Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on decision-making biases in rodents

Major depressive disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABA(A) agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism

Investigating neuropsychological and reward-related deficits in a chronic corticosterone-induced model of depression

Chronic stress is a known risk factor for the development of major depression (MDD) and is commonly used to induce a depression-like phenotype in rodents. Similar phenotypic effects are also observed in rodents when treated chronically with the stress hormone corticosterone. In this study, we investigated the neuropsychological consequences of chronic corticosterone treatment in male rats using two translational rodent assays of affective bias, the judgement bias task (JBT) and affective bias test (ABT). We also used the reward learning assay (RLA) and sucrose preference test (SPT) to quantify reward-related behaviours. Negative biases in decision-making were observed in the chronic corticosterone-treated group but only when the treatment was given shortly before each behavioural session. The same dose of corticosterone, when given daily after completion of the behavioural session had no effects. Chronic corticosterone treatment did not potentiate negative affective biases in the ABT induced by either an acute pharmacological or stress manipulation but both reward learning and reward sensitivity were blunted. Analysis of the brain tissue from animals receiving chronic corticosterone found reduced hippocampal neurogenesis consistent with previous studies suggesting corticosterone-induced neurotrophic deficits. Taken together, these data suggest chronic corticosterone treatment induces neuropsychological effects related to changes in reward learning, memory and negative biases in decision making, but these decision-making biases depend on whether rewarding outcomes were experienced during the acute effects of the drug. These findings suggest an important interaction between psychological and biological factors resulting in negative biases in decision-making in this model

Prevalence and molecular epidemiology of ceftaroline non-susceptible methicillin-resistant Staphylococcus aureus isolates, first clinical report from Iran

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major pathogens in Iran with a high prevalence and a high level of antibiotic resistance. Ceftaroline is a fifth generation cephalosporin binding and inhibiting penicillin binding protein (PBP2a). Methods: In the present study, 228 clinical MRSA isolates were collected from four cities of Iran and their susceptibility to ceftaroline was evaluated by E-test and the disk diffusion method. Results: Our results showed a high susceptibility rate (97.3) to ceftaroline in MRSA strains from Iran. Six isolates were found to be ceftaroline non-susceptible (CPT-NS) with Minimum inhibitory concentration (MIC) �2 mg/mL. All CPT-NS isolates were isolated from blood and tracheal aspirate and belonged to SCCmec type III as well as agr type I and were all susceptible to vancomycin. Out of six isolates, three, two and one belonged to spa type t030, t4864, and t969, respectively. Vancomycin, quinupristin/dalfopristin, linezolid, chloramphenicol, and tigecycline were the most active agents against CPT-NS isolates. Conclusion: Due to the broad-spectrum activity and low toxicity of ceftaroline as well as the increased rate of vancomycin resistance among MRSA strains in recent years, ceftaroline can be considered as a novel approach to treat MRSA-induced infections. © 2020 The Author(s)

An Exploratory Study of OTT Platform Movie Recommendation using Cosine Similarity

“Over the Top” platforms, or OTT platforms, are where movies and TV shows can be watched. The main focus of the research is the recommendation system of OTT platforms, studying its mechanisms. The researchers also aim to identify relevant features that are most useful to a recommendation system. The researchers conducted data preprocessing such as the one hot encoding method. Cosine similarity was employed as the foundational algorithm for the recommendation system. Upon generating several recommendations using different sets of features, the most relevant ones were determined through a survey. By utilizing the cosine similarity algorithm, the research aims to improve the OTT platform recommendation system. This study also seeks to gather data sets using standard pre-processing methods and identify the features that will result in the best recommendations when using the cosine similarity algorithm. The researchers compared different data sets and similarity scores based on various features. The researchers found that the data set with all gathered features had the highest level of similarity and is likely to be used in the recommendation system

Not So Fast Kepler-1513: A Perturbing Planetary Interloper in the Exomoon Corridor

Transit Timing Variations (TTVs) can be induced by a range of physical phenomena, including planet-planet interactions, planet-moon interactions, and stellar activity. Recent work has shown that roughly half of moons would induce fast TTVs with a short period in the range of two-to-four orbits of its host planet around the star. An investigation of the Kepler TTV data in this period range identified one primary target of interest, Kepler-1513 b. Kepler-1513 b is a $8.05^{+0.58}_{-0.40}$ $R_\oplus$ planet orbiting a late G-type dwarf at $0.53^{+0.04}_{-0.03}$ AU. Using Kepler photometry, this initial analysis showed that Kepler-1513 b's TTVs were consistent with a moon. Here, we report photometric observations of two additional transits nearly a decade after the last Kepler transit using both ground-based observations and space-based photometry with TESS. These new transit observations introduce a previously undetected long period TTV, in addition to the original short period TTV signal. Using the complete transit dataset, we investigate whether a non-transiting planet, a moon, or stellar activity could induce the observed TTVs. We find that only a non-transiting perturbing planet can reproduce the observed TTVs. We additionally perform transit origami on the Kepler photometry, which independently applies pressure against a moon hypothesis. Specifically, we find that Kepler-1513 b's TTVs are consistent with an exterior non-transiting $\sim$Saturn mass planet, Kepler-1513 c, on a wide orbit, $\sim$5$\%$ outside a 5:1 period ratio with Kepler-1513 b. This example introduces a previously unidentified cause for planetary interlopers in the exomoon corridor, namely an insufficient baseline of observations.Comment: 20 pages, 13 figures. Accepted to MNRAS. Code available at https://github.com/dyahalomi/Kepler151

Rapid-acting antidepressant drugs modulate affective bias in rats

How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model

A Disintegrating Minor Planet Transiting a White Dwarf

White dwarfs are the end state of most stars, including the Sun, after they exhaust their nuclear fuel. Between 1/4 and 1/2 of white dwarfs have elements heavier than helium in their atmospheres1,2, even though these elements should rapidly settle into the stellar interiors unless they are occasionally replenished3–5. The abundance ratios of heavy elements in white dwarf atmospheres are similar to rocky bodies in the Solar system6,7. This and the existence of warm dusty debris disks8–13 around about 4% of white dwarfs14–16 suggest that rocky debris from white dwarf progenitors’ planetary systems occasionally pollute the stars’ atmospheres17. The total accreted mass can be comparable to that of large asteroids in the solar system1. However, the process of disrupting planetary material has not yet been observed. Here, we report observations of a white dwarf being transited by at least one and likely multiple disintegrating planetesimals with periods ranging from 4.5 hours to 4.9 hours. The strongest transit signals occur every 4.5 hours and exhibit varying depths up to 40% and asymmetric profiles, indicative of a small object with a cometary tail of dusty effluent material. The star hosts a dusty debris disk and the star’s spectrum shows prominent lines from heavy elements like magnesium, aluminium, silicon, calcium, iron, and nickel. This system provides evidence that heavy element pollution of white dwarfs can originate from disrupted rocky bodies such as asteroids and minor planets.Astronom

GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d. It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM. We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice. Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h. Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania

Diazepam impairs place learning in native but not in maze-experienced rats in the Morris water maze.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature