Designer receptors exclusively activated by designer drugs (DREADDs) used for endophenoptyping neuronal networks of depression by functional connectivity magnetic resonance imaging (fc-fMRI)

抑郁症是一种常见的精神疾病，影响多达17%的西方人口，估计到2020年将成为全球残疾的最主要原因。对抑郁症潜在脑回路的更好理解导致使用脑深部电刺激（DBS）治疗抑郁症，但最佳靶点仍不清楚。单胺缺乏假说假定大脑中5-羟色胺或去甲肾上腺素神经传递的缺乏是该疾病的主要病理机制。然而，越来越多的证据表明，神经元系统也发挥了作用。近年来，外侧缰核（lateral habenula，LHb）作为中枢神经系统的一个重要结构，被报道可介导啮齿类动物的抑郁样行为，编码与人类初级惩罚相关的负性动机价值，并为DBS治疗难治性抑郁症提供了一个新的靶点。外侧缰的异常功能与重度抑郁症有直接联系。本项目旨在建立啮齿动物外侧缰核（LHb）的设计者受体（DREADD）作为一种新的实验治疗策略。DREADD是一种新的遗传工具（也称为化学遗传学或药物遗传学），用于减少遗传定义的神经元的活性（或引起爆发放电）。特别是，该项目将提供尽我们所知的DREADD与功能连接fMRI的第一个组合，以确定受影响的缰神经回路的特异性诱导变化。作为一个明确的和全新的未来视角，DREADD可能使耐药抑郁症的新治疗策略超越电脑深部刺激，因为特定的设计药物具有区域和功能特异性，因此可能非常有效，具有理想的副作用。换句话说，我们提出了一个关键的实验，以表明DREADD可能是未来的替代DBS.We将使用LHb-DREADD测试在野生型动物中诱导抑郁样行为，更具体地说，在功能连接网络中诱导抑郁样中间内表型。我们假设LHb-DREADD将诱导增加默认模式网络（DMN）功能连接作为抑郁症的中间内表型/抑郁样行为的相关性。

Depression is a common psychiatric illness affecting up to 17% of the Western population and estimated to be the most prominent cause of disability world-wide by 2020. A better understanding of the underlying brain circuits of depression has led to the use of deep brain stimulation (DBS) to treat depression, but optimal target(s) remain unclear. The monoamine-deficiency hypothesis postulates a deficiency in serotonin or norepinephrine neurotransmission in the brain as a major pathomechanism underlying the disorder. There is, however, a growing body of evidence implicating a role for the glutamatergic system as well. Recently the lateral habenula (LHb) as a central glutamatergic structure was reported to mediate depressive-like behavior in rodents, to encode negative motivational value associated with primary punishment in humans and to reveal a new successful target for DBS for patients with therapy-refractory depression. Abnormal function of the lateral habenula has been directly linked with major depression. This proposed project aims to establish Designer Receptor Exclusively Activated by Designer Drugs (DREADD) of the lateral habenula (LHb) in rodents as a new experimental treatment strategy. DREADD is a new genetic tool (also called chemogenetics or pharmacogenetics) to diminish the activity (or to cause burst firing) of genetically defined neurons. In particular, this project would provide to the best of our knowledge the first combination of DREADD with functional connectivity fMRI to identify specifically induced changes of the affected habenular neurocircuitry. As a clear and fundamentally new future perspective, DREADD might enable novel treatment strategies of drug resistant depression beyond electric deep brain stimulation, since specific designer drugs have regional and functional specificity and may thus be highly effective with a desirable side effect profile. In other words, we propose a key experiment to show that DREADD could be the future alternative to DBS.We will use LHb-DREADD to test for induction of depressive-like behavior in wild-type animals and more specifically for induction of a depressive-like intermediate endophenotype in functional connectivity networks. We hypothesize that LHb-DREADD will induce an increased default mode network (DMN) functional connectivity as an intermediate endophenotype of depression / a correlate of depressive-like behavior.