Dataset Information

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

ABSTRACT: Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this "lag" remains unclear. Laughing gas (N₂O), another NMDA-R (N-methyl-D-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N₂O to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinase-markers of neuronal excitability-were upregulated during N₂O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3? (glycogen synthase kinase 3?) became regulated only gradually upon N₂O discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3? signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of ?₂-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3? signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses.

SUBMITTER: Kohtala S

PROVIDER: S-EPMC6505519 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Kohtala Samuel S Theilmann Wiebke W Rosenholm Marko M Penna Leena L Karabulut Gulsum G Uusitalo Salla S Järventausta Kaija K Yli-Hankala Arvi A Yalcin Ipek I Matsui Nobuaki N Wigren Henna-Kaisa HK Rantamäki Tomi T

Molecular neurobiology 20181004 6

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this "lag" remains unclear. Laughing gas (N<sub>2</sub>O), another NMDA-R (N-methyl-D-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N<sub>2</sub>O to investigate EEG (electroencephalogram) alterations and molecular determinants o ...[more]

PMID: 30288695

Similar Datasets

Project description:Cortical slow oscillations (?1 Hz) are an emergent property of the cortical network that integrate connectivity and physiological features. This rhythm, highly revealing of the characteristics of the underlying dynamics, is a hallmark of low complexity brain states like sleep, and represents a default activity pattern. Here, we present a methodological approach for quantifying the spatial and temporal properties of this emergent activity. We improved and enriched a robust analysis procedure that has already been successfully applied to both in vitro and in vivo data acquisitions. We tested the new tools of the methodology by analyzing the electrocorticography (ECoG) traces recorded from a custom 32-channel multi-electrode array in wild-type isoflurane-anesthetized mice. The enhanced analysis pipeline, named SWAP (Slow Wave Analysis Pipeline), detects Up and Down states, enables the characterization of the spatial dependency of their statistical properties, and supports the comparison of different subjects. The SWAP is implemented in a data-independent way, allowing its application to other data sets (acquired from different subjects, or with different recording tools), as well as to the outcome of numerical simulations. By using the SWAP, we report statistically significant differences in the observed slow oscillations (SO) across cortical areas and cortical sites. Computing cortical maps by interpolating the features of SO acquired at the electrode positions, we give evidence of gradients at the global scale along an oblique axis directed from fronto-lateral toward occipito-medial regions, further highlighting some heterogeneity within cortical areas. The results obtained using the SWAP will be essential for producing data-driven brain simulations. A spatial characterization of slow oscillations will also trigger a discussion on the role of, and the interplay between, the different regions in the cortex, improving our understanding of the mechanisms of generation and propagation of delta rhythms and, more generally, of cortical properties.

Dataset Information

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Publications

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure