Cholinergic Pathways in Depression

抑郁症的胆碱能通路

• 批准号: 8969456
• 负责人: YANN Sebastien MINEUR
• 金额: $ 8.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969456
• 关键词: Acetylcholine; Acetylcholinesterase; Adaptive Behaviors; Address; Affect; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavior; Brain; Brain region; Choline O-Acetyltransferase; Cholinergic Antagonists; Chronic; Clinical; Coupled; Data; Depressed mood; Designer Drugs; Development; Diagnostic; Diagonal Band of Broca; Disease; Enzymes; Etiology; Exposure to; Fluoxetine; Future; Gene Transfer; Goals; Hippocampus (Brain); Human; Image; Individual; Lead; Measures; Medial; Mediating; Mental Depression; Modeling; Mood Disorders; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Neuronal Plasticity; Neurons; Neurotransmitters; Nicotinic Receptors; Norepinephrine; Pathway interactions; Pharmaceutical Preparations; Phenotype; Predisposition; Public Health; Regulation; Research Personnel; Risk Factors; Role; Serotonin; Social Development; Source; Specificity; Stress; System; Techniques; Viral; cholinergic; cholinergic neuron; depressed patient; design; driving behavior; human subject; innovation; mood regulation; mouse model; nerve supply; new technology; novel; novel strategies; prevent; promoter; public health relevance; receptor; recombinase; research study; resilience; social; social stress; stress resilience; stressor; targeted treatment

 DESCRIPTION (provided by applicant): Clinical imaging studies have suggested that nicotinic acetylcholine receptor (nAChR) occupancy by acetylcholine (ACh) is increased in the brains of human subjects with depression. In addition, blockade of either nicotinic or muscarinic ACh receptors can have antidepressant effects in human subjects. Thus, changes in ACh levels in specific brain regions could be critical for the control of circuits involved in mood regulation. W have recently shown that blocking ACh degradation in the hippocampus increases anxiety- and depression-like behaviors in mice, and increases susceptibility to social stress, all of which can be reversed by treatment with fluoxetine, an antidepressant effective in human depressed individuals. This suggests that cholinergic regulation of the hippocampus is critical for behaviors related to depression, but the necessity of hippocampal cholinergic innervation in stress-induced behaviors related to depression, and the role of different cholinergic circuitry in depression-like behavior remains unknown. Using novel technologies, we will silence or activate the cholinergic neurons innervating the hippocampus and measure the effects of these manipulations on the ability of a social stressor to increase depression-like behavior in mice, or the effects on mouse models of depression-like behavior at baseline. We will control cholinergic neuronal firing by expressing Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in cholinergic neurons using viral-mediated gene transfer to infuse conditional DREADD constructs locally in mice expressing Cre recombinase under the control of the choline acetyltransferase promoter. We will first determine whether silencing the activity of the cholinergic neurons from the medial septum and the diagonal band of Broca (MS/VDB; the primary cholinergic input to the hippocampus) can block the effects of social stress on the development of social avoidance, a phenotype sensitive to chronic treatment with antidepressant medications. To determine the anatomical specificity of this effect, we will also silence another source of hippocampal ACh, the sparse cholinergic neurons intrinsic to the hippocampus. In a second set of studies, we will determine whether activating ACh neurons in the MS/VDB is sufficient to induce depression-like behaviors, and whether this can be also observed by activating the intrinsic cholinergic neurons of the hippocampus. These experiments take advantage of novel and innovative techniques that allow local control of the activity of specific ACh neurons. These results will determine whether stress-induced firing of cholinergic inputs to the hippocampus mediate effects of a social stressor on depression-like behavior. These studies will be important in determining whether medications that target the cholinergic system could be useful for treating depression.

 描述（由应用提供）：临床成像研究表明，乙酰胆碱（ACH）的烟碱乙酰胆碱受体（NACHR）在抑郁症患者的大脑中增加。此外，烟碱或毒蕈碱ACH受体的阻塞可能对人类受试者产生抗抑郁作用。这对于特定大脑区域的ACH水平的变化对于控制情绪调节涉及的电路可能至关重要。 W最近表明，海马中的ACH降解会增加小鼠的焦虑和抑郁样行为，并增加对社会压力的敏感性，所有这些行为都可以通过用氟西汀治疗氟西汀来逆转，氟西汀是一种在人类抑郁症患者中有效的抗抑郁药。这表明海马的胆碱能调节对于行为至关重要 与抑郁有关，但与抑郁症相关的压力引起的行为以及不同的胆碱能回路在抑郁症状中的作用 行为仍然未知。使用新技术，我们将沉默或激活支配海马的胆碱能神经元，并测量这些操纵对社会压力源增加小鼠抑郁症行为的能力的影响，或者对基线时类似抑郁症行为的小鼠模型的影响。我们将通过使用病毒介导的基因转移到胆碱重症组织酶促进酶的控制下表达CRE重物组织酶的小鼠局部局部的有条件的Dreadd构建体中，通过表达胆碱能神经元中的设计师药物（Dreadds）专门激活胆碱能药物（Dreadds）来控制胆碱能神经元的发射。我们将首先确定使胆碱能神经元的活性从内侧隔膜和肉体的对角线带（MS/VDB；对海马的主要胆碱能输入）阻止社会压力对社会避免的发展的影响，这是对抗抑郁药的表型治疗敏感的社会型敏感的。为了确定这种作用的解剖学特异性，我们还将使海马ACH的另一个来源沉默，即海马固有的稀疏胆碱能神经元。在第二组研究中，我们将确定MS/VDB中激活ACH神经元是否足以诱导抑郁症样行为，以及是否也可以通过激活海马的固有性胆碱能神经元观察到这一点。这些实验利用了新颖和创新的技术，可以局部控制特定ACH神经元的活性。这些结果将确定压力引起的胆碱能输入向海马的发射是否介导了社会压力源对抑郁症样行为的影响。这些研究对于确定靶向胆碱能系统的药物是否对治疗抑郁症有用。