{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE282nnn/GSE282867/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Mus"],"gds_type":[" Expression profiling by high throughput sequencing","Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE282867"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation","description":"Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its underlying mechanisms are not well understood. Indirect evidence from clinical studies suggests that TMS may act by enhancing plasticity locally within the prefrontal cortical (PFC) target or through network-level effects on downstream areas, but establishing causal mechanisms and optimizing a large stimulation parameter space has been challenging. In an optogenetic model of accelerated intermittent theta burst stimulation targeting the prelimbic PFC (PL-aiTBS), we show that PL-aiTBS drives rapid, antidepressant-like effects on multiple measures of motivated approach and avoidance behavior and reverses stress effects on reward devaluation, with repeated stimulation potentiating local aiTBS-evoked neuronal responses. Spatial transcriptomic profiling revealed a host of cell type-specific effects implicating prefrontal intratelencephalic (IT) projection neurons, including altered expression of genes associated synapse assembly, which in turn was associated with increased postsynaptic dendritic spine density and excitatory currents in prelimbic IT neurons. Using SHIELD tissue clearing, c-Fos immunolabeling, and light sheet imaging to map whole-brain responses to aiTBS, we delineate a network of downstream structures activated by PL-aiTBS, including pronounced effects in insular cortex, which were confirmed by fiber photometry. Chemogenetic and projection-specific optogenetic studies established the necessity and sufficiency of a fronto-insular circuit in mediating aiTBS effects on motivated approach and avoidance behavior. Finally, we validate a key role for TMS-evoked responses in the human insula, showing in intracortical stereo-EEG recordings that prefrontal TMS modulates neuronal activity in insular cortex acutely and that resting state fMRI measures of fronto-insular connectivity predict individual differences in antidepressant responses to aiTBS. Together, these results identify a critical role for aiTBS-induced activation of a fronto-insular circuit in supporting specific antidepressant-like behavioral effects and establish a model for studying aiTBS mechanisms and optimizing stimulation parameters.","dates":{"publication":"2026/04/29"},"accession":"GSE282867","cross_references":{"GSM":["GSM8651767","GSM8651766","GSM8651758","GSM8651763","GSM8651762","GSM8651765","GSM8651764","GSM8651761","GSM8651760","GSM8651759"],"GPL":["35134"],"GSE":["282867"],"taxon":["Mus"]}}