Transcriptional activation, deactivation and rebound patterns in cortex, hippocampus and amygdala in response to ketamine infusion (Rattus norvegicus)

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that is increasingly used for treatment of depression and pain. Despite advances in clinical applications, the neural mechanisms remain incompletely defined. To address these questions, an intravenous ketamine infusion model was developed to probe molecular-level alterations in discrete rat brain regions following short term (1hr) and sustained (10hr) drug infusion, as well as recovery (24hrs). RNA-Seq revealed distinct brain regional transcription signatures that were most accentuated at 10 hours, followed by lower magnitude changes, frequently in the opposite direction, at recovery. Upregulated genes comprise 75% of the differentially expressed genes in the hippocampus, and 85% in the amygdala whereas in the cortex, only 35% of the differential genes showed increased expression. Immediate early genes such as Fos, Fosl2, and Maff increased across all regions suggesting a shared transcriptional activation pattern, which also extended to upregulation of the Nrf2-mediated antioxidant response pathway. Multiplex in situ hybridization of 10hr samples localized Fos upregulation in cortical layers III and V, indicating involvement of recurrent excitatory and efferent pathways, respectively. These activated neurons also upregulated the transcription factor Nr4a1 and Bdnf, the latter being a putative transducer of antidepressant effects. Distinct regional patterns were observed for transcriptional signatures within pathways for synaptic remodeling, glutamate receptors, and corticotropin-releasing hormone signaling. At 24hrs recovery, we observed downregulation or overshoot of activity-related transcripts rather than return to homeostasis. These data delineate critical molecular regulatory actions downstream of ketamine administration that may contribute to establishment of antidepressant and analgesic actions.