NEURONAL DYNAMICS UNDERLYING DEPRESSIVE-LIKE STATES

Chronic stress induces lasting neurobiological adaptations that can progressively lead to behaviors reminiscent of depressive states. However, the temporal dynamics of cellular and behavioral adaptations remain poorly understood. Altered neuronal activity in the lateral habenula (LHb) – a neural substrate encoding aversion and negative affect – has been implicated in stress-related behavioral effects and depression. Yet, the timing and trajectory of stress-induced LHb functional changes remain unresolved. Here, we mapped the temporal emergence of depression-related behaviors and their LHb neuronal correlates in mice undergoing chronic corticosterone (CORT) administration, a model mimicking prolonged stress hormone elevation.
Longitudinal two-photon calcium imaging to track the encoding properties of individual LHb neurons uncovered progressively increased responses to airpuff over CORT treatment. Analysis of ~500 LHb neurons identified clusters with stable excitatory or inhibitory responses, as well as dynamic clusters that gradually increased their response and exhibited spatial segregation within LHb. In parallel, behavioral phenotyping during CORT exposure revealed a gradual shift towards maladaptive states, characterized by reduced active coping and enhanced apathy-like behaviors. The emergence of these behavioral phenotypes paralleled the reorganization of LHb ensembles, suggesting coordinated circuit and behavioral adaptations. Remarkably, early intervention with ketamine reversed CORT-induced LHb remodeling, while chemogenetic inhibition of LHb neuronal hyperactivity within this critical window also normalized depression-related behaviors.
Thus, we identified a temporally defined and topographically organized remodeling of LHb neuronal ensembles during chronic stress that matched the onset of depressive behaviors and was reversed by timely antidepressant strategies. These findings could have implications for temporally tailoring therapeutic interventions.