Mechanisms of BDNF and Glucocorticoid Action

描述（由申请人提供）：肾上腺皮质产生的糖皮质激素在中枢神经系统中发挥许多作用，从空间学习和认知到压力和抑郁。虽然高水平的糖皮质激素可能是有害的，但在中等浓度下，它们可以促进海马中的突触可塑性和神经元细胞存活。糖皮质激素的神经保护、抗焦虑和代谢作用是通过糖皮质激素受体来实现的，糖皮质激素受体在大脑中大量表达。有趣的是，糖皮质激素对神经元回路的影响也受到神经营养因子如脑源性神经营养因子（BDNF）的强烈影响。然而，这种调节的分子机制尚未被探索。我们实验室的最新证据表明糖皮质激素和神经营养因子之间存在双向信号传导。例如，虽然BDNF通过Trk受体酪氨酸激酶进行信号传导，但糖皮质激素受体可以绕过对BDNF的需要并激活神经元细胞中的Trk信号传导（Jeanneteau等PNAS 2008）。在相互作用中，我们最近发现BDNF治疗促进了神经元中糖皮质激素受体在几个新发现的位点的磷酸化。该建议将剖析BDNF依赖的糖皮质激素受体磷酸化的生物学后果。我们的假设是，通过改变磷酸化，BDNF调节糖皮质激素受体基因的调节功能，这反过来又影响了脑垂体肾上腺（HPA）轴的活动。这些研究将开始确定影响HPA系统反馈控制和活性的分子机制，并提供糖皮质激素和BDNF如何影响与记忆形成、应激反应和抑郁相关的适应性和适应不良行为的见解。

DESCRIPTION (provided by applicant): Glucocorticoids produced by the adrenal cortex exert many effects in the central nervous system ranging from spatial learning and cognition to stress and depression. Although high levels of glucocorticoids can be detrimental, in moderate concentrations, they can facilitate synaptic plasticity in the hippocampus and neuronal cell survival. The neuroprotective, anti-anxiety, and metabolic effects of glucocorticoids are carried out by the glucocorticoid receptor, which is abundantly expressed in the brain. Interestingly, the effects of glucocorticoids upon neuronal circuits are also strongly influenced by neurotrophins, such as Brain Derived Neurotrophic Factor (BDNF). However, the molecular mechanism of this regulation has not been explored. Recent evidence from our laboratories indicates there is bi-directional signaling between glucocorticoids and neurotrophins. For example, while BDNF signals through a Trk receptor tyrosine kinase, glucocorticoid receptor can bypass the need for BDNF and activate Trk signaling in neuronal cells (Jeanneteau et al PNAS 2008). In a reciprocal interaction, we have recently found that BDNF treatment promotes the phosphorylation of glucocorticoid receptor in neurons at several newly discovered sites. This proposal will dissect the biological consequences of BDNF-dependent phosphorylation of glucocorticoid receptor. Our hypothesis is that by altering phosphorylation, BDNF modulates glucocorticoid receptor gene regulatory functions, which in turn affects hippocampal-pituitary-adrenal (HPA) axis activity. These studies will begin to define the molecular mechanisms that affect feedback control and activity of the HPA system, and provide insight into how glucocorticoids and BDNF influence adaptive and maladaptive actions that are relevant to memory formation, stress response and depression.