Augmentation of Neurogenesis and Recovery After Stroke

描述（由申请人提供）：本研究计划的总体目标是确定药理学和行为干预是否刺激成年大鼠卒中后的神经发生并改善功能恢复。神经干细胞在成年哺乳动物脑中的持久性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脑缺血增加成年大鼠脑室下区（SVZ）的神经发生。一些SVZ神经母细胞分化为受损纹状体中的神经元，这些新细胞在中风后持续至少5周，并表达适合于新纹状体神经元的表型标记。然而，更多的神经母细胞到达受伤的纹状体后，却无法存活。最近的研究还表明，行为操纵影响成年神经发生和中风后的恢复，但尚不清楚这些过程是否相关。这个建议的主要假设是，增加新纹状体神经发生将改善成年大鼠中风后感觉运动功能的恢复。具体假设如下：1）生长/分化因子或星形胶质细胞来源的线索将刺激完整SVZ-嗅球通路中的神经发生，并增加中风后的纹状体神经发生（目的1和2）; 2)神经发生是由药物或康复干预诱导的中风后功能恢复的主要因素（目的2和3）; 3）将生长/分化因子治疗和运动训练组合将增加神经发生并改善中风后的功能，比单独的任一种治疗更好。(Aim 4）。具体目标是：1）确定特异性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）确定用特异性促有丝分裂和分化因子治疗是否会通过纹状体神经发生增加成年大鼠中风后的功能恢复; 3）研究刺激受损肢体运动活动的行为干预是否会增强脑卒中后神经母细胞的存活和功能恢复，and 4）测定结合生长分化因子 治疗和行为治疗比单独治疗更能增强卒中后的神经发生或功能结局。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机制的理解，并可能导致新的中风再生疗法。

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.