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

Abstract

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.

Acute social defeat stress activated neurons project to the claustrum and basolateral amygdala

“…We quantified the number of labeled neurons in each brain region by hemisphere, as recent findings suggest that even if the CLA predominantly receives ipsilateral inputs, specific brain areas such as the prefrontal cortices also provide contralateral inputs [1,4]. Analyses of ipsilateral inputs to the CLA showed a similar pattern to our previous work [10], with a large number of EGFP-positive neurons being found in the AI, BLA, PL/ILA, ECT/PERI, and ENT (Fig. 2A).…”

“…1A). The anterior part of the CLA was targeted since the anterior part of the CLA shows the highest increase in cells activated by psychological stress along the rostocaudal axis [10]. We specifically targeted the anterior part of the BLA as the distribution of stress activated BLA neurons projecting to the CLA is abundant there [10].…”

“…The anterior part of the CLA was targeted since the anterior part of the CLA shows the highest increase in cells activated by psychological stress along the rostocaudal axis [10]. We specifically targeted the anterior part of the BLA as the distribution of stress activated BLA neurons projecting to the CLA is abundant there [10]. Mice were then subjected to a single bout of social defeat stress 6 hours after an intraperitoneal tamoxifen injection to specifically tag neurons activated by exposure to the stressor.…”

“…Activity-dependent genetic labeling of TRAP2 mice with retrograde AAVs was performed as previously described [10]. Briefly, a single brain hemisphere in TRAP2 mice was unilaterally injected with 100 nL of AAVrg-hSyn-DIO-EGFP (≥ 7 × 10 12 particles/mL; gifted from Bryan Roth; Addgene viral prep # 50457-AAVrg; http://n2t.net/addgene:50459; RRID:Addgene_50457) in the CLA and 100 nL of AAVrg-hSyn-DIO-mCherry (≥ 7 × 10 12 particles/mL; gifted from Bryan Roth; Addgene viral prep # 50459-AAVrg; http://n2t.net/addgene:50459; RRID:Addgene_50459) in the BLA.…”

“…Advances in genetic labeling and manipulation techniques have provided detailed insights into the actual function of the CLA, including how the CLA regulates cortical slow wave activity [2,9]. Recently, our group applied immediate early gene-dependent genetic tools to demonstrate that a subpopulation of CLA neurons activated by acute social defeat stress controls stress-induced anxiety responses [10]. We also observed that most inputs to the CLA activated upon stressor exposure come from the anterior part of the basolateral amygdala (BLA), a brain region critically involved in the processing of emotionally relevant information.…”