Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

Chronic stress (CS) is a major contributor to depression in humans, yet animal models often treat stressed subjects as a homogeneous group. This study adopts a more nuanced approach, using behavioral screening to classify mice based on specific phenotypes—such as passive coping (PC), anxiety, and anhedonia—rather than simple binary 'stressed vs. control' labels. The researchers focused on the lateral habenula (LHb), a brain structure implicated in negative motivation, to determine how chronic stress rearranges neural circuits and gene expression.

By subjecting mice to chronic mild stress (CMS) and performing behavioral tests, the researchers generated 'D-scores' to categorize individual animals based on their symptomatic profiles. They performed whole-cell patch-clamp electrophysiology and in vivo tetrode recordings to observe the activity of LHb neurons. They specifically compared two major output pathways: LHb neurons projecting to the ventral tegmental area (LHb→VTA) and those projecting to the dorsal raphe (LHb→DR). Finally, they used single-cell transcriptomics to map gene expression differences associated with the passive coping phenotype.

The study reveals that chronic stress induces hyperactivity specifically in LHb→VTA neurons, characterized by increased burst and tonic firing. This hyperactivity is driven by maladaptive synaptic changes—specifically, enhanced excitatory input from the entopeduncular nucleus (EP) and an increase in calcium-permeable AMPA receptors. Optogenetic and chemogenetic experiments confirmed that this pathway directly modulates passive coping and effort-related motivation; silencing these neurons in stressed mice restored motivated behavior. Conversely, LHb→DR neurons did not exhibit stress-induced hyperactivity, highlighting the topographic specificity of the LHb's response to stress. Transcriptomic analysis identified a set of biomarker genes (such as Kcnc1) that distinguish between projection-defined subpopulations and behavioral phenotypes, providing a molecular basis for the observed circuit dysfunction.