Inhibition Within the Lateral Habenula—Implications for Affective Disorders

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.

Disrupted development from head to tail: Pervasive effects of postnatal restricted resources on neurobiological, behavioral, and morphometric outcomes

“…Also related to the stress response, the finding of increased GR-IR in the LHb of the LR animals (see Figures 11A,C for GR results) suggests that they developed heightened stress-mediated inhibitory effects, in accordance with past research documenting stress-induced modification of GR levels in limbic areas such as the hippocampus (Ga ¸dek- Michalska et al, 2013;Sullivan et al, 2019). The LHb is associated with depressive symptoms, especially related to the inhibition of reward processing (as reviewed by Webster et al, 2021). Additional research tracking the specific area of activation of GR-IR cells (e.g., cytoplasmic vs. nuclear) will be informative in understanding the short-and long-term effects of stress on the LHb GRs (Han et al, 2017).…”

Effects of early life stress and subsequent re-exposure to stress on neuronal activity in the lateral habenula

“…As a final note, here we have focused specifically on early life stress-induced alterations in excitatory and inhibitory signalling within the LHb. However, it should also be noted that there is growing evidence that other neurotransmitters influence LHb activity [50], and conversely that the LHb can influence other transmitter systems downstream. As such it may be the case that alterations in other transmitter systems are driving the physiological changes within our model.…”

Multi-level variations of lateral habenula in depression: A comprehensive review of current evidence

“…Additionally, the medial portion of the LHb receives GABAergic inhibitory inputs from the basal forebrain ( 40 , 108 ), LPO ( 37 ), VP ( 109 ), and PV-positive neurons within MDT ( 38 ). Overall, inhibitory innervation in the LHb encodes a reward ( 110 ). vLGN–IGL, a visual thalamic region, provides a GABAergic input to LHb.…”

“…Synaptic transmission is the vital physiological basis of the LHb mechanism in depression ( 110 ). Synaptic transmission profoundly affects the intrinsic excitability and potential levels of LHb neurons.…”