Targeted neuromodulation to enhance recovery of the aged brain after ischemic stroke

摘要 缺血性中风是一种主要影响老年人的破坏性疾病，是导致长期残疾的主要原因。 全世界。目前的治疗主要依赖于在中风后的急性期恢复血流。 然而，这种再灌注治疗只适用于一小部分中风患者，甚至在 这些患者中，许多人仍然患有终生神经功能障碍。因此，迫切需要新的复苏-- 在慢性卒中阶段加强治疗。在中风后的慢性期，自发的，但 通常情况下，神经功能的缓慢和部分恢复是由于内源性恢复剂的激活 不仅在梗塞周围区域，而且在遥远的脑区也有反应。这些过程涉及神经元 可塑性。为了增强神经元的可塑性，神经调节策略，包括脑刺激，已经被 探讨神经康复治疗中风的方法。然而，临床结果并不一致，突出表明 我们对特定神经元活动在中风后神经恢复中的作用的认识不足。我们的 长期目标是帮助设计有效的神经调节性中风疗法，以促进康复，特别是在 老化的大脑。我们的目标是结合新的和最先进的方法来阐明 慢性卒中恢复期的神经元活动，通过对细胞机制的详细剖析 以及老年小鼠的网络水平，无论性别。特别是，我们将利用设计师的力量 受体仅由设计药物(DREADD)为基础的化学遗传学激活，以调节特定的 中风后大脑中的神经元。我们的中心假设是，在缺血性中风后，适当的调节 慢性恢复期靶向神经元活动促进皮质脊髓束(CST)血管形成 重组、大脑半球间的连接和大脑功能的恢复。为了检验这一假设，我们将 追求两个特定的目标：1)在慢性卒中康复过程中调节梗塞周围区域的兴奋性神经元 2)慢性卒中恢复期对侧M1区兴奋性神经元的调节。 这项拟议的研究意义重大，因为我们将从这项研究中获得的知识有望为未来提供参考 通过靶向促进缺血性卒中后脑功能恢复的新干预措施的开发 神经调节，从而改善中风患者的生活质量。

Abstract Ischemic stroke, a devasting disease that primarily affects the elderly, is a leading cause of long-term disability worldwide. Current treatment relies primarily on restoring blood flow during the acute phase after stroke. However, this reperfusion treatment is applicable to only a small fraction of stroke patients, and even among these patients, many still suffer life-long neurologic impairment. Thus, there is an urgent need for new recovery- enhancing treatments during the chronic stroke phase. In the chronic phase after stroke, spontaneous, but typically slow and partial, recovery of neurologic function occurs due to activation of endogenous restorative processes not only in the peri-infarct region but also in remote brain regions. These processes involve neuronal plasticity. To enhance neuronal plasticity, neuromodulation strategies, including brain stimulation, have been explored in neurorehabilitation stroke therapy. However, the clinical results have been inconsistent, highlighting a deficiency in our knowledge about the role of specific neuronal activity in neurorestoration after stroke. Our long-term goal is to help design effective neuromodulatory stroke therapy that enhances recovery, particularly in the aged brain. Our objective here is to combine novel and state-of-the-art approaches to clarify the role of neuronal activity in the chronic stroke recovery phase, through a detailed dissection of mechanisms at cellular and network levels in aged mice of both sexes. In particular, we will capitalize on the power of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)-based chemogenetics to modulate specific neurons in the post-stroke brain. Our central hypothesis is that after ischemic stroke, proper modulation of targeted neuronal activity during the chronic recovery phase promotes vascularization, corticospinal tract (CST) reorganization, interhemispheric connectivity, and restoration of brain function. To test this hypothesis, we will pursue 2 specific aims: 1) Modulate excitatory neurons in peri-infarct regions during chronic stroke recovery phase; and 2) Modulate excitatory neurons in the contralateral M1 region during chronic stroke recovery phase. The proposed research is significant because knowledge we will gain from this study is expected to inform future development of novel interventions that promote recovery of brain function after ischemic stroke through targeted neuromodulation, thus improving quality of life in stroke patients.