Amygdalar Orexin Modulation of Affective Disorders

杏仁核食欲素对情感障碍的调节

• 批准号: 8878512
• 负责人: CLIFF H SUMMERS
• 金额: $ 42.65万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878512
• 关键词: Affect; Agonist; American; Amygdaloid structure; Anhedonia; Anti-Anxiety Agents; Anxiety; Basic Science; Behavior; Behavioral; Brain; Chronic; Dose; Etiology; Event; Gene Expression; Generations; Glutamates; Goals; Hormones; Human; Individual; Intercalated Cell; Laboratories; Lateral; Learning; Maintenance; Mechanics; Medial; Mental Depression; Mental disorders; Methodology; Modeling; Mood Disorders; Mus; Narcolepsy; Neurons; Outcome; Output; Patients; Population; Predisposition; Property; Proteins; Relative (related person); Research; Role; Sleep Deprivation; Staging; Stress; Structure; Sucrose; Swimming; Symptoms; System; Techniques; Testing; Therapeutic Uses; adeno-associated viral vector; anxiety symptoms; anxious; anxious behavior; behavior test; clinically significant; depressive behavior; design; hypocretin; monoamine; neurotrophic factor; novel therapeutics; preference; public health relevance; receptor; research study; resilience; response; small hairpin RNA; social; social anxiety; theories; therapeutic target

 DESCRIPTION (provided by applicant): Functionally opposed Orx1 and Orx2 systems suggest the potential for orexins to powerfully influence the onset and maintenance of affective disorders such as anxiety and depression. Recent exciting results from our laboratory suggest that activation of Orexin (Orx) type 1 and 2 receptors (Orx1 and Orx2) in the basolateral amygdala (BLA) are functionally opposed, and may differentially trigger or inhibit anxious and depressive behavior. Interplay between Orx1 and Orx2receptors on the excitatory and inhibitory systems of the BLA makes them potential targets for therapeutic treatments of affective disorders. As anxiogenic and anxiolytic properties are both encoded into the circuitry associated with the BLA, what remains is the discovery of the trigger that initiates the change between them. While several limbic and cortical regions may be involved in the onset of affective disorders, the research in this proposal is focused on the BLA, because it is necessary for learning related to fearful and aversive events. The excitatory (glutamatergic) circuit in which th BLA receives input from limbic and cortical structures, and projects to the principle output of the amygdala, (medial Central Amygdala; mCeA), produces learning and expression of anxious or fearful behavior. Modified by inhibitory GABAergic neurons of the BLA, intercalated cells (ITC) and the lateral CeA (lcCeA and lCeA) to reduce fearful responses or produce anxiolytic effects. In the interplay between these excitatory and inhibitory systems Orx activity in the BLA has the potential to enhance or diminish anxious and depressive behaviors. We propose that orexinergic functions are organized in specific local BLA neurocircuitry so as to produce opposing actions and functional responses via the two Orx receptor subtypes. To facilitate the discovery of the trigger that initiates the change between the orexin receptor subtypes we have designed experiments that utilize a model limited or chronic social defeat to produce threshold or dramatic changes in social anxiety, general anxiety, despair, and anhedonia. To test the effects of Orx1 and Orx2 systems on these behaviors, we employ two approaches: pharmacological and shRNA knockdown of gene expression in mice. Antagonists of Orx1 and Orx2 receptors, Orx1 stimulation via OrxA + Orx2 antagonist, and an Orx2 agonist are applied bilaterally to the BLA, examining dose response, social defeat and a battery of tests for anxious and depressive behavior: Social preference (social anxiety, depressive behavior), Elevated plus maze and open field (general anxiety), sucrose preference test (anhedonia, depression) and forced swim (despair, depression). To demonstrate the role of endogenous orexin in these behaviors, AAV vectors for shRNA will be used to bilaterally knockdown gene expression of Orx1 and Orx2 receptors in the BLA, followed by social defeat and the battery of behavioral tests. Using these techniques (without social defeat) we have demonstrated that shRNA KD of the BLA Orx2 receptor significantly enhances anxious behavior.

 描述（由申请人提供）：功能上相反的Orx 1和Orx 2系统表明食欲素有可能强烈影响情感障碍（如焦虑和抑郁）的发作和维持。我们实验室最近令人兴奋的结果表明，基底外侧杏仁核（BLA）中Orexin（Orx）1型和2型受体（Orx 1和Orx 2）的激活在功能上是相反的，并且可能不同地触发或抑制焦虑和抑郁行为。在BLA的兴奋和抑制系统上，Orx 1和Orx 2受体之间的相互作用使它们成为情感障碍治疗的潜在靶点。由于致焦虑和抗焦虑特性都被编码到与BLA相关的电路中，剩下的就是发现引发它们之间变化的触发因素。虽然几个边缘系统和皮质区域可能参与情感障碍的发作，但本提案中的研究集中在BLA上，因为它是与恐惧和厌恶事件相关的学习所必需的。BLA接受来自边缘系统和皮层结构的输入，并投射到大脑皮层的主要输出的兴奋性（脑电能）回路。 杏仁核（内侧中央杏仁核; mCeA）产生学习和焦虑或恐惧行为的表达。由BLA、闰间细胞（ITC）和外侧CeA（lcCeA和lCeA）的抑制性GABA能神经元修饰，以减少恐惧反应或产生抗焦虑作用。在这些兴奋和抑制系统之间的相互作用中，BLA中的Orx活动有可能增强或减少焦虑和抑郁行为。我们建议，食欲素能功能组织在特定的本地BLA神经回路，从而产生相反的行动和功能反应，通过两个Orx受体亚型。为了促进发现引发食欲素受体亚型之间变化的触发因素，我们设计了实验，利用模型有限或慢性社交失败来产生社交焦虑、一般性焦虑、绝望和快感缺乏的阈值或戏剧性变化。为了测试Orx 1和Orx 2系统对这些行为的影响，我们采用了两种方法：药理学和小鼠基因表达的shRNA敲低。将Orx 1和Orx 2受体的拮抗剂、通过OrxA + Orx 2拮抗剂的Orx 1刺激和Orx 2激动剂双侧应用于BLA，检查剂量反应、社交失败和一系列焦虑和抑郁行为的测试：社会偏好（社交焦虑，抑郁行为），高架加迷宫和开放领域（一般性焦虑）、蔗糖偏好测试（快感缺乏、抑郁）和强迫游泳（绝望、抑郁）。为了证明内源性食欲素在这些行为中的作用，将使用shRNA的AV载体来双向敲除BLA中Orx 1和Orx 2受体的基因表达，然后进行社交失败和一系列行为测试。使用这些技术（没有社交失败），我们已经证明了BLA Orx 2受体的shRNA KD显著增强了焦虑行为。

项目成果

Learning and CRF-Induced Indecision during Escape and Submission in Rainbow Trout during Socially Aggressive Interactions in the Stress-Alternatives Model.

• DOI: 10.3389/fnins.2017.00515
• 发表时间: 2017
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Summers TR;Summers TL;Carpenter RE;Smith JP;Young SL;Meyerink B;Orr TZ;Arendt DH;Summers CH
• 通讯作者: Summers CH

Evidence for the role of corticotropin-releasing factor in major depressive disorder.

• DOI: 10.1016/j.neubiorev.2015.07.011
• 发表时间: 2015-11
• 期刊: Neuroscience and biobehavioral reviews
• 影响因子: 8.2
• 作者: Waters RP;Rivalan M;Bangasser DA;Deussing JM;Ising M;Wood SK;Holsboer F;Summers CH
• 通讯作者: Summers CH

Curiosity as an approach to ethoexperimental analysis: Behavioral neuroscience as seen by students and colleagues of Bob Blanchard.

• DOI: 10.1016/j.neubiorev.2016.03.012
• 发表时间: 2017-05
• 期刊: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
• 影响因子: 8.2
• 作者: Pearson, Brandon L.;Crawley, Jacqueline N.;Eilam, David;Pentkowski, Nathan S.;Summers, Cliff H.
• 通讯作者: Summers, Cliff H.

Putting the "Biology" Back into "Neurobiology": The Strength of Diversity in Animal Model Systems for Neuroscience Research.

• DOI: 10.3389/fnsys.2016.00069
• 发表时间: 2016
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Keifer J;Summers CH
• 通讯作者: Summers CH