RT Journal Article SR Electronic T1 Disentangling neuronal inhibition and inhibitory pathways in the lateral habenula JF bioRxiv FD Cold Spring Harbor Laboratory SP 633271 DO 10.1101/633271 A1 Jack F. Webster A1 Rozan Vroman A1 Kira Balueva A1 Peer Wulff A1 Shuzo Sakata A1 Christian Wozny YR 2019 UL http://biorxiv.org/content/early/2019/11/19/633271.abstract AB The lateral habenula (LHb) is hyperactive in depression, and thus potentiating inhibition of this structure makes an interesting target for future antidepressant therapies. However, the circuit mechanisms mediating inhibitory signalling within the LHb are not well-known. We addressed this issue by studying LHb neurons expressing either parvalbumin (PV), neuron-derived neurotrophic factor (Ndnf) or somatostatin (SOM), three markers of particular sub-classes of neocortical inhibitory neurons. While we report that Ndnf is not representative of any particular sub-population of LHb neuron, we find that both PV and SOM are expressed by physiologically distinct sub-classes. Furthermore, we describe multiple sources of inhibitory input to the LHb arising from both local PV-positive neurons, and from PV-positive neurons in the medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral pallidum. These findings hence provide new insight into inhibitory control within the LHb, and highlight that this structure is more neuronally diverse than previously thought.Summary The lateral habenula receives inhibitory input from three distinct sources: from local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic nucleus (MDT); and from SOM-positive neurons in the ventral pallidum (VP).Significance statement The circuitry by which inhibitory signalling is processed within the lateral habenula is currently not well understood; yet this is an important topic as inhibition of the lateral habenula has been shown to have antidepressant efficacy. We therefore investigated inhibitory signalling mechanisms within the lateral habenula by studying input neurons expressing markers commonly associated with inhibitory identity. We identity sources of inhibitory input from both local neurons, and arising from neurons in the medial dorsal thalamic nucleus and ventral pallidum.Contributions J.F.W. performed the experiments. R.V. contributed to experiments. J.F.W. analysed the data. K.B. and P.W. designed and performed the in situ hybridisation experiments. C.W. designed and supervised the study, and helped J.F.W write the manuscript. R.V. and S.S. contributed to the manuscript and discussions.