Disentangling neuronal inhibition and inhibitory pathways in the lateral habenula

Jack F Webster,Kira Balueva,Shuzo Sakata,Christian Wozny,Peer Wulff,Rozan Vroman

doi:10.1038/s41598-020-65349-7

Jack F Webster, Kira Balueva + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-65349-7

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Journal: Scientific Reports	Publication Date: May 22, 2020
Citations: 32	License type: open-access

Affiliation: University of Strathclyde, Kiel University

Abstract

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) or somatostatin (SOM), two markers of particular sub-classes of neocortical inhibitory neurons. Here, 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, 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.

Highlights

The lateral habenula (LHb) is hyperactive in depression, and potentiating inhibition of this structure makes an interesting target for future antidepressant therapies
The lateral habenula (LHb) is an epithalamic brain structure, which acts as an inhibitory modulator of the midbrain reward circuitry, including the ventral tegmental area (VTA)[1,2,3] and the raphe nuclei[4]
Referring to the question of inhibitory control within the LHb, we asked if these markers represented distinct sub-populations of inhibitory neurons within this structure, and aimed to characterise the circuitry formed by neurons expressing them

Summary

Introduction

The lateral habenula (LHb) is hyperactive in depression, and potentiating inhibition of this structure makes an interesting target for future antidepressant therapies. We describe multiple sources of inhibitory input to the LHb arising from both local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral pallidum These findings provide new insight into inhibitory control within the LHb, and highlight that this structure is more neuronally diverse than previously thought. The LHb has drawn renewed attention[5] due to the revelation that it becomes pathologically hyperactive in major depressive disorder (MDD)[6,7,8,9,10,11,12], providing excessive inhibition to these reward centres and silencing the associated positive emotions This makes the LHb an intriguing target for novel antidepressant therapies[6,7,9,11,12,13,14]. We report three sources of inhibitory input to the LHb arising from locally-targeting PV-positive neurons within the LHb, from PV-positive neurons within the medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral pallidum

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