Since the start of the pandemic, stress-induced anxiety and depression have increased by 25%, reports the World Health Organization. This isn’t surprising. The links between stress and neuropsychiatric problems is well studied but the mechanisms underpinning stress processing in the brain remain unclear. This has resulted in an unmet need for diagnostic markers and targeted treatments for stress-related disorders.

Earlier studies have suggested processing of stress depends on brain-wide communication between cortical and subcortical regions but the molecular mechanisms and neurons involved were not known.

In a new study, researchers at the Osaka University in Japan, have used a recently developed technology called block-face serial microscopy tomography (FAST) and identified cells that control stress-induced responses in a thin layer called the claustrum that connects the cerebral cortex to subcortical regions. These cells could be key to understanding the origin of stress-related mental disorders and developing new treatments for stress-induced anxiety.

The findings were published on March 18, 2022, in the journal Science Advances, in an article titled, “Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses.”

The use of unbiased approaches to detect small populations of cells has been challenging, until now. In this study, FAST enabled the researchers to examine changes in cellular activity at the resolution of a single cell, brain-wide.

The researchers adopted established experimental paradigms to model stress in mice though physical restraint and social defeat. They then mapped patterns of cellular activity in mice that were exposed to stress in multiple regions of the brain.

Using the FAST, the team collected whole-brain images of control, unstressed mice and mice exposed to stress induced by restraint or defeat. The researchers found the activity in the claustrum differentiated stressed from non-stressed brains in the 22 brain regions they studied.

“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,” said lead authors Misaki Niu, PhD and Atsushi Kasai, PhD.

Using TRAP2 mice that allow activity-dependent genetic labeling, the team then activated cells in the claustrum using chemogenetic technology, causing mice to exhibit anxiety-related behaviors. On the other hand, when the researchers deactivated the same cells, the mice became more resilient to stress. From these experiments, the team concluded that the claustrum is important for the control of stress-induced anxiety-related behaviors.

“Claustrum activation serves as a reliable marker of exposure to acute stressors,” the authors note. “The claustrum bidirectionally controls stress-induced emotional responses, and its inactivation can serve as a preventative strategy to increase stress resilience.”

The authors also show that the cells in the claustrum that regulate stress processing receive strong input from neurons that are activated upon social defeat in the basolateral amygdala—a region known to play a role in emotional behavior.

“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,” said Hitoshi Hashimoto, PhD, who is senior author of the paper.

In addition to providing insights on mechanisms regulating stress-response, the discovery opens new avenues of developing targeted therapies for stress-induced anxiety and related disorders.

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