Stress Interferes with Lateral Habenula Signaling and Reward-Seeking

Post by Deborah Joye

What's the science?

Our brains help us form goal-directed behaviors in pursuit of a reward. We know that the prefrontal cortex has a lot to do with reward-guided cognition, but we don’t know very much about how subcortical systems might regulate these aspects of behavior and cognition. What we do know is that one subcortical structure, the lateral habenula conveys both reward signals and aversive signals, like disappointment. We also know that neurons in the lateral habenula help shape decision-making and retrieval of spatial memories (e.g. “How did I get to that reward before?”) and that disrupting the lateral habenula negatively impacts the ability to make a choice during a cognitive task.

When we experience stress, changes in our brain can interfere with our ability to make reward-guided decisions. Exposure to stress promotes long-lasting changes in how our brain cells communicate with one another and can be associated with subsequent mood disorders (e.g. depression). However, it is not well understood whether neural changes in the lateral habenula and stress-driven cognitive changes are causally linked. This week in Neuron, Nuno-Perez and colleagues demonstrate that a stressful experience drives synaptic depression in the lateral habenula, which is sufficient to produce cognitive deficits in a reward task.

How did they do it?

To test how the lateral habenula is involved with reward and stress-driven brain changes, the authors designed a reward-guided task using a T-maze paradigm (shaped like a T). Mice were habituated to the maze task with a reward that could be found in one arm before they were tested. On test day, the location of the reward was switched to the other arm. Task performance was defined as the number of times mice dipped into the non-rewarded arm of the maze. To test whether a stressful experience alters performance on this task, the authors exposed some of the mice to a single session of unpredictable foot shocks, then had mice complete the task a week later. To evaluate whether specific parts of this task correlated to neuronal activity in the lateral habenula, the authors injected a virus into the lateral habenula allowing them to visualize calcium activity within cells (a marker of cellular activation) in freely-moving mice. Using this virus paired with fiber photometry the authors were able to study the activity of lateral habenula neurons in real-time as stressed and unstressed mice completed the maze task.

The authors then tested whether silencing lateral habenula neurons during the task altered task performance by injecting a red-light activated inhibitor of cellular activity into the lateral habenula. The authors recorded electrophysiological activity from the lateral habenula to measure AMPA/NMDA ratios - a proxy measure of how strong a particular neuronal response is. The authors also used electrophysiology to test whether activity changes in the lateral habenula were specific to particular brain circuits, by activating lateral habenula inputs from specific brain regions and measuring the response. Finally, to test whether changes in AMPA activation on lateral habenula neurons are causally linked to task performance, the authors used viruses that either overexpress Rab5, which reduces AMPA receptor expression and function, or Rac1, which increases AMPA expression and function. The authors used a Rac1 that can be activated by light, which means they could time the activation of AMPA increase specifically to when mice received a negative outcome (no reward).

What did they find?

The authors found that when a mouse encountered the non-rewarded arm in the maze task, neurons in the lateral habenula were recruited to encode that negative outcome. Mice that had more excitatory transmission onto lateral habenula neurons made fewer errors when looking for the reward. When mice were exposed to a stressful experience known to disrupt the lateral habenula, they made more errors when looking for the reward arm. Similarly, when the authors mimicked reduced excitatory transmission by silencing lateral habenula neurons, the mice made more errors. Exposure to stress reduced post-synaptic AMPA receptors at lateral habenula synapses, which led to decreased activation of those neurons. In summary, the authors demonstrate that exposure to a stressful experience weakened excitatory transmission onto lateral habenula neurons via a reduction in AMPA receptors. 

The authors also found that incoming signals from a variety of brain regions were similarly weakened by AMPA reductions on lateral habenula neurons, meaning this reduction in excitatory transmission occurs regardless of where in the brain the excitatory signals are coming from and are not dependent on a particular brain circuit. When the authors mimicked weakened excitatory transmission onto lateral habenula neurons, they found that this alone was sufficient to reproduce the stress-driven increase in errors on the maze task.

What's the impact?

This study demonstrates that a single stressful experience can drive behavioral deficits through synaptic depression (a weakening of the connection between two neurons, in this case by decreasing excitatory transmission) in the lateral habenula. These findings support the view that stress can drive behavioral deficits by interfering with synaptic transmission. This raises interesting questions about how chronic stress may also change this lateral habenula circuit. Furthermore, this study highlights a somewhat new role for the lateral habenula, which is typically considered a “disappointment brain center.” The authors demonstrate that the “disappointment” signal from the lateral habenula is important for learning how to acquire a reward more efficiently. Finally, it’s important to note that this study uses only male mice but raises questions about how this circuit may differ in females, opening exciting avenues for future work on sex differences in this link between stress, cognition, and behavior.

Nuno-Perez et al., Stress undermines reward-guide cognitive performance through synaptic depression in the lateral habenula (2021). Access the original scientific publication here.