Abstract
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.
Highlights
IntroductionThe lateral habenula (LHb) is a brain structure which is known to be hyperactive in depression (Cui et al, 2018; Li et al, 2011; Shabel et al, 2014; Yang, Cui, et al, 2018), potentiating inhibitory input to the midbrain reward centres (Christoph et al, 1986; Ji & Shepard, 2007; Matsumoto & Hikosaka, 2007; Wang & Aghajanian, 1977) and rendering the sufferer incapable of experiencing positive emotionsEdited by: Dr Yoland Smith associated with these centres (Yang et al, 2018)
These neurons mediate both feed-forward synaptic inhibition (Armstrong et al, 2011; Price et al, 2008) and slow inhibitory signalling via volume transmission, whereby GABA spill-over from neurogliaform cell axon terminals can act on extra-synaptic GABAB receptors (Oláh et al, 2009)
Our results are consistent with other recent reports (Abs et al, 2018; Tasic et al, 2018) in that we find Ndnf to be mostly, but not exclusively, confined to inhibitory neurons which mediate inhibitory transmission through both GABAA and GABAB receptors (Figures 2 and 7)
Summary
The lateral habenula (LHb) is a brain structure which is known to be hyperactive in depression (Cui et al, 2018; Li et al, 2011; Shabel et al, 2014; Yang, Cui, et al, 2018), potentiating inhibitory input to the midbrain reward centres (Christoph et al, 1986; Ji & Shepard, 2007; Matsumoto & Hikosaka, 2007; Wang & Aghajanian, 1977) and rendering the sufferer incapable of experiencing positive emotionsEdited by: Dr Yoland Smith associated with these centres (Yang et al, 2018). Neurogliaform cells are a very distinct class of inhibitory neuron known to be present in the neocortex (Olah et al, 2007; Tamás et al, 2003; Wozny & Williams, 2011), hippocampus (Armstrong et al, 2011; Price et al, 2005, 2008; Vida et al, 1998) and striatum (Ibanez-Sandoval et al, 2011) These neurons mediate both feed-forward synaptic inhibition (Armstrong et al, 2011; Price et al, 2008) and slow inhibitory signalling via volume transmission, whereby GABA spill-over from neurogliaform cell axon terminals can act on extra-synaptic GABAB receptors (Oláh et al, 2009). Studying the local microcircuitry that these neurons form within the LHb is an intriguing prospect
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