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，影响着多达17%的西方人口，据估计，到2020年，抑郁症将成为全球最主要的残疾原因。对抑郁症潜在的大脑回路的更好的了解导致了使用脑深部刺激(DBS)来治疗抑郁症，但最佳靶点(S)仍不清楚。单胺缺乏假说假设大脑中5-羟色胺或去甲肾上腺素神经传递不足是导致这种疾病的主要病理机制。然而，越来越多的证据表明谷氨酸能系统也有作用。最近有报道称，外侧缰核(LHb)作为一种中枢谷氨酸能结构，可以调节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激励价值，并为DBS治疗难治性抑郁症提供了一个新的成功靶点。外侧缰核功能异常与抑郁症有直接关系。这项拟议的项目旨在建立啮齿动物外侧缰核(LHb)的设计师受体(DREADD)，作为一种新的实验性治疗策略。DREADD是一种新的遗传工具(也称为化学遗传学或药物遗传学)，可以减少遗传定义的神经元的活动(或导致爆发放电)。具体地说，据我们所知，该项目将提供DREADD与功能连接功能磁共振成像的第一个组合，以识别受影响缰核神经回路的特定诱导变化。作为一种明确和根本的未来前景，DREADD可能使抗药性抑郁症的新治疗策略超越脑深部电刺激，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，以证明DREADD可能是未来的DB的替代品。我们将使用LHb-DREADD来测试在野生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表型。我们假设LHb-DREADD将诱导默认模式网络(DMN)功能连接增加，作为抑郁的中间内表型/抑郁样行为的相关因素。

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.