Mechanisms of BDNF and Glucocorticoid Action

描述(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，它们可以促进海马区突触的可塑性和神经细胞的存活。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实现的，而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的强烈影响，如脑源性神经营养因子(BDNF)。然而，这种调控的分子机制还没有被探索。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转导。例如，虽然BDNF通过Trk受体酪氨酸激酶发出信号，但糖皮质激素受体可以绕过对BDNF的需要，在神经细胞中激活Trk信号(Jeanneteau等人PNAS 2008)。在一种相互作用中，我们最近发现，BDNF治疗促进了几个新发现的部位的神经元中糖皮质激素受体的磷酸化。这项建议将剖析依赖BDNF的糖皮质激素受体磷酸化的生物学后果。我们的假设是，BDNF通过改变磷酸化，调节糖皮质激素受体基因的调节功能，进而影响海马-垂体-肾上腺(HPA)轴的活动。这些研究将开始定义影响HPA系统反馈控制和活性的分子机制，并深入了解糖皮质激素和BDNF如何影响与记忆形成、应激反应和抑郁相关的适应性和非适应性行为。

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.