Switching off Specific Brain Cells Protects Against Stress

Summary: Using chemogenetic technology to deactivate a small group of neurons in the claustrum made mice more resilient against chronic stress and reduced anxiety behaviors.

Source: Osaka University

It is well known that long-term exposure to stress can lead to serious psychiatric problems. However, the precise mechanisms underpinning the stress response have remained elusive.

Recent advances in microscopic imaging by researchers from Japan have led to the exciting discovery of a small group of brain cells that control stress-induced responses. These cells could be the key to understanding the origin of stress-related mental disorders.

In a study published this month in Science Advances, researchers from Osaka University discovered a small group of brain cells in the claustrum of mice that controls stress-induced anxiety behaviors.

When these cells were activated using chemogenetic technology, mice exhibited anxiety-related behaviors, whereas deactivation of the cells made mice more resilient against chronic stress.

Until recently, the identification of such small populations of cells using an unbiased and hypothesis-free approach has been challenging because of technical limitations.

Now, the recent development of block-face serial microscopy tomography (known as FAST) by researchers at Osaka University has made this possible. This technique allowed the researchers to examine changes in cellular activity at the resolution of a single cell. It is widely understood that the processing of stress relies on the communication between cortical and subcortical regions of the brain; however, the exact mechanism underlying this communication is uncertain, which is what the researchers aimed to uncover using this technique.

The researchers used well-established psychological animal models of restraint and social defeat stress to map patterns of cellular activity in mice that were exposed to stress. Using the FAST technique, the team collected whole-brain images of control mice and mice exposed to these stressful conditions. Of the 22 brain regions studied, the claustrum was identified as a key region that differentiated stressed brains from non-stressed brains:

“A combined approach using brain activation mapping and machine learning showed that the claustrum activation serves as a reliable marker of exposure to acute stressors,” say lead authors Misaki Niu and Atsushi Kasai.

Crucially, by manipulating the activity of these cells using chemogenetic technology, they concluded that the claustrum is crucial for the control of stress-induced anxiety-related behaviors. When the activity of these cells was amplified, mice exhibited anxious behaviors; these could then be reversed by suppressing claustrum cell activity.

“Inactivation of stress-responsive claustrum neurons can serve as at least a partially preventative measure for the emergence of depression-like behavior, and moreover, for stress susceptibility to increase resilience to emotional stress,” explains senior author Hitoshi Hashimoto.

This discovery opens new opportunities for claustrum activity as a new treatment target for anxiety-related conditions and gaining a better understanding of the cause of stress-related disorders.

Abstract

Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses

The processing of stress responses involves brain-wide communication among cortical and subcortical regions; however, the underlying mechanisms remain elusive.

Here, we show that the claustrum (CLA) is crucial for the control of stress-induced anxiety-related behaviors. A combined approach using brain activation mapping and machine learning showed that the CLA activation serves as a reliable marker of exposure to acute stressors.

In TRAP2 mice, which allow activity-dependent genetic labeling, chemogenetic activation of the CLA neuronal ensemble tagged by acute social defeat stress (DS) elicited anxiety-related behaviors, whereas silencing of the CLA ensemble attenuated DS-induced anxiety-related behaviors.

Moreover, the CLA received strong input from DS-activated basolateral amygdala neurons, and its circuit-selective optogenetic photostimulation temporarily elicited anxiety-related behaviors.

Last, silencing of the CLA ensemble during stress exposure increased resistance to chronic DS. The CLA thus bidirectionally controls stress-induced emotional responses, and its inactivation can serve as a preventative strategy to increase stress resilience.