Encoding, Consolidation, and Renormalization in Depression : Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. Significance Statement-Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as N-methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.Peer reviewe

Digital autoradiography for efficient functional imaging without anesthesia in experimental animals : Reversing phencyclidine-induced functional alterations using clozapine

Autoradiography (ARG) is a high-resolution imaging method for localization of radiolabeled biomarkers in ex vivo specimen. ARG using 2-deoxy-D-glucose (2-DG) method is used in to study drug actions on brain functional activity, as it provides results comparable to clinically used functional positron-emission tomography (PET). The requirement of slow analog detection methods and emerging advances in small animal PET imaging have, however, reduced the interest in ARG. In contrast to ARG, experimental animals need to be restrained or sedated/anesthetized for PET imaging, which strongly influence functional activity and thus complicate the interpretation of the results. Digital direct particle-counting ARG systems have gained attraction during the last decade to overcome the caveats of conventional ARG methods. Here we demonstrate that the well-established 2-DG imaging method can be adapted into use with contemporary digital detectors. This method readily and rapidly captures the characteristic effects of phencyclidine (5 mg/kg, i.p.), a dissociative agent targeting the NMDAR (N-methyl-D-aspartate receptor), on regional glucose utilization in the adult mouse brain. Pretreatment with antipsychotic drug clozapine (6 mg/kg, i.p.) essentially abolishes these effects of phencyclidine on brain functional activity. Digital ARG produces viable data for the regional analysis of functional activity in a fraction of time required for film development. These results support the use of digital ARG in preclinical drug research, where high throughput and response linearity are preferred and use of sedation/anesthesia has to be avoided.Peer reviewe

Tianeptine induces expression of dual specificity phosphatases and evokes rebound emergence of cortical slow wave electrophysiological activity

Funding Information: This work was supported by the Academy of Finland (grant numbers 276333 , 305195 , 312664 , 322906 ) and the Finnish Pharmaceutical Society . Funding Information: This work was supported by the Academy of Finland (grant numbers 276333, 305195, 312664, 322906) and the Finnish Pharmaceutical Society. T.R. is listed as a co-inventor on a patent application wherein new EEG monitoring tools potentially enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed. T.R. has assigned his patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki. Publisher Copyright: © 2021 The AuthorsBackground: The precise mechanism governing the antidepressant effects of tianeptine is unknown. Modulation of brain glutamatergic neurotransmission has been however implicated, suggesting potential shared features with rapid-acting antidepressants targeting N-methyl-D-aspartate receptors (NMDAR). Our recent studies suggest that a single subanesthetic dose of NMDAR antagonists ketamine or nitrous oxide (N2O) gradually evoke 1–4 Hz electrophysiological activity (delta-rhythm) of cerebral cortex that is accompanied by molecular signaling associated with synaptic plasticity (e.g. activation of tropomyosin receptor kinase B (TrkB) and inhibition of glycogen synthase kinase 3β (GSK3β)). Methods: We have here investigated the time-dependent effects of tianeptine (30 mg/kg, i.p.) on electrocorticogram, focusing on potential biphasic regulation of the delta-rhythm. Selected molecular markers associated with ketamine's antidepressant effects were analyzed in the medial prefrontal cortex after the treatment using quantitative polymerase chain reaction and western blotting. Results: An acute tianeptine treatment induced changes of electrocorticogram typical for active wakefulness that lasted for 2–2.5 h, which was followed by high amplitude delta-activity rebound. The levels of Arc and Homer1a, but not c-Fos, BdnfIV and Zif268, were increased by tianeptine. Phosphorylation of mitogen-activated protein kinase (MAPK), TrkB and GSK3β remained unaltered at 2-hours and at 3-hours post-treatment. Notably, tianeptine also increased the level of mRNA of several dual specificity phosphatases (Duspss) – negative regulators of MAPK. Conclusion: Tianeptine produces acute changes of electrocorticogram resembling rapid-acting antidepressants ketamine and N2O. Concomitant regulation of Dusps may hamper the effects of tianeptine on MAPK pathway and influence the magnitude of homeostatic emergence of delta-activity and TrkB-GSK3β signaling.Peer reviewe

Improving Group Work Practices in Teaching Life Sciences : Trialogical Learning

Trialogical learning, a collaborative and iterative knowledge creation process using real-life artefacts or problems, familiarizes students with working life environments and aims to teach skills required in the professional world. We target one of the major limitation factors for optimal trialogical learning in university settings, inefficient group work. We propose a course design combining effective group working practices with trialogical learning principles in life sciences. We assess the usability of our design in (a) a case study on crop science education and (b) a questionnaire for university teachers in life science fields. Our approach was considered useful and supportive of the learning process by all the participants in the case study: the students, the stakeholders and the facilitator. Correspondingly, a group of university teachers expressed that the trialogical approach and the involvement of stakeholders could promote efficient learning. In our case in life sciences, we identified the key issues in facilitating effective group work to be the design of meaningful tasks and the allowance of sufficient time to take action based on formative feedback. Even though trialogical courses can be time consuming, the experience of applying knowledge in real-life cases justifies using the approach, particularly for students just about to enter their professional careers.Peer reviewe

Neurobiologiset ilmiöt nopean masennuslääkevasteen taustalla

English summaryPeer reviewe

Lack of antidepressant effects of burst-suppressing isoflurane anesthesia in adult male Wistar outbred rats subjected to chronic mild stress

Post-ictal emergence of slow wave EEG (electroencephalogram) activity and burst-suppression has been associated with the therapeutic effects of the electroconvulsive therapy (ECT), indicating that mere “cerebral silence” may elicit antidepressant actions. Indeed, brief exposures to burst-suppressing anesthesia has been reported to elicit antidepressant effects in a subset of patients, and produce behavioral and molecular alterations, such as increased expression of brain-derived neurotrophic factor (BDNF), connected with antidepressant responses in rodents. Here, we have further tested the cerebral silence hypothesis by determining whether repeated exposures to isoflurane anesthesia reduce depressive-like symptoms or influence BDNF expression in male Wistar outbred rats (Crl:WI(Han)) subjected to chronic mild stress (CMS), a model which is responsive to repeated electroconvulsive shocks (ECS, a model of ECT). Stress-susceptible, stress-resilient, and unstressed rats were exposed to 5 doses of isoflurane over a 15-day time period, with administrations occurring every third day. Isoflurane dosing is known to reliably produce rapid EEG burst-suppression (4% induction, 2% maintenance; 15 min). Antidepressant and anxiolytic effects of isoflurane were assessed after the first, third, and fifth drug exposure by measuring sucrose consumption, as well as performance on the open field and the elevated plus maze tasks. Tissue samples from the medial prefrontal cortex and hippocampus were collected, and levels of BDNF (brain-derived neurotrophic factor) protein were assessed. We find that isoflurane anesthesia had no impact on the behavior of stress-resilient or anhedonic rats in selected tests; findings which were consistent—perhaps inherently related—with unchanged levels of BDNF.Peer reviewe

Repeated brief isoflurane anesthesia during early postnatal development produces negligible changes on adult behavior in male mice

Brain development is a complex process regulated by genetic programs and activity-dependent neuronal connectivity. Anesthetics profoundly alter neuronal excitability, and anesthesia during early brain development has been consistently associated with neuroapoptosis, altered synaptogenesis, and persistent behavioral abnormalities in experimental animals. However, the depth, and even more the duration and developmental time point(s) of exposure to anesthesia determine the neuropathological and long-term behavioral consequences of anesthetics. Here, we have investigated adulthood phenotypic changes induced by repeated but brief (30 min) isoflurane anesthesia delivered during two distinct developmental periods in male mice. A set of animals were subjected to anesthesia treatments at postnatal days 7, 8 and 9 (P7-9) when the animals are susceptible to anesthesia-induced neuroapoptosis and reduced synaptogenesis. To control the potential influence of (handling) stress, a separate group of animals underwent repeated maternal separations of similar durations. Another set of animals were exposed to the same treatments at postnatal days 15, 16 and 17 (P15-17), a developmental time period when anesthetics have been shown to increase synaptogenesis. Starting from postnatal week 9 the mouse phenotype was evaluated using a battery of behavioral tests that assess general locomotor activity (home cage activity, open field), learning and memory (water maze) and depression- (saccharin preference, forced swim test), anxiety- (light-dark box, stress-induced hyperthermia) and schizophrenia- (nesting, prepulse inhibition) related endophenotypes. Apart from mild impairment in spatial navigation memory, exposure to anesthesia treatments during P7-9 did not bring obvious behavioral alterations in adult animals. Importantly, maternal separation during the same developmental period produced a very similar phenotype during the water maze. Mice exposed to anesthesia during P15-17 showed mild hyperactivity and risk-taking behavior in adulthood, but were otherwise normal. We conclude that significantly longer administration periods are needed in order for early-life repeated exposures to anesthetics to produce behavioral alterations in adult mice.Peer reviewe

Dose-dependent effects of isoflurane on TrkB and GSK3β signaling: Importance of burst suppression pattern

Objectives: Deep burst-suppressing isoflurane anesthesia regulates signaling pathways connected with antidepressant responses in the rodent brain: activation of TrkB neurotrophin receptor and inhibition of GSK3 beta kinase (glycogen synthase kinase 3 beta). The main objective of this study was to investigate whether EEG (electroencephalogram) burst suppression correlates with these intriguing molecular alterations induced by isoflurane. Methods: Adult male mice pre-implanted with EEG recording electrodes were subjected to varying concentrations of isoflurane (1.0-2.0% ad 20 min) after which medial prefrontal cortex samples were collected for molecular analyses, and the data retrospectively correlated to EEG ( + /- burst suppression). Results: Isoflurane dose-dependently increased phosphorylation of TrkB(Y816), CREBS133 (cAMP response element binding protein), GSK3 beta(S9) and p70S6k(T412/S424). The time spent in burst suppression mode varied considerably between individual animals. Notably, a subset of animals subjected to 1.0-1.5% isoflurane showed no burst suppression. While p-GSK3 beta(S9), p-CREBS133 and p-p70S6k(T412/S424) levels were increased in the samples obtained also from these animals, p-TrkB(Y816) levels remained unaltered. Conclusions: Isoflurane dose-dependently regulates TrkB and GSK3 beta signaling and dosing associated with therapeutic outcomes in depressed patients produces most prominent effects.Peer reviewe

A wake-up call : Sleep physiology and related translational discrepancies in studies of rapid-acting antidepressants

Depression is frequently associated with sleep problems, and clinical improvement often coincides with the normalization of sleep architecture and realignment of circadian rhythm. The effectiveness of treatments targeting sleep in depressed patients, such as sleep deprivation, further demonstrates the confluence of sleep and mood. Moreover, recent studies showing that the rapid-acting antidepressant ketamine influences processes related to sleep-wake neurobiology have led to novel hypotheses explaining rapid and sustained antidepressant effects. Despite the available evidence, studies addressing ketamine's antidepressant effects have focused on pharmacology and often overlooked the role of physiology. To explore this discrepancy in research on rapid acting antidepressants, we examined articles published between 2009-2019. A keyword search algorithm indicated that vast majority of the articles completely ignored sleep. Out of the 100 most frequently cited pre clinical and clinical research papers, 89 % and 71 %, respectively, did not mention sleep at all. Furthermore, only a handful of these articles disclosed key experimental variables, such as the times of treatment administration or behavioral testing, let alone considered the potential association between these variables and experimental observations. Notably, in preclinical studies, treatments were preferentially administered during the inactive period, which is the polar opposite of clinical practice and research. We discuss the potential impact of this practice on the results in the field. Our hope is that this perspective will serve as a wake-up call to (re)-examine rapid-acting antidepressant effects with more appreciation for the role of sleep and chronobiology.Peer reviewe

Potential consequences of hypothetical nuclear power plant accidents in Finland

An assessment of the environmental consequences of radioactive releases from severe reactor accidents was performed for Finnish nuclear power plants (NPP) in operation (Loviisa 1 and 2, and Olkiluoto 1 and 2), in commissioning (Olkiluoto 3) and in the preparatory phase (Hanhikivi 1). Three hypothetical radioactive releases (Basic, Large and Very Large cases) with different magnitudes were considered. Basic case represents a release corresponding to the limit set in requirements for severe reactor accidents, and thus, the other two represent extremely unlikely situations where severe accident management has failed. The magnitude of Very Large case is similar to the Fukushima NPP accident and roughly one order of magnitude smaller than the Chernobyl NPP accident, while the magnitude of Large case is roughly one order of magnitude smaller. The environmental assessment on the consequences of the releases was performed using a probabilistic approach. The aim is to estimate radiation doses to the population around the NPP and land contamination resulting from the release of radioactive material. The results of the assessment were compared to the protective action criteria for radioactive release from an NPP, and further used to evaluate the sufficiency of the Precautionary Action Zone (PAZ) and Emergency Planning Zone (EPZ) given in Finnish regulation. The probability of exceeding different operational intervention levels (OIL) and dose criteria set for external dose rate, effective dose, thyroid dose, deposition of strong gamma emitters, deposition of cesium, and concentration of gamma emitters in the air were estimated for distances up to 300 km from each site. Dispersion and deposition of releases were modelled with the dispersion model SILAM of the Finnish Meteorological Institute. The modelling applied historical weather forecast data from the years 2012–2015 retrieved with operative weather forecast models AROME and HARMONIE. Dose rates and doses were determined from the radionuclide air concentrations and depositions with the threat assessment tool TIUKU. The assessment was preformed using 2920 dispersion realizations for each reactor type and release scenario. For the assessment, the 95th percentile of the modelled dispersion, deposition and dose data was selected. The assessment showed that it is unlikely that any OILs or dose criteria would be exceeded outside PAZ and EPZ in a Basic case. In a Large case, the OILs may be exceeded up to about 110 km from the NPP sites, while it could be up to 170 km for dose criteria for the recommendation to limit being outside and iodine prophylaxis for children and pregnant females. The assessment indicated that it is unlikely that sheltering indoors or evacuation are needed outside the PAZ and EPZ during the early phase of the emergency due to the release in a Large case. In a Very Large case, extensive protective actions including permanent or temporary relocation are needed outside EPZ and less restrictive protective actions (i.e., recommendation to limit being outside and iodine prophylaxis for children and pregnant females) are needed beyond the area considered in this study (> 300 km). It was shown, however, that the protective actions outside the PAZ and EPZ are strongly dependent on prevailing weather conditions. It was observed that the dose criteria for an adult’s effective and thyroid dose were exceeded in larger areas than suggested by the criteria based on the external dose rate. Furthermore, dose criteria for a child’s thyroid dose were exceeded in larger areas than the dose criteria for the recommendation to limit being outside, even though the iodine prophylaxis for children and pregnant females is set as a complementary protective action for the recommendation to limit being outside. The observation demonstrates that the content of the radioactive release must be carefully considered in a severe NPP accident as the amount of released iodine isotopes affect the thyroid dose, while other nuclides make only a small contribution to it. It was also observed that precipitation may cause the deposition of radioactive substances such that in large areas the criteria for protective action based on deposition may be exceeded, even when protective actions would not be warranted according to dose criteria for effective doses. In Large and Very Large cases, the deposition may lead to the need for decontamination of large areas, and temporary or even permanent relocation of people. These findings demonstrate the importance of primarily using dose criteria in decision making if dose calculations can be performed reliably during the actual nuclear or radiological emergency. The OILs shall be used only if measures with dose criteria cannot be determined reliably e.g., due to a lack of information. Based on the results, it was concluded that further study is needed to set an Extended Planning Distance (EPD) and Ingestion and Commodities Planning Distance (ICPD). In such a study, a level 2 Probabilistic Risk Assessments (PRA) considering the probability of atmospheric releases should be better linked with environmental consequence assessment. The International Atomic Energy Agency (IAEA) recommends the EPD and ICPD to facilitate preparedness planning and the execution of protective actions beyond the PAZ and EPZ. The existence of an EPD and ICPD could also improve the effective co-operation of different authorities and emergency workers in a nuclear emergency. In Large and Very Large cases, the seasonal variations between summer and winter were found to be significant especially when considering deposition of cesium and strong gamma emitters. It was observed that precipitation during the winter season causes more wet deposition than in the summer. In a Very Large case, the seasonal variations were also significant in other measures