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.
The lateral habenula (LHb) is a key brain region implicated in the pathology of major depressive disorder (MDD). Specifically, excitatory LHb neurons are known to be hyperactive in MDD, thus resulting in a greater excitatory output mainly to downstream inhibitory neurons in the rostromedial tegmental nucleus. This likely results in suppression of downstream dopaminergic ventral tegmental area neurons, therefore, resulting in an overall reduction in reward signalling. In line with this, increasing evidence implicates aberrant inhibitory signalling onto LHb neurons as a co-causative factor in MDD, likely as a result of disinhibition of excitatory neurons. Consistently, growing evidence now suggests that normalising inhibitory signalling within the LHb may be a potential therapeutic strategy for MDD. Despite these recent advances, however, the exact pharmacological and neural circuit mechanisms which control inhibitory signalling within the LHb are still incompletely understood. Thus, in this review article, we aim to provide an up-to-date summary of the current state of knowledge of the mechanisms by which inhibitory signalling is processed within the LHb, with a view of exploring how this may be targeted as a future therapy for MDD.
The lateral habenula (LHb) is a brain structure which is known to be pathologically hyperactive in depression, whereby it shuts down the brains' reward systems. Interestingly, inhibition of the LHb has been shown to have an antidepressant effect, hence making the LHb a fascinating subject of study for developing novel antidepressant therapies. Despite this however, the exact mechanisms by which inhibitory signalling is processed within the LHb remain incompletely understood. Some studies have proposed the existence of locally targeting inhibitory interneuron populations within the LHb. One such population is believed to be akin to neocortical neurogliaform cells, yet specific molecular markers for studying these neurons are sparse and hence their function remains elusive. Recently, neuron‐derived neurotrophic factor (NDNF) has been proposed as one such marker for neocortical neurogliaform cells. Using a combination of histological, physiological and optogenetic tools, we hence sought to first validate if NDNF was selectively expressed by such inhibitory neurons within the neocortex, and then if it was confined to a similar population within the LHb. While we report this to be true for the neocortex, we find no such evidence within the LHb; rather that NDNF is expressed without restriction to a particular neuronal subpopulation. These results hence indicate that molecular markers can represent broadly diverse populations of neurons on a region‐to‐region basis and that therefore each population as defined by molecular marker expression should be validated in each brain structure.
22 Phone: +44 (0)141 548 2122 23 24 2 25 Summary: The lateral habenula receives inhibitory input from three distinct sources: 26 from local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic 27 nucleus (MDT); and from SOM-positive neurons in the ventral pallidum (VP). 28 3 Abstract 29 The lateral habenula (LHb) is hyperactive in depression, and thus potentiating 30 inhibition of this structure makes an interesting target for future antidepressant 31 therapies. However, the circuit mechanisms mediating inhibitory signalling within the 32 LHb are not well-known. We addressed this issue by studying LHb neurons expressing 33 either parvalbumin (PV), neuron-derived neurotrophic factor (Ndnf) or somatostatin 34 (SOM), three markers of particular sub-classes of neocortical inhibitory neurons. While 35 we report that Ndnf is not representative of any particular sub-population of LHb 36 neuron, we find that both PV and SOM are expressed by physiologically distinct sub-37 classes. Furthermore, we describe multiple sources of inhibitory input to the LHb 38 arising from both local PV-positive neurons, and from PV-positive neurons in the 39 medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral 40 pallidum. These findings hence provide new insight into inhibitory control within the 41 LHb, and highlight that this structure is more neuronally diverse than previously 42 thought. 43 44Significance statement 45 The circuitry by which inhibitory signalling is processed within the lateral habenula is 46 currently not well understood; yet this is an important topic as inhibition of the lateral 47 53We are grateful to Hongkui Zeng from the Allen Brain Institute, Seattle, for kindly 54 sharing the Ai9 reporter mice with us, and we thank Csaba Földy, Brain Research 55
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