Stress, Adrenal Steroids and the Brain

描述（由申请人提供）：在大脑中，应激激素和内源性兴奋性氨基酸（EAA）的过度活性导致CA 3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，虽然损害了一些功能，如陈述性记忆，可能不构成“损害”，而是一种适应性可塑性的形式，是保护免受永久性损害，也是可逆的，并可能治疗抗抑郁药和情绪稳定剂。我们把我们的研究集中在DG-CA 3上，因为它是神经发生和树突重塑发生的地方。DG-CA 3是海马体信息处理的关键入口点，由于其电路，它也容易受到损伤。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，并导致海马依赖性记忆受损。我们相信，树突的重塑是应力累积效应最终是否不可逆的关键。我们的主要假设是，DG-CA 3在压力下的树突重塑是一个可逆的，适应性的过程，涉及EAA和糖皮质激素，就像保险丝盒，减少永久性损伤的可能性，这个重要的和脆弱的系统，并提供一些神经保护和可逆性的机会。DG-CA 3涉及兴奋其他CA 3神经元的侧枝，以及前馈和反馈效应两者，其微妙地平衡并有助于记忆处理;慢性应激导致EAA释放的激活，导致驱动树突重塑的慢性“开”状态。这驱动微管和相关蛋白的重组，其依赖于细胞外调节剂，例如DG-CA 3中表达的PSA-NCAM，其促进细胞过程的运动并调节BDNF。我们预测，从NCAM中去除PSA将防止应激诱导的重构，并导致CA 3锥体神经元的永久性损伤。转化研究表明，海马萎缩发生在重度抑郁症和双相情感障碍以及库欣氏病中，其中海马萎缩是部分可逆的，这为逆转精神疾病中海马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.