Stress-Induced Lateral Habenula Changes and the Association with Depressive Behavior in Mice

Post by Lincoln Tracy

What's the science?

Chronic stress has been identified as a prominent risk factor for the development of depression in humans. Several animal models of depression exist that involve exposing the animals to chronic stressors, leading to behavioral changes that mimic a subset of core depression symptoms in humans. The problem with this approach is that while depression often presents in different ways in different people, patients are often grouped into one category. Recent studies have identified that the lateral habenula—a small section of the brain near the pineal gland—is hyperactive in depression. This week in Neuron, Cerniauskas and colleagues developed a novel approach to examine the molecular, synaptic, and circuit basis of unique chronic stress-induced behavioral characteristics in mice.

How did they do it?

First, the authors used a chronic mild stress model to induce depression-like symptoms in mice. This involved exposing the mice to a series of stressors over an eight-week period. The authors then used a series of behavioral tasks to assess anxiety-related behaviors (elevated plus maze), interest in rewarding stimuli (sucrose preference test), responses to being placed in an inescapable situation (tail suspension test), and deficits in sociability behavior (social interaction test). Second, they used receiver operating characteristic (ROC) curves to make an unbiased decision as to whether each individual mouse displayed a certain set of behavioral characteristics. Third, they used histology, microscopy, single-cell RNA sequencing, whole-brain input mapping, and electrophysiological techniques to analyze the molecular, synaptic, and circuit adaptions in the lateral habenula after chronic stress.

What did they find?

First, the authors found that mice exposed to chronic stress and the control mice both showed considerable variability in three of the four behavioral tasks. Second, the stress-induced hyperactivity in the lateral habenula was directly associated with connections to the ventral tegmental area and the rostromedial tegmental nucleus—two areas of the brain involved in dopaminergic (or reward) signalling in the brain—rather than the dorsal raphe nucleus, where the serotoninergic neurons are located. Specifically, lateral habenula excitability was associated with increased passive coping rather than anhedonia (an inability to feel pleasure) or anxiety, which are other common symptoms of depression in humans. The authors also identified a subset of genes that together can be used as biomarkers to identify mice that display increased passive coping and allow for the differentiation of lateral habenula neurons that project to the ventral tegmental area or the dorsal raphe nucleus.   

LHb = lateral habenula, EP = entopeduncular nucleus, DR = dorsal raphe, VTA = ventral tegmental area

What's the impact?

This study demonstrated that mice, like humans, have considerable individual variability in how they respond to chronic stress. It is the first study to link a specific behavioral phenotype (reduced motivated behavior), which is commonly observed in depression in humans to specific molecular, cellular, and circuit changes in the lateral habenula. Even though the study was performed in mice, lateral habenula hyperactivity has also been observed in humans with depression, suggesting that there may be — at least in part — a translational aspect of these findings. This study may serve as a foundation for future research investigating symptom-specific therapeutic interventions as well as predictive biomarkers for depression. 

Cerniauskas et al. Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors. Neuron (2019). Access the original scientific publication here.