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Selective effects of acute and chronic stress on slow and alpha-theta cortical functional connectivity and reversal with subanesthetic ketamine

Abstract

Anxious, depressive, traumatic, and other stress-related disorders are associated with large scale brain network functional connectivity changes, yet the relationship between acute stress effects and the emergence of persistent large scale network reorganization is unclear. Using male Thy 1-jRGECO1a transgenic mice, we repeatedly sampled mesoscale cortical calcium activity across dorsal neocortex. First, mice were imaged in a homecage control condition, followed by an acute foot-shock stress, a chronic variable stress protocol, an acute on chronic foot-shock stress, and finally treatment with the prototype rapid acting antidepressant ketamine or vehicle. We derived functional connectivity metrics and network efficiency in two activity bands, namely slow cortical activity (0.3–4 Hz) and theta-alpha cortical activity (4–15 Hz). Compared to homecage control, an acute foot-shock stress induced widespread increases in cortical functional connectivity and network efficiency in the 4–15 Hz temporal band before normalizing after 24 h. Conversely, chronic stress produced a selective increase in between-module functional connectivity and network efficiency in the 0.3–4 Hz band, which was reversed after treatment with the rapid acting antidepressant ketamine. The functional connectivity changes induced by acute stress in the 4–15 Hz band were strongly related to those in the slow band after chronic stress, as well as the selective effects of subanesthetic ketamine. Together, this data indicates that stress induces functional connectivity changes with spatiotemporal features that link acute stress, persistent network reorganization after chronic stress, and treatment effects.

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Fig. 1: Mesoscale cortical imaging in Thy-1 jRGECO1a mice.
Fig. 2: Acute foot-shock stress elevates functional connectivity in the 4–15 Hz band.
Fig. 3: Chronic variable stress elevates functional connectivity in the 0.3–4 Hz band.
Fig. 4: Correlation between Acute Stress and Chronic Stress connectivity changes.
Fig. 5: Ketamine reverses functional connectivity changes after chronic stress in the 0.3–4 Hz band.

Data availability

The datasets generated and analysed for the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Kylie Meir for technical assistance.

Funding

This study was funded through the Campus Alberta Innovates Program Chair in Neurostimulation to AM. DMA is supported by a Canadian Open Neuroscience Platform (CONP) Scholar Award.

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DMA & AM conceived of the study, conducted experiments, analyzed data, and wrote the manuscript.

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Correspondence to Alexander McGirr.

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Ashby, D.M., McGirr, A. Selective effects of acute and chronic stress on slow and alpha-theta cortical functional connectivity and reversal with subanesthetic ketamine. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01506-y

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