Stress, Adrenal Steroids and the Brain

描述(申请人提供)：在大脑中，应激激素和内源性兴奋性氨基酸(EAA)的过度活动导致CA3区树突缩短，并抑制齿状回(DG)的神经发生。然而，即使是这些变化，尽管损害了一些功能，如陈述性记忆，也可能不构成“损害”，而是一种适应性可塑性，可以防止永久性损害，也是可逆的，可能可以用抗抑郁药物和情绪稳定剂来治疗。我们将重点放在DG-CA3上，因为它是树突发生神经发生和重塑的地方。DG-CA3是海马体信息处理的关键入口点，由于其电路，它也容易受到损害。因此，它也是涉及糖皮质激素和兴奋性氨基酸的应激重塑效应的联系纽带，并导致海马区依赖记忆的损害。我们认为，树突的重塑是应力累积效应是否最终不可逆转的关键。我们的主要假设是，应激下DG-CA3中的树突重塑是一个涉及EAA和糖皮质激素的可逆、适应性过程，就像保险丝盒一样，降低了这个重要而脆弱的系统受到永久性损害的可能性，并提供了一些神经保护和可逆性机会。DG-CA3涉及刺激其他CA3神经元的侧支，以及微妙平衡和辅助记忆处理的前馈和反馈效应；慢性应激导致EAA释放的激活，导致慢性“开”状态，驱动树突重塑。这推动了微管和相关蛋白的重组，这依赖于细胞外调节剂，如DG-CA3中表达的PSA-NCAM，它促进了细胞过程的移动，并调节了BDNF。我们预测，从NCAM中去除PSA将防止应激诱导的重塑，并导致CA3锥体神经元的永久性损伤。翻译研究表明，严重抑郁症和双相情感障碍以及部分可逆的库欣病都会出现海马体萎缩，这给精神障碍患者逆转海马体萎缩的能力带来了希望。

DESCRIPTION (provided by applicant): In brain, the over-activity of stress hormones and endogenous excitatory amino acids (EAA) causes shortening of dendrites in the CA3 region and suppresses neurogenesis in the dentate gyrus (DG). Yet, even these changes, although impairing some functions such as declarative memory, may not constitute "damage" but rather a form of adaptive plasticity that is protective against permanent damage and also reversible and potentially treatable with antidepressants and mood stabilizers. We focus our studies on the DG-CA3 because it is where both neurogenesis and remodeling of dendrites occurs. The DG-CA3 is the critical entry point for information processing by the hippocampus and it is also vulnerable to damage because of its circuitry. Hence it is also a nexus for the remodeling effects of stress that involve glucocorticoids and excitatory amino acids and which cause impairment of hippocampal dependent memory. We believe that the remodeling of dendrites holds the key to whether the cumulative effects of stress may be ultimately irreversible. Our main hypothesis is that dendrite remodeling in DG-CA3 under stress is a reversible, adaptive process involving EAA and glucocorticoids that, like a fuse box, reduces the likelihood of permanent damage to this important and vulnerable system and affords some neuroprotection and the opportunity for reversibility. The DG-CA3 involves collaterals that excite other CA3 neurons and both feed-forward and feed-back effects that are delicately balanced and subserve memory processing; Chronic stress leads to activation of EAA release resulting in a chronic "on" state that drives dendritic remodeling. This drives the reorganization of the microtubules and associated proteins which is dependent on extracellular modulators such as PSA-NCAM expressed in DG-CA3 that facilitates movement of cellular processes and modulates BDNF. We predict that removal of PSA from NCAM will prevent stress-induced remodeling and lead to permanent damage to CA3 pyramidal neurons. Translational studies have shown that hippocampal shrinkage occurs in major depression and bipolar disorder as well as Cushing's Disease, where it is partially reversible, lending hope to the ability to reverse hippocampal atrophy in psychiatric disorders.