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. 2022 Mar 3;16:826475. doi: 10.3389/fnsys.2022.826475

FIGURE 1.

FIGURE 1

(A) In a given situation, the LHb can be viewed as a recipient of multiple types of information stemming from cortical and subcortical regions. Those include memory- and flexibility-related information from the mPFC, or hippocampal memory-related information from the septum. Emotional information arises from the AMG while stress-related information from the mPFC and the LH. Reward and valence-related information reach the LHb from the EPN and the dopamine system. Finally, light-related information reaches the LHb from the retina, either directly or through the vLGN and SCN. Once the LHb has processed this information, they are communicated to the dopamine and serotonin systems, as well as to the HPA axis in order to adapt behavioral responses to changes in environmental constraints. AMG, amygdala; CORT, corticosterone; EPN, entopeduncular nucleus; HPC, hippocampus; LH, lateral hypothalamus; LHb, lateral habenula; mPFC, medial prefrontal cortex; RMTg, rostromedial tegmental nucleus; SCN, suprachiasmatic nucleus; vLGN, ventral lateral geniculate nucleus; VTA, ventral tegmental area. (B) Early life stress, such as maternal deprivation (MD) and repeated daily maternal separation (MS) lead to LHb hyperexcitability. Maternal deprivation in particular also increases LHb neuronal bursting and intrinsic excitability. MS-induced LHb hyperactivity is the consequence of altered input communication from at least the EPN with down-regulation of GABABR-GIRK signaling. On the other hand, MD dysregulates Dyn/KOR and CRF-CRFR1 signaling pathways while increasing PKA activity that promotes the downregulation of small conductance (SK2) potassium channels. Increases in LHb bursting and activity can in turn downregulate dopaminergic and serotonergic transmissions through hyperactivation of the RMTg, and therefore promote stress-related disorders such as anxiety and depression. Future studies will require an exploration of the potential contributions of other LHb inputs to such intra-LHb molecular disturbances, for example from the mPFC, NAc, AMG, and LH. AMG, amygdala; EPN, entopeduncular nucleus; LH, lateral hypothalamus; LHb, lateral habenula; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; RMTg, rostromedial tegmental nucleus; VTA, ventral tegmental area. Dashed lines indicate that there are no known direct connections.