Ionic and Second Messanger Basis of Stress-Induced Prefrontal Dysfunction (#2 of

压力引起的前额叶功能障碍的离子和第二信使基础（

• 批准号: 8101941
• 负责人: AMY F.T. ARNSTEN
• 金额: $ 31.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101941
• 关键词: Actins; Acute; Adrenergic Receptor; Agonist; Animals; Apamin; Apical; Behavior; Behavior Control; Behavioral; CNR1 gene; Cells; Chronic; Chronic stress; Collaborations; Coupled; Dendrites; Dendritic Spines; Development; Dopamine; Endocannabinoids; Functional disorder; Glycerol; Habits; Head; Human; Impaired cognition; In Vitro; Infusion procedures; Inositol; MARCKS gene; Mediating; Mediation; Molecular; Monkeys; Neurons; Norepinephrine; Norepinephrine Receptors; Pattern; Performance; Pharmaceutical Preparations; Phosphorylation; Physiology; Prazosin; Prefrontal Cortex; Process; Production; Property; Protein Kinase C; Proteins; Pyramidal Cells; Rattus; Regulation; Research; Resolution; Role; Saccades; Second Messenger Systems; Short-Term Memory; Signal Transduction; Slice; Stress; Techniques; Testing; Time; Tissues; Translating; Vertebral column; Work; XeC compound; acute stress; anandamide; awake; base; carvedilol; channel blockers; cognitive function; density; fluorescence imaging; hippocampal pyramidal neuron; in vivo; induced pluripotent stem cell; inhibitor/antagonist; patch clamp; preclinical safety; prevent; receptor; research clinical testing; response; restraint stress; rimonabant; safety testing; second messenger; therapeutic target

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.

压力减少了前额叶皮层（PFC）对行为的调节控制;同时提高了皮层下的 习惯的调解。该联盟的项目2将研究RFC的分子和细胞基础 在急性和慢性应激过程中的功能障碍，目的是确定hovel治疗目标。先前 研究发现，压力通过以下方式损害PFC：1）通过多巴酚丁胺产生过量的CAMP (DA)D1和nOrepinephririe（KlE）β!受体，和2）NE α-1-磷脂酰肌醇（PI）的激活 DAG-蛋白激酶C（PKC）信号传导，抑制PFC细胞放电。该研究将进一步 通过检查IP3-Ca2+的作用，探索导致PFC功能障碍的信号级联 PI信号的组成部分。与这种可能性相一致的是，来自PFC神经元的体外记录显示， rP3介导的二氢Ca 2+释放打开SK通道，从而抑制PFC细胞的兴奋性， 拟议的研究将检查这种rhechahisn是否有助于压力诱导的PFC功能障碍， 水平：目标1将使用PFC锥体神经元的体外记录和Ca2+荧光成像， 研究PI级联的细胞基础，Aim 2将这些结果扩展到PFC的体内记录 Aim 3将测试PFC的认知功能， 可以通过阻断IPS受体或SK通道来保护其免受应激。Aim 3还将评估 可以施用于人类。我们将测试卡维地洛阻断α-1和β Kl'E受体是否 保护PFC功能免受压力。如果在动物中成功，卡维地洛可以在暴露于 项目9中的压力;我们还将测试endbcanrtabanoids（eCB）在压力诱导的PFC功能障碍中的作用 作为项目5的延伸。由于eCB依赖于DG和Ca 2+，因此这项工作与PI直接相关 信号我们将测试是否与Rimbnabant和hd药理学操纵eCB信号传导 URB597改变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信号是否有助于在慢性应激过程中PFC神经元上的棘丢失。 MARCKS的PKC磷酸化破坏肌动蛋白，这可能导致脊柱丢失。我们将测试 白屈菜红碱慢性PKC抑制可保护PFC神经元免受脊髓损伤。由于白屈菜红碱在临床上 这可能为增加PFC对人类行为的调节提供了另一种策略。

项目成果

Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses.

• DOI: 10.1016/j.neuron.2012.08.038
• 发表时间: 2012-10-04
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Arnsten AF;Wang MJ;Paspalas CD
• 通讯作者: Paspalas CD

Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction.

• DOI: 10.1038/tp.2013.104
• 发表时间: 2013-12-03
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Gamo NJ;Duque A;Paspalas CD;Kata A;Fine R;Boven L;Bryan C;Lo T;Anighoro K;Bermudez L;Peng K;Annor A;Raja A;Mansson E;Taylor SR;Patel K;Simen AA;Arnsten AF
• 通讯作者: Arnsten AF

Chronic Stimulation of Alpha-2A-Adrenoceptors With Guanfacine Protects Rodent Prefrontal Cortex Dendritic Spines and Cognition From the Effects of Chronic Stress.

• DOI: 10.1016/j.ynstr.2015.01.001
• 发表时间: 2015
• 期刊: NEUROBIOLOGY OF STRESS
• 影响因子: 5
• 作者: Hains, Avis Brennan;Yabe, Yoko;Arnsten, Amy F T
• 通讯作者: Arnsten, Amy F T