF1R拮抗。HPA的中枢神经系统控制 轴的激活可能是IS后CRH和皮质激素升高的主要因素。腹侧海马体 通过向纹状体床核的兴奋性投射调节CRH的产生和HPA的激活 终末核(BNST)，它向室旁核的CRH+神经元发送抑制性投射 下丘脑(PVN)。该电路代表了时间调制干预的一个可行目标 中风后。在这项建议中，我们将研究BNST和PVN神经元活动如何在中风后急剧变化， 以及调节这些核团中的关键神经元群体的活动将如何在 改善功能结果，减少海马区和整个大脑的神经元损伤 在缺血后。

Stroke is a severe ischemic neurovascular injury, with high rates of incidence in the developed world, high mortality, and long-term disability for survivors. It is critical for the development of improved interventions that novel therapies take into account post-ischemic stroke (IS) temporality to target appropriate time windows for intervention. Hypothalamic-pituitary-adrenal (HPA) axis activation, which effectuates the neuroendocrine stress response, is elevated in the hyperacute phase post-IS, increasing corticotropin releasing hormone (CRH) and corticosteroid (CORT) signaling. Elevated stress and HPA activity pre-IS is associated with worse outcomes, and hypercortisolism in the subacute and chronic phases is both typical and deleterious. The hippocampus provides crucial negative feedback regulation of the HPA axis, and secondary post-IS damage to the hippocampus is common. Secondary damage to the hippocampus post-IS may depend on corticoiddependent signaling; this could set up a feed-forward loop whereby post-stroke potentiation of stress signaling propagates itself, promoting further excitotoxicity and neurodegeneration. A growing body of evidence suggests that targeting CRH signaling could reduce post-IS morbidity and mortality; this includes advanced anti-CRH antibody treatment and CRF1R antagonism. CNS control of HPA axis activation is likely a major contributor to CRH and corticoid elevation post-IS. The ventral hippocampus regulates CRH production and HPA activation through excitatory projections to the bed nucleus of the stria terminalis (BNST), which in turn sends inhibitory projections to CRH+ neurons in the paraventricular nucleus (PVN) of the hypothalamus. This circuit represents a viable target for temporally-modulated interventions after stroke. In this proposal we will investigate how BNST and PVN neuronal activity changes acutely poststroke, and how modulating the activity of key neuronal populations in these nuclei will be effective in improving functional outcomes and reducing neuronal damage in the hippocampus and throughout the brain after ischemia.