Trophic Factors in Cognition

在了解神经元功能障碍如何导致神经系统紊乱方面取得了进展 提请注意营养因子在调节大脑功能中所起的中心作用。认知缺陷， 在神经精神障碍中广泛流行，已知受营养因子调节。 神经营养因子在海马区的作用已被证明尤为重要， 影响细胞途径和机制以产生行为效果的。促红细胞生成素，一种 天然激素和营养因子被广泛用于治疗贫血，发挥了强大的作用 大脑中的神经营养作用。此外，外周给药足以引起中枢神经系统的影响 几项临床前和临床精神病学研究。多项人体研究表明，促红细胞生成素 产生认知增强效果。对行为的规范被认为是 神经营养活性独立于促红细胞生成素的生理和止血调节作用 造血术。然而，大脑中的特定营养机制尚未确定。 此外，使用一种固有的红系分子来产生治疗神经营养作用 会导致血液粘度升高，增加发生不良血管事件的风险。因此，我们 利用化学工程的EPO衍生物，这些衍生物不是红血球，但保留了神经营养活性， 探讨其海马区活动在认知中的作用。使用有条件的、 我们将确定特定区域、受体敲除小鼠和病毒介导的基因操纵的作用 在分子、细胞和行为水平上研究海马神经营养因子驱动的机制。 我们的研究有望为营养因子介导的认知调节提供新的见解 行为，也为新型营养因子治疗剂的开发提供了信息。

The progress in understanding how neuronal dysfunction can lead to nervous system disorders has drawn attention to the central role played by trophic factors in modulating brain function. Cognitive deficits, which are widely prevalent in neuropsychiatric disorders, are known to be regulated by trophic factors. The hippocampal actions of neurotrophic factors have been shown to be particularly important, influencing cellular pathways and mechanisms to produce behavioral effects. Erythropoietin (EPO), a naturally occurring hormone and trophic factor, widely prescribed to treat anemia, exerts robust neurotrophic actions in the brain. Moreover, peripheral administration is sufficient to elicit CNS effects in several preclinical and clinical psychiatry studies. Multiple human studies have demonstrated that EPO produces cognitive enhancing effects. The regulation of behavior is considered to be a result of neurotrophic activity that is independent of EPO’s physiological and hemostatic role in regulating hematopoiesis. However, the specific trophic mechanisms in the brain have not been characterized. Furthermore, the use of an inherently erythropoietic molecule to produce therapeutic neurotrophic effects can lead to elevated blood viscosity and increase the risk for adverse vascular events. We therefore utilize chemically engineered EPO derivatives that are non-erythropoietic but retain neurotrophic activity, to investigate the role of its hippocampal actions in cognition. Employing a combination of conditional, region-specific, receptor knockout mice and viral-mediated gene manipulation we will determine the role of hippocampal neurotrophic factor-driven mechanisms at the molecular, cellular and behavioral levels. Our studies are expected to provide new insight into trophic factor-mediated modulation of cognitive behavior and also inform the development of novel trophic factor based therapeutic agents.