Biology subjects

Kohtala, S.

Publications and source records attributed to Kohtala, S..

4 recordsLinked to original sources

bioRxiv2025

Nitrous oxide modulates cortical activity, wake-sleep oscillations, and produces antidepressant-like effects in mice

Emerging evidence suggests that nitrous oxide (N2O), a gaseous NMDA receptor antagonist and dissociative anesthetic, exerts rapid antidepressant effects akin to subanesthetic ketamine. However, its cellular, molecular, and behavioral effects remain poorly understood. Using in vivo two-photon imaging through cortical microprisms, we demonstrate that 50% N2O/O2 rapidly increases neuronal calcium activity in the mouse medial prefrontal cortex (mPFC). This was corroborated by elevated c-Fos expression at both protein and mRNA levels in mPFC lysates. Cortical EEG recordings revealed that N2O increased subsequent wake-associated gamma oscillations and enhanced slow-wave activity during sleep, suggestive of cortical activation and synaptic potentiation. In a chronic corticosterone stress model, N2O elicited antidepressant-like behavioral effects in several, though not all, domains. Together, these findings indicate that a single treatment with N2O rapidly enhances cortical activity, modulates sleep and wake EEG oscillations, and produces antidepressant-like effects, paralleling key actions associated with subanesthetic ketamine.

neuroscience↗

bioRxiv2021

Physiological basis underlying antidepressant-induced activation of TrkB receptors

We show that both pharmacological and non-pharmacological treatments of depression activate TrkB receptors--a well-established target of antidepressants--by inducing a physiological response coupled to sedation. Several rapid-acting antidepressants trigger TrkB signaling by evoking a state associated with electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. Remarkably, antidepressant-induced TrkB signaling was not compromised in animals exhibiting reduced activity-dependent release of BDNF but was diminished by maintaining animals in warm ambient temperature. Most importantly, prevention of the hypothermic response attenuated the behavioral effects produced by rapid-acting antidepressant nitrous oxide. Our results suggest that the phenomenon underlying TrkB transactivation--changes in energy expenditure and thermoregulation--is essential, but not sufficient, for antidepressant responses. Indeed, regardless of differential clinical and pharmacodynamic properties, all drugs that disrupt energy metabolism and induce hypothermia activated TrkB. This study challenges pharmacology-centric hypotheses regarding antidepressant effects and highlight the role of complex changes in bioenergetics and thermoregulation. HighlightsO_LIRapid-acting antidepressants evoke homeostatic emergence of slow-wave sleep during which TrkB signaling becomes regulated. C_LIO_LINon-antidepressant metabolic inhibitors and diverse sedatives activate TrkB signaling. C_LIO_LIReduction in body temperature determined the ability of antidepressants to transactivate TrkB. C_LIO_LIDrug-induced TrkB signaling was blunted by maintenance of normothermic body temperature. C_LIO_LIWarm ambient temperature after nitrous oxide exposure blocked the antidepressant-like effects. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/458151v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1f7351borg.highwire.dtl.DTLVardef@bf920forg.highwire.dtl.DTLVardef@10e34eaorg.highwire.dtl.DTLVardef@1b42bb6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2018

Putative rapid-acting antidepressant nitrous oxide ("laughing gas") evokes rebound emergence of slow EEG oscillations during which TrkB signaling is induced

Electroconvulsive therapy (ECT) remains among the most efficient antidepressants but it seldom brings immediate remedy. However, a subanesthetic dose of NMDA-R (N-methyl-D-aspartate receptor) blocker ketamine ameliorates symptoms of depression already within hours. Glutamatergic excitability and regulation of TrkB neurotrophin receptor and GSK3{beta} (glycogen synthase kinase 3{beta}) signaling are considered as molecular-level determinants for ketamines antidepressant effects. Recent clinical observations suggests that nitrous oxide (N2O, \"laughing gas\"), another NMDA-R blocking dissociative anesthestic, also produces rapid antidepressant effects but the underlying mechanisms remain essentially unstudied. In this animal study we show that N2O, with a clinically relevant dosing regimen, evokes an emergence of rebound slow EEG (electroencephalogram) oscillations, a phenomenon considered to predict the efficacy and onset-of-action ECT. Very similar rebound slow oscillations are induced by subanesthetic ketamine and flurothyl (a treatment analogous to ECT). These responses become best evident upon drug withdrawal, i.e. after the peak of acute pharmacological actions, when their most prominent effects on cortical excitability have subsided. Most importantly, TrkB and GSK3{beta} signaling remain unchanged during N2O administration (ongoing NMDA-R blockade) but emerge gradually upon gas withdrawal along with increased slow EEG oscillations. Collectively these findings reveal that rapid-acting antidepressants produce cortical excitability that triggers \"a brain state\" dominated by ongoing slow oscillations, sedation and drowsiness during which TrkB and GSK3{beta} signaling alterations are induced.

pharmacology and toxicology↗

bioRxiv2016

TrkB signaling underlies the rapid antidepressant effects of isoflurane

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3{beta} (GSK3{beta}). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

neuroscience↗