Abstract
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.
Highlights
The lateral habenula (LHb) is a brain structure within the epithalamus which is well established to have a causative role in the pathogenesis of major depressive disorder (MDD; Sartorius et al, 2010; Li et al, 2011; Yang et al, 2018a; Hu et al, 2020)
These include the internal segment of the globus pallidus (Hong and Hikosaka, 2008), analogous to the rodent entopeduncular nucleus (Shabel et al, 2014; Meye et al, 2016; Wallace et al, 2017), the lateral hypothalamus (Stamatakis et al, 2016; Lecca et al, 2017; Lazaridis et al, 2019; Trusel et al, 2019) and the ventral pallidum (Knowland et al, 2017; Faget et al, 2018; Stephenson-Jones et al, 2020; Pribiag et al, 2021), as well as receiving reciprocal input from the ventral tegmental area (VTA) (Stamatakis et al, 2013; Root et al, 2014)
These structures provide a combination of excitatory, inhibitory and GABA/glutamate co-releasing input to the LHb, in a very fine balance which has been shown to be altered in depressive states (Shabel et al, 2014; Knowland et al, 2017)
Summary
Excitatory LHb neurons are known to be hyperactive in MDD, 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, resulting in an overall reduction in reward signalling. Growing evidence suggests that normalising inhibitory signalling within the LHb may be a potential therapeutic strategy for MDD. Despite these recent advances, the exact pharmacological and neural circuit mechanisms which control inhibitory signalling within the LHb are still incompletely understood.
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