Augmentation of Neurogenesis and Recovery After Stroke

描述(申请人提供)：这项研究计划的总体目标是确定药物和行为干预是否刺激成年大鼠中风后的神经发生和改善功能恢复。成年哺乳动物脑内神经干细胞的持续存在和损伤刺激前脑神经发生的证据表明，内源性祖细胞是脑损伤或神经变性后神经元替代的来源。我们最近发现，局灶性缺血增加了成年大鼠室下区(SVZ)的神经发生。一些SVZ神经母细胞在损伤的纹状体中分化为神经元，这些新细胞在中风后至少持续5周，并表达适合新纹状体神经元的表型标记。然而，更多到达受损纹状体的神经母细胞未能存活。最近的研究还表明，行为操作既影响成人的神经发生，也影响中风后的康复，但尚不清楚这些过程是否存在联系。这一建议的主要假设是，促进新纹状体神经发生将促进成年大鼠中风后感觉运动功能的恢复。具体的假设是：1)生长/分化因子或星形胶质细胞来源的线索将刺激完整的SVZ-嗅球通路中的神经发生，并增加卒中后纹状体的神经发生(目标1和2)； 2)神经发生是药物或康复干预(目标2和3)诱导的卒中后功能恢复的主要因素；3)生长/分化因子治疗和运动训练相结合比单用任何一种治疗更能增加神经发生和改善功能。(目标4)。具体目的是：1)确定特定的生长分化因子或星形胶质细胞衍生的信号是否刺激前脑SVZ神经母细胞的增殖或分化；2)确定特定的有丝分裂和分化因子治疗是否会通过纹状体神经发生促进成年大鼠中风后的功能恢复；3)调查刺激受损肢体运动活动的行为干预是否会促进中风后神经母细胞的存活和功能恢复；以及4)确定联合生长分化因子是否会促进中风后神经母细胞的存活和功能恢复。 治疗和行为疗法比单独治疗更能增强中风后的神经再生或功能预后。这些目标的进展将促进我们对脑损伤后神经干细胞调节和康复可塑性的潜在机制的理解，并可能导致中风的新的再生疗法。

DESCRIPTION (provided by applicant): The overall goal of this research plan is to determine whether pharmacological and behavioral interventions stimulate neurogenesis and improve functional recovery after stroke in the adult rat. The persistence of neural stem cells in the adult mammalian brain and evidence that injury stimulates forebrain neurogenesis suggest that endogenous progenitors are a source for neuronal replacement after brain insults or neurodegeneration. We have recently discovered that focal ischemia increases neurogenesis in the adult rat subventricular zone (SVZ). Some SVZ neuroblasts differentiate into neurons in the injured striatum, and these new cells persist for at least 5 weeks after stroke and express phenotypic markers appropriate for neostriatal neurons. Many more neuroblasts that reach the injured striatum, however, fail to survive. Recent work also suggests that behavioral manipulations influence both adult neurogenesis and recovery from stroke, but it is not known whether these processes are linked. The main hypothesis of this proposal is that augmenting neostriatal neurogenesis will improve recovery of sensorimotor function after stroke in the adult rat. The specific hypotheses are: 1) growth/differentiation factors or astrocyte-derived cues will stimulate neurogenesis in the intact SVZ-olfactory bulb pathway, and increase striatal neurogenesis after stroke (Aims 1 and 2); 2) neurogenesis is a major factor in the functional recovery after stroke induced by pharmacological or rehabilitative interventions (Aims 2 and 3); 3) combining growth/differentiation factor treatment and motor training will increase neurogenesis and improve function after stroke more than either treatment alone. (Aim 4). The specific aims are: 1) To determine whether specific growth differentiation factors or astrocyte-derived cues stimulate the proliferation or differentiation of forebrain SVZ neuroblasts; 2) To determine whether treatment with specific mitogenic and differentiation factors will augment, via striatal neurogenesis, functional recovery after stroke in the adult rat; 3) To investigate whether behavioral interventions to stimulate motor activity in the impaired limbs will enhance neuroblast survival and functional recovery after stroke," and 4) To determine whether combined growth differentiation factor treatment and behavioral therapy enhance neurogenesis or fimctional outcome after stroke more than either treatment alone. Progress in these aims will advance our understanding of mechanisms underlying neural stem cell regulation and rehabilitative plasticity after brain injury, and may lead to novel regenerative therapies for stroke.