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.

We recently reported that a neuronal population in the claustrum (CLA) identified under exposure to psychological stressors plays a key role in stress response processing. Upon stress exposure, the main inputs to the CLA come from the basolateral amygdala (BLA); however, the upstream brain regions that potentially regulate both the CLA and BLA during stressful experiences remain unclear. Here by combining activity-dependent viral retrograde labeling with whole brain imaging, we analyzed neurons projecting to the CLA and BLA activated by exposure to social defeat stress. The labeled CLA projecting neurons were mostly ipsilateral, excluding the prefrontal cortices, which had a distinctly labeled population in the contralateral hemisphere. Similarly, the labeled BLA projecting neurons were predominantly ipsilateral, aside from the BLA in the opposite hemisphere, which also had a notably labeled population. Moreover, we found co-labeled double-projecting single neurons in multiple brain regions such as the ipsilateral ectorhinal/perirhinal cortex, entorhinal cortex, and the contralateral BLA. These results suggest that CLA and BLA receive inputs from neuron collaterals in various brain regions during stress, which may regulate the CLA and BLA forming in a stress response circuitry.

We have recently reported that excitatory neurons in the claustrum mediate anxiety responses to acute psychological stressors that induce negative emotional states. However, it is unclear how claustral neurons represent information related to anxiety responses to a stressor. To address this question, here we performed calcium imaging of GCaMP6fexpressing claustral neurons in freely moving mice during three behavioral tests; the elevated plus maze, the open field test, and a second open field test after an exposure to a ten-minute single social defeat stress. Prior to exposure to a stressor, we found that a subset of claustral neurons displayed an increase in calcium levels upon transitioning to areas associated with increased anxiety in the elevated plus maze and the open field. In the open field test after exposure to social defeat stress, a different subset of neurons, including neurons that were activated by of stress, exhibited sustained high levels of calcium when entering and exiting the less anxiogenic corner zones of the open field. These results suggest that stress-related anxiety information is represented in a claustral neuronal population that is different from the population representing anxiety under non-stressed conditions.

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