Studying some neuroprotective effects of Calotropis procera extracts against scopolamine- induced neuropschiatric comorbidities in a rodent model of epilepsy

Many plants are largely used in alternative medicine of Burkina Faso for neuropsychiatric disorders treatment. However, their neuro-pharmacological properties are less evaluated through scientific studies. The present study aims to evaluate the neuroprotective effect of Calotropis procera leaves and root-bark aqueous extract, focusing on a scopolamine-induced model of epilepsy in rodents. In this study, we evaluated this plant extracts possible protective effects on the central nervous system, through the behavioral tests and the enzymes activity assays. Thus, elevated plus-maze test and Y-maze task were used to evaluate animals behavioral and UV/visible spectrophotometer methods were used to evaluate the enzyme’s activities in brain’s supernatant. Our results are showing no significant protective effects of leaves extract, but it revealed a significant neuroprotective effect of root-bark aqueous extract, as well as in the behavioral tests and the brain’s oxidative enzymes specific activity evaluation. Indeed, anti-amnesic and anxiolytic activities were observed through Y maze task and elevated plus maze tests for the groups of animals receiving root-bark extract (100 mg/kg b.w.). In these test, inhibition of disturbances of Time spent in Open Arms, Spontaneous Alternation, and Transfer Latency induced after scopolamine administration were recorded with animals received root-bark extract. Likewise, the superoxide dismutase and catalase activity disturbance induced by scopolamine were also inhibited in root-bark extract pre-administered group. Thus, our study provides biochemical and neuro-pharmacological data for traditional use of C. procera for neuropsychiatric disorders treatment, including scopolamine-induced epilepsy symptoms (mainly referring to the psychiatric comorbidities of this disorder).

What do zebrafish prefer? Directional and color preferences in maze tasks

Studies regarding the animals innate preferences help elucidate and avoid probable sources of bias and serve as a reference to improve and develop new behavioral tasks. In zebrafish research, the results of innate directional and color preferences are often not replicated between research groups or even inside the same laboratory raising huge concerns on the replicability and reproducibility. Thus, this study aimed to investigate the male and female zebrafish innate directional and color preferences in the plus-maze and T-maze behavioral tasks. As revealed by the percentage of time spent in each zone of the maze, our results showed that males and females zebrafish demonstrated no difference in directional preference in the plus-maze task. Surprisingly, male and female zebrafish showed color preference differences in the plus-maze task; males did not show any color preference, while female zebrafish demonstrated a red preference compared to white, blue, and yellow colors. Moreover, both male and female zebrafish demonstrated a strong black color preference compared to the white color in the T-maze task. Thus, our results demonstrate the importance of innate preference assays involved with the directionality of the apparatus or the application of colors as a screening process conducting behavioral tests (e.g., anxiety, learning and memory assessment, locomotion, and preference) and highlight the need to analyze sex differences.

Potential improvements of the cognition of piglets through a synbiotic supplementation from 1 to 28 days via the gut microbiota

The influence of feed supplements on behavior and memory has been recently studied in livestock. The objectives of the study were to evaluate the effects of a synbiotic on: an episodic-like (SOR: Spontaneous Object Recognition), a working (BARR: Fence barrier task), a long-term (TMAZE: Spatial T-maze task) memory test and on gut microbiota composition. Eighteen female piglets were supplemented from 1 to 28 days of age with a synbiotic (SYN), while 17 served as control (CTL). Feces were collected on days 16, 33 and 41 for 16S rRNA gene composition analyses. In the SOR, SYN piglets interacted more quickly with the novel object than CTL piglets. In the BARR, SYN piglets had shorter distances to finish the test in trial 3. In the TMAZE, SYN piglets were quicker to succeed on specific days and tended to try the new rewarded arm earlier during the reversal stage. Difference of microbiota composition between treatments was nonexistent on D16, a tendency on D33 and significant on D41. The synbiotic supplement may confer memory advantages in different cognitive tasks, regardless of the nature of the reward and the memory request. Difference in memory abilities can potentially be explained by differences in microbiota composition.

Autonomic Modulation in Duchenne Muscular Dystrophy During a Computer Task: A Prospective Transversal Controlled Trial Assessment by Non-linear Techniques

Introduction: Due to functional and autonomic difficulties faced by individuals with Duchenne Muscular Dystrophy (DMD), the use of assistive technology is critical to provide or facilitate functional abilities. The key objective was to investigate acute cardiac autonomic responses, by application of Heart Rate Variability (HRV), during computer tasks in subjects with DMD via techniques based on non-linear dynamics.Method: HRV was attained via a Polar RS800CX. Then, was evaluated by Chaotic Global Techniques (CGT). Forty-five male subjects were included in the DMD group and age-matched with 45 in the healthy Typical Development (TD) control group. They were assessed for 20 min at rest sitting, and then 5 min whilst performing the maze task on a computer.Results: Both TD and DMD subjects exhibited a significantly reduced HRV measured by chaotic global combinations when undertaking the computer maze paradigm tests. DMD subjects presented decreased HRV during rest and computer task than TD subjects.Conclusion: While there is an impaired HRV in subjects with DMD, there remains an adaptation of the ANS during the computer tasks. The identification of autonomic impairment is critical, considering that the computer tasks in the DMD community may elevate their level of social inclusion, participation and independence.

Limits on semantic prediction in the processing of extraction from adjunct clauses

Processing filler-gap dependencies (‘extraction’) depends on complex top-down predictions. This is observed in comprehenders’ ability to avoid resolving filler-gap dependencies in syntactic island contexts, and in the immediate sensitivity to the plausibility of the resulting interpretation. How complex can these predictions be? In this paper, we examine the processing of extraction from adjunct clauses. Adjunct clauses are argued to be syntactic islands, however, extraction is permitted if the adjunct clause and main clause satisfy specific compositional and conceptual semantic criteria. In an acceptability judgment task, we found that this generalization is robust. Additionally, our results show that this is a property specific to adjunct clauses by comparing adjunct clauses to conjunct VPs, which are similarly argued to permit extraction depending on semantic factors. However, in an A-Maze task, we found no evidence that this knowledge is deployed in real-time sentence processing. Instead, we found that comprehenders attempted to resolve a filler-gap dependency in an adjunct clause regardless of its island status. We propose that this is because deploying this linguistic constraint depends on a second-order serial search over event schemata, which is likely costly and time-consuming. Thus, comprehenders opt for a riskier strategy and attempt resolution into adjunct clauses categorically.

Voluntary oral methamphetamine increases memory deficits and contextual sensitization during abstinence associated with decreased PKMζ and increased κOR in the hippocampus of female mice

Background: Female populations exhibit vulnerabilities to psychostimulant addiction, as well as cognitive dysfunction following bouts of abuse. Aims: The goal for this study was to advance our understanding of the mechanisms that produce sex disparities in drug addiction. Methods: We used an animal model for voluntary oral methamphetamine administration (VOMA) and focused on male and female mice that consumed 7.6–8.2 mg/kg of methamphetamine (MA) per day during the last 18 days of the paradigm. Results: The VOMA-exposed female mice displayed increased locomotor activity in the drug-administration context compared to male mice, demonstrating sex-specific changes in contextual sensitization. During 2 weeks of forced abstinence, mice underwent further behavioral testing. We show that abstinence increased open-arm entries on the elevated plus maze in both sexes. There were no differences in immobility on the tail suspension test. In a hippocampal-dependent radial arm maze task, VOMA-treated female mice, but not male mice, showed working memory deficits. Hippocampal tissue was collected and analyzed using Western blotting. VOMA-exposed female mice exhibited increased kappa opioid receptor (κOR) expression in the hippocampus compared to male mice, suggesting a vulnerability toward abstinence-induced dysphoria. Female VOMA mice also exhibited a decrease in the memory protein marker, protein kinase M zeta (PKMζ), in the hippocampus. Conclusions: Our study reveals sex-specific effects following abstinence from chronic MA consumption on hippocampal κOR and PKMζ expression, suggesting that these neural changes in female mice may underlie spatial memory deficits and identify an increased susceptibility to dysregulated neural mechanisms. These data validate VOMA as a model sensitive to sex differences in behavior and hippocampal neurochemistry following chronic MA exposure.

Transferrin-Pep63-liposomes accelerate the clearance of Aβ and rescue impaired synaptic plasticity in early Alzheimer’s disease models

Alzheimer’s disease (AD) is characterized by aberrant accumulation of extracellular β-amyloid (Aβ) peptides in the brain. Soluble Aβ oligomers are thought to be the most neurotoxic species and are correlated with cognitive dysfunction in early AD. However, there is still no effective treatment so far. We determined that Pep63, a small peptide, had a neuroprotective effect on synaptic plasticity and memory in our previous study. Here, we developed novel and multifunctional liposomes targeting both Aβ oligomers and fibrils based on a liposome delivery system. Transferrin-Pep63-liposomes (Tf-Pep63-Lip), possessing the ability for blood-brain barrier targeting, were also incorporated with phosphatidic acid (PA) and loaded with neuroprotective Pep63. We discovered that administration of Tf-Pep63-Lip could significantly reduce the Aβ burden in the hippocampus, and improve cognitive deficits in 6-month-old APP/PS1 mice in the Morris-Water maze task and fear-conditioning test with the combined effects of PA and Pep63. Tf-Pep63-Lip could capture Aβ oligomers or fibrils and then facilitated microglial chemotaxis nearby for clearance. Simultaneously, Tf-Pep63-Lip hindered Aβ1-42 aggregation and disaggregated Aβ1-42 assembly due to multivalent PA-Aβ. Pep63 effectively inhibited the binding between EphB2 and Aβ oligomers after release from liposomes and rescued NMDA receptors trafficking, the basis of synaptic plasticity. No side effects were observed in either APP/PS1 or wild-type mice, indicating that Tf-Pep63-Lip might be safe under the dosing regimen used in our experiment. Taken together, our results suggested that Tf-Pep63-Lip may serve as a safe and efficient agent for AD combination therapy.

Energizing effects of bupropion on effortful behaviors in mice under positive and negative test conditions: modulation of DARPP-32 phosphorylation patterns

Motivational symptoms such as anergia, fatigue, and reduced exertion of effort are seen in depressed people. To model this, nucleus accumbens (Nacb) dopamine (DA) depletions are used to induce a low-effort bias in rodents tested on effort-based decision-making. We evaluated the effect of the catecholamine uptake blocker bupropion on its own, and after administration of tetrabenazine (TBZ), which blocks vesicular storage, depletes DA, and induces depressive symptoms in humans. Male CD1 mice were tested on a 3-choice-T-maze task that assessed preference between a reinforcer involving voluntary physical activity (running wheel, RW) vs. sedentary activities (sweet food pellet intake or a neutral non-social odor). Mice also were tested on the forced swim test (FST), two anxiety-related measures (dark–light box (DL), and elevated plus maze (EPM)). Expression of phosphorylated DARPP-32 (Thr34 and Thr75) was evaluated by immunohistochemistry as a marker of DA-related signal transduction. Bupropion increased selection of RW activity on the T-maze. TBZ reduced time running, but increased time-consuming sucrose, indicating an induction of a low-effort bias, but not an effect on primary sucrose motivation. In the FST, bupropion reduced immobility, increasing swimming and climbing, and TBZ produced the opposite effects. Bupropion reversed the effects of TBZ on the T-maze and the FST, and also on pDARPP32-Thr34 expression in Nacb core. None of these manipulations affected anxiety-related parameters. Thus, bupropion improved active behaviors, which were negatively motivated in the FST, and active behaviors that were positively motivated in the T-maze task, which has implications for using catecholamine uptake inhibitors for treating anergia and fatigue-like symptoms.

Potentiation of cognitive enhancer effects of Alzheimer’s disease medication memantine by alpha7 nicotinic acetylcholine receptor agonist PHA-543613 in the Morris water maze task

Rationale There are controversial pieces of evidence whether combination therapies using memantine and cholinesterase inhibitors are beneficial over their monotreatments. However, results of preclinical studies are promising when memantine is combined with agonists and allosteric modulators of the alpha7 nicotinic acetylcholine receptor (nAChR). Objectives Here, we tested the hypothesis that cognitive enhancer effects of memantine can be potentiated through modulating alpha7 nAChRs in a scopolamine-induced amnesia model. Methods Monotreatments, as well as co-administrations of selective alpha7 nicotinic acetylcholine receptor agonist PHA-543613 and memantine were tested in the Morris water maze task in rats. The efficacy of the co-administration treatment was observed on different domains of spatial episodic memory. Results Low dose of memantine (0.1 mg/kg) and PHA-543613 (0.3 mg/kg) successfully reversed scopolamine-induced short-term memory deficits both in monotreatments and in co-administration. When recall of information from long-term memory was tested, pharmacological effects caused by co-administration of subeffective doses of memantine and PHA-543613 exceeded that of their monotreatments. Conclusion Our results further support the evidence of beneficial interactions between memantine and alpha7 nAChR ligands and suggest a prominent role of alpha7 nAChRs in the procognitive effects of memantine.

Lateral Habenula Inactivation Alters Willingness to Exert Physical Effort Using a Maze Task in Rats

An impairment in willingness to exert physical effort in daily activities is a noted aspect of several psychiatric conditions. Previous studies have supported an important role for the lateral habenula (LHb) in dynamic decision-making, including decisions associated with discounting costly high value rewards. It is unknown whether a willingness to exert physical effort to obtain higher rewards is also mediated by the LHb. It also remains unclear whether the LHb is critical to monitoring the task contingencies generally as they change, or whether it also mediates choices in otherwise static reward environments. The present study indicates that the LHb might have an integrative role in effort-based decision-making even when no alterations in choice contingencies occur. Specifically, pharmacological inactivation of the LHb showed differences in motivational behavior by reducing choices for the high effort (30cm barrier) high reward (2 pellets) choice versus the low effort (0 cm) low reward (1 pellet) choice. In sessions where the barrier was removed, rats demonstrated a similar preference for the high reward arm under both control and LHb inactivation. Further, no differences were observed when accounting for sex as a biological variable. These results support that effort to receive a high-value reward is considered on a trial-by-trial basis and the LHb is part of the circuit responsible for integrating this information during decision-making. Therefore, it is likely that previously observed changes in the LHb may be a key contributor to changes in a willingness to exert effort in psychiatric conditions.