RESUMEN
The lateral habenula (LHb) has emerged as a pivotal brain region implicated in depression, displaying hyperactivity in human and animal models of depression. While the role of LHb efferents in depressive disorders has been acknowledged, the specific synaptic alterations remain elusive. Here, employing optogenetics, retrograde tracing and ex vivo whole-cell patch clamp techniques, we investigated synaptic transmission in male mice subjected to chronic social defeat stress (CSDS) at three major LHb neuronal outputs: the dorsal raphe nucleus (DRN), the ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). Our findings uncovered distinct synaptic adaptations in LHb efferent circuits in response to CSDS. Specifically, CSDS induced in susceptible mice postsynaptic potentiation and postsynaptic depression respectively at the DRN and VTA neurons receiving excitatory inputs from the LHb, while CSDS altered presynaptic transmission at the LHb terminals in RMTg in both susceptible and resilient mice. Moreover, whole cell recordings at projection-defined LHb neurons indicate decreased spontaneous activity in VTA-projecting LHb neurons, accompanied by an imbalance in excitatory-inhibitory inputs at the RMTg-projecting LHb neurons. Collectively, these novel findings underscore the circuit-specific alterations in LHb efferents following chronic social stress, shedding light on potential synaptic adaptations underlying stress-induced depressive-like states.Significance statement The lateral habenula (LHb) is a brain region responsible for encoding negative signals and tends to be overactive in both depressed individuals and animal models of depression. Distinct groups of neurons within the LHb connect with the dorsal raphe nucleus, the ventral tegmental area, and the rostromedial tegmental area, implying that they serve distinct functions. Our study demonstrates that chronic social defeat stress, a widely used animal model of clinical depression, leads to specific adaptations in synaptic transmission and neuronal activity along these pathways. These findings suggest that the outputs of LHb neurons play distinct roles in the onset and progression of depressive symptoms commonly observed in major depression.
RESUMEN
BACKGROUND: The medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown, and the distinct contribution of these pathways to stress responses in males and females is unclear. METHODS: Behavioral stress responses were induced by 21 days of chronic variable stress in male and female C57BL/6NCrl mice. An intersectional viral approach was used to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes. RESULTS: Chronic variable stress induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more severe in females in NAc-projecting mPFC neurons, while males exhibited more drastic reductions in dendritic complexity in VTA-projecting mPFC neurons after chronic variable stress. Finally, chemogenetic overactivation of the corticoaccumbal pathway triggered anxiety and behavioral despair in both sexes, while its inhibition rescued the phenotype only in females. CONCLUSIONS: Our results suggest that stress responses in males and females result from pathway-specific changes in the activity of transcriptional programs controlling the morphological and synaptic properties of corticoaccumbal and corticotegmental pathways in a sex-specific fashion.