Ionic and Second Messanger Basis of Stress-Induced Prefrontal Dysfunction

应激减弱了前额叶皮质(PFC)对行为的调节控制；而增强了皮质下皮质 习惯的调停。该联盟的项目2将研究RFC的分子和细胞基础 急性和慢性应激期间的功能障碍，目的是确定棚屋的治疗靶点。上一首 研究发现，压力通过1)通过多巴胺过度产生cAMP来损害PFC功能 (Da)d1和nOriginephririe(Kle)beta！受体；2)去甲肾上腺素α-1激活磷脂酰肌醇(PI) DAG-蛋白基酶C(PKC)信号转导，抑制PFC细胞的激活。拟议的研究将进一步 通过检测IP3-Ca~(2+)的作用探讨PFC功能障碍的信号级联反应 PI信号的组成部分。与这种可能性一致的是，来自PFC神经元的体外记录显示 RP3介导的钙释放开放SKs通道从而抑制PFC细胞的兴奋性 拟议中的研究将检验这种人脑是否会在3岁时导致应激诱导的PFC功能障碍。 水平：AIM 1将使用PFC锥体神经元的体外记录和钙荧光成像来 研究PI级联的细胞基础，Aim 2将把这些结果扩展到PFC的活体记录 动物的神经元执行工作的快乐任务，目标3将测试PFC的认知功能 可以通过阻断IPS受体或SK通道来保护自己免受压力。AIM 3还将评估符合以下条件的代理 可以用在人类身上。我们将测试卡维地洛能否阻断α-1和β-Kl‘e受体 保护PFC功能免受压力。如果在动物身上成功，卡维地洛可以在暴露于 项目9中的压力；我们还将测试endbcanrtabanoid(ECB)在应激诱导的PFC功能障碍中的作用 作为项目5的扩展。由于ECB依赖于DAG和Ca2，因此这项工作与PI直接相关 发信号。我们将测试Rimbnabant和Rimbnabant对ECB信号的药理学操纵 URB597改变了PFC生理学和cbghitibn，作为项目9中可能的人体测试的前奏。最后， 目的4将确定PI信号是否与慢性应激时PFC神经元上的脊髓丢失有关。 Marcks的PKC磷酸化破坏了肌动蛋白，这可能导致结核病脊柱丢失。我们将测试一下 用白屈菜红碱慢性抑制PKC可保护PFC神经元免受脊髓丢失的影响。因为白屈菜红碱在pececlinical 发展，这可能为加强对人类行为的PFC调控提供另一种策略。

Stress diminishes regulatory control of behavior by the prefrontal cortex (PFC); while heightening subcortical mediation of habits. Project 2 of this consortium will examine the molecular' and cellular basis of RFC dysfunction during acute and chronic stress, with the aim of identifying hovel therapeutic targets. Previous research has found that stress impairs PFC funetibh through 1) excessive production of CAMP via dopamihe (DA) D1 and nOrepinephririe (KlE) beta! receptors, and 2) NE alpha-1-activation of phosphbtidyl inositoi (PI) DAG-prOtein kihase C (PKC) signaling, suppressing PFC cell firing. The proposed research will further explore the signaling cascades contributing to PFC dysfunction by examining the role of the IP3-Ca2+ component of PI signaling. Consistent with this possibility, in vitro recordings from PFC neurons show that rP3-mediatedihterharCa2+ release opens SKchannels thereby suppressing PFC cell excitability, the proposed research will examinei whether this rhechahisnrcontributes to stress-induced PFC dysfunction at 3 levels: Aim 1 will use in vitro recordings and Ca2+ fluorescence imaging of PFC pyramidal neurons to examine the cellular basis of the PI cascade, Aim 2 will extend these results to in vivo recordings of PFC neurons in animals performing working merhbry tasks, and Aim 3 will test whether PFC cognitive functions can be protected from stress by blocking IPS receptors or SK channels. Aim 3 will also assess agents that can be administered to humans. We will test whether blocking alpha-1 and beta Kl'E receptors with carvedilol protects PFC function from stress. If successful in animals, carvedilol can be tested in humEins exposed to stress in Project 9; We will also test the role of endbcanrtabanoids (eCB) in stres^induCed PFC dysfunction as an extension of Project 5. Because eCBs depend on DAG and Ca2+, this work is diredtly relevant to PI signaling. We will test whether pharmacological manipulation of eCB signaling with Rimbnabant ahd URB597 alters PFC physiology and cbghitibn as a prelude to possible human testing in Project 9. Finally, Aim 4 will determine whether PI signaling contributes to spine loss on PFC neurons during chronic stress. PKC phosphorylation of MARCKS disrupts actin, which may contribute tb spine loss. We will test whether Chronic PKC inhibition with Chelerythrine protects PFC neurons from spine loss. As chelerythrine is in pfeclinical development, this may provide another strategy for increasing PFC regulation of behavior in humans.