Cholinergic Pathways in Depression

 描述（由申请人提供）：临床成像研究表明，在抑郁症受试者的大脑中，乙酰胆碱（ACh）对烟碱乙酰胆碱受体（nAChR）的占用增加。此外，阻断烟碱型或毒蕈碱型ACh受体可在人类受试者中具有抗抑郁作用。因此，特定大脑区域ACh水平的变化可能对控制涉及情绪调节的回路至关重要。W最近表明，阻断海马体中ACh的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易感性，所有这些都可以通过氟西汀治疗逆转，氟西汀是一种对人类抑郁个体有效的抗抑郁药。这表明海马的胆碱能调节对行为至关重要 与抑郁症有关，但海马胆碱能神经支配在抑郁症相关的应激诱导行为中的必要性，以及不同胆碱能回路在抑郁症样行为中的作用 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，并测量这些操作对社会应激源增加小鼠抑郁样行为能力的影响，或对小鼠抑郁样行为模型的影响。我们将通过在胆碱能神经元中表达由设计药物专门激活的设计受体（DREADD）来控制胆碱能神经元放电，所述胆碱能神经元使用病毒介导的基因转移以在胆碱乙酰转移酶启动子的控制下在表达Cre重组酶的小鼠中局部注入条件DREADD构建体。我们将首先确定是否沉默内侧隔和Broca斜角带（MS/VDB;海马的主要胆碱能输入）的胆碱能神经元的活性可以阻断社会应激对社交回避发展的影响，这是一种对抗抑郁药物长期治疗敏感的表型。为了确定这种效应的解剖学特异性，我们还将沉默海马ACh的另一个来源，海马固有的稀疏胆碱能神经元。在第二组研究中，我们将确定激活MS/VDB中的ACh神经元是否足以诱导抑郁样行为，以及这是否也可以通过激活海马的内源性胆碱能神经元来观察。这些实验利用了新颖和创新的技术，允许局部控制特定ACh神经元的活动。这些结果将确定是否应激诱导的海马胆碱能输入放电介导的抑郁样行为的社会应激的影响。这些研究对于确定靶向胆碱能系统的药物是否可用于治疗抑郁症具有重要意义。

 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.