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

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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.