MEDIAN RAPHE CONTROLS NEGATIVE EXPERIENCE: THE ANATOMICAL EVIDENCE
Abel Major1, András Szőnyi1, Krisztián Zichó1, Roland T. Gönczi1, Dániel Schlingloff1, 3, Bibiána Török2, 3, Eszter Sipos2, Zsuzsanna Bardóczi1, Katalin E. Sos1, 3, Attila I. Gulyás1, Dóra Zelena2, Tamás F. Freund1 and Gábor Nyiri1
The lateral habenula (LHb) is involved in responses to negative experience, stress and anxiety. LHb glutamatergic neurons activate negative experience-processing medial ventral tegmental area dopaminergic neurons and innervate median raphe region respectively. Moreover, over activation of LHb neurons causes depressive behavior. Here, we show that median raphe region (MRR) harbors a new type of excitatory population of neurons that expresses vesicular glutamate transporter 2 (vGluT2) and heavily innervates LHb. Using double retrograde and anterograde tracing, we present, that LHb neurons establish contacts on the MRR vGluT2 neurons, resulting a positive feedback loop between LHb and MRR. MRR vGluT2 neurons form NMDA receptor positive synapses in LHb and our 3D serial section block-face immune-electron microscopy data showed highly effective synaptic targeting of LHb neurons. Around these synapses we found robust glial coverage, which can regulate synaptic transmission through astroglial potassium channels. Our in vitro data showed that MRR vGluT2-terminals can trigger depressive behavior-related NMDA receptor-dependent bursting activity of LHb neurons. Chronic chemogenetic stimulation of MRR vGluT2-neurons induced depression-related anhedonia, suggesting that the MRR vGluT2 neuron population can play essential role in several types of mood disorders.