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

测量和操纵压力反应性神经元活动以改善中风后的结果

• 批准号: 10796766
• 负责人: Morgan Stuart Bridi
• 金额: $ 15.64万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796766
• 关键词: Acute; Adrenal Cortex Hormones; Adrenal Gland Hyperfunction; Adrenal Glands; Agonist; Animals; Antibody Therapy; Behavioral; Bilateral; Biological Assay; Brain; Calcium; Cell Nucleus; Centers of Research Excellence; Chemosensitization; Chronic; Chronic Phase; Clozapine; Color; Corticosterone; Corticotropin-Releasing Hormone; Development; Feedback; Fiber; Genetic; Glutamates; Hippocampus; Hypothalamic structure; Incidence; Infarction; Injury; Intervention; Ischemia; Ischemic Stroke; Measures; Middle Cerebral Artery Occlusion; Morbidity - disease rate; Mus; Nerve Degeneration; Neurons; Neurosecretory Systems; Outcome; Oxides; Pattern; Phase; Photometry; Pituitary Gland; Plasma; Population; Production; Regulation; Reporter; Signal Transduction; Stress; Stroke; Structure of terminal stria nuclei of preoptic region; Survivors; Synapses; Time; Universities; West Virginia; antagonist; behavioral outcome; biological adaptation to stress; designer receptors exclusively activated by designer drugs; disability; excitotoxicity; falls; functional improvement; functional outcomes; gamma-Aminobutyric Acid; hormonal signals; hypothalamic-pituitary-adrenal axis; improved; mortality; neurovascular injury; novel therapeutics; osmotic minipump; paraventricular nucleus; post stroke; sensor; sex; stem; stress reactivity; stressor; stroke outcome

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.

脑卒中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。制定更好的干预措施至关重要， 新的治疗方法考虑到缺血性卒中后（IS）的暂时性， 进行干预。下丘脑-垂体-肾上腺（HPA）轴激活，实现神经内分泌 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）信号传导。IS前应激和HPA活性升高与IS恶化相关。 结果，亚急性和慢性阶段的皮质醇增多症是典型的和有害的。的 海马提供HPA轴的重要负反馈调节， 是很常见的IS后海马的继发性损害可能依赖于皮质激素依赖性 信号;这可能会建立一个前馈回路， 信号传导自身传播，促进进一步的兴奋性毒性和神经变性。 越来越多的证据表明，靶向CRH信号传导可以降低IS后的发病率， 死亡率;这包括晚期抗CRH抗体治疗和CRF 1 R拮抗作用。HPA的CNS控制 轴激活可能是IS后CRH和皮质激素升高的主要原因。腹侧海马 通过对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），其反过来向室旁核中的CRH+神经元发送抑制性投射 (PVN)下丘脑该回路代表了时间调制干预的可行目标 中风后在本研究中，我们将研究脑卒中后BNST和PVN神经元活动的急性变化， 以及如何调节这些核中关键神经元群体的活性， 改善海马和整个大脑的功能结果并减少神经元损伤 缺血后。