The mediating role of lower body muscle strength and IGF-1 level in the relationship between age and cognition. A MIDUS substudy.

OBJECTIVE: Aging is a natural process associated with a decline in cognition. However, the mediating effect of physical function and circulating myokines on this relationship has yet to be fully clarified. This study investigated how muscle strength and circulating insulin-like growth factor-1 (IGF-1) levels mediate the relationship between age and cognitive functions. SUBJECTS AND METHODS: A total of 1255 participants aged 25-74 years included in the Midlife in the United States II study were retrospectively analyzed. In this cross-sectional analysis, we applied a serial mediation model to explore the mediating effects of muscle strength and circulating IGF-1 levels on the relationship between age and cognitive functions. We included potential confounding factors related to sociodemographics, lifestyle, and health status as covariates in the model. RESULTS: The results showed that aging had both direct and indirect effects on cognition. As predicted, muscle strength and IGF-1 levels mediated the relationship between age and specific cognitive functions. In addition, mediation analyses indicated that the association between aging and cognitive flexibility, immediate and delayed memory, and inductive reasoning were partially mediated by muscle strength and IGF-1 levels in a serial manner. CONCLUSIONS: Our study demonstrated the serial multiple mediation roles of muscle strength and IGF-1 levels on the relationship between age and specific cognitive functions. Further longitudinal research should be performed to confirm the serial mediation results.

Vulnerability of Spatial Pattern Separation in 5xFAD Alzheimer's Disease Mouse Model.

Background: Alzheimer's disease (AD) is the most common cause of dementia and remains incurable. This age-related neurodegenerative disease is characterized by an early decline in episodic and spatial memory associated with progressive disruption of the hippocampal functioning. Recent clinical evidence suggests that impairment of the spatial pattern separation (SPS) function, which enables the encoding and storage of episodic spatial information, may be an indicator of the early stages of AD. Objective: The aim of our study was to characterize SPS performance at a prodromal stage in 5xFAD transgenic mouse model of AD. Methods: Behavioral performance of male wild-type (WT) and 5xFAD mice (n = 14 per group) was assessed from the age of 4 months in two validated paradigms of SPS function either based on spontaneous exploration of objects or on the use of a touchscreen system. Results: Compared with age-matched WT littermates, a mild deficit in SPS function was observed in the object recognition task in 5xFAD mice, whereas both groups showed similar performance in the touchscreen-based task. These results were observed in the absence of changes in locomotor activity or anxiety-like behavior that could have interfered with the tasks assessing SPS function. Conclusions: Our results indicate an early vulnerability of the SPS function in 5xFAD mice in the paradigm based on spontaneous exploration of objects. Our work opens up the possibility of examining the early neurobiological processes involved in the decline of episodic memory and may help to propose new therapeutic strategies in the context of AD.

A Dual-Task Paradigm Combining Physical and Cognitive Training in Mice: Application to Aging.

Physical Activity (PA) is often associated with better overall health status, especially in older adults. Numerous pieces of evidence indicate that PA would be more beneficial when applied in conjunction with Cognitive Training (CT) either simultaneously (i.e., in Dual-Task [DT]) or sequentially. Nonetheless, the underlying mechanisms of such benefits remain elusive. To help delve deeper into their understanding, we developed a cognitive-motor DT paradigm in young adult mice and subsequently tested its effect in old age. Three groups of young adults C57BL/6J mice (3.5 months of age; n=10/group) were required. They were given cognitive tasks, either alone (Control) or in combination with PA which was administered either sequentially (SeqT group) or simultaneously (DT group). Mice were trained in a touchscreen chamber: first on a Visual Discrimination (VD) learning task, then on its Reversal (RVD) which assesses cognitive flexibility alongside procedural learning. PA was given through a homemade treadmill, designed to fit in the touchscreen chambers and set at 9 m/min. Fourteen months later, we further evaluated the effects of PA administered in both DT and SeqT groups, on the performance of the now 19-month-old mice. When compared to SeqT and control groups, DT mice significantly displayed better procedural learning in both VD and RVD tasks as young adults. In the RVD task, this enhanced performance was associated with both poorer inhibition and motor performance. Finally, in 19-month-old mice, both DT and SeqT mice displayed better motor and cognitive performances than control mice. This new cognitive-motor DT paradigm in mice yields an interesting framework that should be useful for adapting DT training in aging, including providing knowledge on the neurobiological correlates, to get the most out of its benefits.

The 3-hit animal models of schizophrenia: Improving strategy to decipher and treat the disease?

Schizophrenia is a complex disease related to combination and interactions between genetic and environmental factors, with an epigenetic influence. After the development of the first mono-factorial animal models of schizophrenia (1-hit), that reproduced patterns of either positive, negative and/or cognitive symptoms, more complex models combining two factors (2-hit) have been developed to better fit with the multifactorial etiology of the disease. In the two past decades, a new way to design animal models of schizophrenia have emerged by adding a third hit (3-hit). This review aims to discuss the relevance of the risk factors chosen for the tuning of the 3-hit animal models, as well as the validities measurements and their contribution to schizophrenia understanding. We intended to establish a comprehensive overview to help in the choice of factors for the design of multiple-hit animal models of schizophrenia.

Micropipette-guided Drug Administration (MDA) as a non-invasive chronic oral administration method in male rats.

BACKGROUND: In preclinical studies resorting to rodents, the effects of prolonged oral intake of active substances are difficult to evaluate. Indeed, to get closer to clinical reality, oral gavage (OG) is frequently used but the repetition of administrations induces risks of lesions of the digestive tract, and stress for animals which can compromise the quality of the results. NEW METHOD: This study describes the development of a non-invasive oral administration method in male Sprague Dawley rats, as a safe alternative of OG, more faithful to clinical reality and limiting biases in pharmacokinetics and/or pharmacodynamics interpretation. Micropipette-guided Drug Administration (MDA) is based on the administration by micropipette of a sufficiently palatable vehicle for the animals to voluntarily take its contents. RESULTS: MDA was not demonstrated as less stressful than OG. A pharmacokinetics equivalence between MDA and OG was demonstrated for pregabalin administration but not for aripiprazole. Despite the use of a sweet vehicle, the MDA method does not result in weight gain or significant elevation of blood glucose and fructosamines level. Regarding the time needed to administrate the solution, the MDA method is significantly faster than OG. COMPARISON WITH EXISTING METHOD(S): Contrastingly to procedures using food or water, this method allows for a rigorous control of the time and dose administered and is delivered in discrete administration windows which is therefore closer to the clinical reality. This method appears particularly suitable for pharmacological evaluation of hydrophilic compounds. CONCLUSIONS: The MDA procedure represents a respectful and adapted pharmacological administration method to study the effects of chronic oral administration in rats.

5-HT6 Receptors Sex-Dependently Modulate Hippocampal Synaptic Activity through GABA Inhibition.

The subtype 6 of the serotoninergic receptors (5-HT6Rs) is highly expressed in the hippocampus, and evidence indicates the beneficial effects of 5-HT6Rs blockade on short- and long-term memory in rodents. Nevertheless, the underlying functional mechanisms still need to be established. To this end, we performed electrophysiological extracellular recordings to assess the effects of the 5-HT6Rs antagonist SB-271046 on the synaptic activity and functional plasticity at the CA3/CA1 hippocampal connections of male and female mice slices. We found that basal excitatory synaptic transmission and isolated N-methyl-D-aspartate receptors (NMDARs) activation were significantly increased by SB-271046. The NMDARs-related improvement was prevented by the GABAAR antagonist bicuculline in male but not in female mice. Regarding synaptic plasticity, neither paired-pulse facilitation (PPF) nor NMDARs-dependent long-term potentiation (LTP) (induced either by high-frequency or theta-burst stimulation) was affected by the 5-HT6Rs blockade. Taken together, our results indicate a sex-dependent 5-HT6Rs effect on synaptic activity at the CA3/CA1 hippocampal connections through changes in the excitation/inhibition balance.

Genetic Background Influence on Hippocampal Synaptic Plasticity: Frequency-Dependent Variations between an Inbred and an Outbred Mice Strain.

For almost half a century, acute hippocampal slice preparations have been widely used to investigate anti-amnesic (or promnesic) properties of drug candidates on long-term potentiation (LTP)-a cellular substrate that supports some forms of learning and memory. The large variety of transgenic mice models now available makes the choice of the genetic background when designing experiments crucially important. Furthermore, different behavioral phenotypes were reported between inbred and outbred strains. Notably, some differences in memory performance were emphasized. Despite this, investigations, unfortunately, did not explore electrophysiological properties. In this study, two stimulation paradigms were used to compare LTP in the hippocampal CA1 area of both inbred (C57BL/6) and outbred (NMRI) mice. High-frequency stimulation (HFS) revealed no strain difference, whereas theta-burst stimulation (TBS) resulted in significantly reduced LTP magnitude in NMRI mice. Additionally, we demonstrated that this reduced LTP magnitude (exhibited by NMRI mice) was due to lower responsiveness to theta-frequency during conditioning stimuli. In this paper, we discuss the anatomo-functional correlates that may explain such hippocampal synaptic plasticity divergence, although straightforward evidence is still lacking. Overall, our results support the prime importance of considering the animal model related to the intended electrophysiological experiments and the scientific issues to be addressed.

Chronotype influence on the effects of COVID-19 lockdown on sleep and psychological status in France.

The present study aims to assess the influence of chronotype on lockdown-induced effects on sleep and psychological outcomes. A total of 1671 participants were recruited in France and filled out online questionnaires about their sleeping hours and sleep quality, their chronotype (morning, intermediate, evening type), and their depressive, anxiety and stress symptoms both retrospectively (before lockdown) and currently (during the lockdown). Statistical analyses estimated the chronotype effect on the impact of the lockdown on sleep and psychological outcomes. Results show that during the lockdown, sleep quality decreased, sleep duration increased, and sleep midpoint was delayed and, while fatigue perception decreased, anxiety and depression increased. The decrease in sleep quality varied according to the participants' chronotype. The evening type's sleep quality decreased the most. A similar chronotype effect was also observed on sleep duration and sleep midpoint. Evening-type participants also increased their depressive symptoms. These results suggest that evening-type individuals have lower resilience to lockdown effect on psychological status and sleep pattern.

Time-course of age-related temporal order memory decline in an object recognition paradigm in mice.

Temporal order memory refers to the ability to remember the order of occurrence of items across time. It is a critical feature of episodic memory that is often tested in rodents using spontaneous object recognition paradigms. However, impact of aging over performances of temporal order memory decline is barely known. Herein, we characterized here the effect of normal aging on the temporal order memory performances in NMRI mice between 3 and 19months of age, with an inter-session interval of 24h.We found that temporal order memory was impaired as soon as7 months of age. These results provide strong evidence that temporal order memory is particularly vulnerable to the deleterious effect of normal aging.

Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

Improved NMDA Receptor Activation by the Secreted Amyloid-Protein Precursor-α in Healthy Aging: A Role for D-Serine?

Impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) by D-serine is linked to cognitive aging. Whether this deregulation may be used to initiate pharmacological strategies has yet to be considered. To this end, we performed electrophysiological extracellular recordings at CA3/CA1 synapses in hippocampal slices from young and aged mice. We show that 0.1 nM of the soluble N-terminal recombinant fragment of the secreted amyloid-protein precursor-α (sAPPα) added in the bath significantly increased NMDAR activation in aged but not adult mice without impacting basal synaptic transmission. In addition, sAPPα rescued the age-related deficit of theta-burst-induced long-term potentiation. Significant NMDAR improvement occurred in adult mice when sAPPα was raised to 1 nM, and this effect was drastically reduced in transgenic mice deprived of D-serine through genetic deletion of the synthesizing enzyme serine racemase. Altogether, these results emphasize the interest to consider sAPPα treatment targeting D-serine-dependent NMDAR deregulation to alleviate cognitive aging.

Memory Disorders Related to Hippocampal Function: The Interest of 5-HT4Rs Targeting.

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level.

Fast Anxiolytic-Like Effect Observed in the Rat Conditioned Defensive Burying Test, after a Single Oral Dose of Natural Protein Extract Products.

Anxiety appears among the most frequent psychiatric disorders. During recent years, a growing incidence of anxiety disorders can be attributed, at least in part, to the modification of our eating habits. To treat anxiety disorders, clinicians use benzodiazepines, which unfortunately display many side effects. Herein, the anxiolytic-like properties of two natural products (αS1-casein hydrolysate and Gabolysat®) were investigated in rats and compared to the efficacy of benzodiazepine (diazepam). Thus, the conditioned defensive burying test was performed after a unique oral dose of 15 mg/kg, at two time-points (60 min and then 30 min post oral gavage) to show potential fast-onset of anxiolytic effect. Both natural products proved to be as efficient as diazepam to reduce the time rats spent burying the probe (anxiety level). Additionally, when investigated as early as 30 min post oral gavage, Gabolysat® also revealed a fast-anxiolytic activity. To date, identification of bioactive peptide, as well as how they interact with the gut-brain axis to sustain such anxiolytic effect, still remains poorly understood. Regardless, this observational investigation argues for the consideration of natural compounds in care pathway.

Combination of MAP6 deficit, maternal separation and MK801 in female mice: A 3-hit animal model of neurodevelopmental disorder with cognitive deficits.

Schizophrenia is a major psychiatric disease still lacking efficient treatment, particularly for cognitive deficits. To go further in research of new treatments that would encompass all the symptoms associated with this pathology, preclinical animal models need to be improved. To date, the aetiology of schizophrenia is unknown, but there is increasing evidence to highlight its multifactorial nature. We built a new neurodevelopmental mouse model gathering a triple factor combination (3-M): a genetic factor (partial deletion of MAP6 gene), an early stress (maternal separation) and a late pharmacological factor (MK801 administration, 0.05 mg/kg, i.p., daily for 5 days). The effects of each factor and of their combination were investigated on several behaviours including cognitive functions. While each individual factor induced slight deficits in one or another behavioural test, 3-M conditioning induces a wider phenotype with hyperlocomotion and cognitive deficits (working memory and social recognition). This study confirms the hypothesis that genetic, environmental and pharmacological factors, even if not deleterious by themselves, could act synergistically to induce a deleterious behavioural phenotype. It moreover encourages the use of such combined models to improve translational research on neurodevelopmental disorders.

Effects of chronic tramadol administration on cognitive flexibility in mice.

RATIONALE: Tramadol is widely used for pain relief especially in seniors. However, long-term use of tramadol has serious adverse effects, including cognitive impairment. Besides its memory effects, already demonstrated in animals, a recent clinical report suggests that tramadol could also affect executive function in seniors. Several studies have hypothesized that the anti-muscarinic properties of tramadol could be responsible for the deleterious effects of tramadol on cognition. OBJECTIVES: We aimed at investigating the effects of chronic administration of tramadol on cognitive flexibility in adult male mice, as assessed by a visual discrimination reversal task using a touchscreen device. The effects of tramadol were further compared to those of scopolamine, a reference muscarinic antagonist. RESULTS: We found that, during the early phase of the reversal task, when cognitive flexibility is most in demand, both tramadol-treated mice (20 mg/kg, s.c., twice a day) and scopolamine-treated mice (0.5 mg/kg, s.c., twice a day) needed more correction trials and showed a higher perseveration index than saline-treated mice. Therefore, tramadol affects cognitive flexibility, and its anticholinergic properties could be at least partly involved in these deficits. CONCLUSIONS: In view of these deleterious cognitive effects of tramadol, physicians should be cautious when prescribing this analgesic, especially in seniors who are more vulnerable to adverse drug events and in which alternative prescription should be preferred whenever possible.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.

Functional Dysregulations in CA1 Hippocampal Networks of a 3-Hit Mouse Model of Schizophrenia.

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility-partial deletion of the MAP6 gene, early-life stress-maternal separation, and pharmacological treatment-chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.

Long-Term Music Exposure Prevents Age-Related Cognitive Deficits in Rats Independently of Hippocampal Neurogenesis.

Cognitive decline appears across aging. While some studies report beneficial effects of musical listening and practice on cognitive aging, the underlying neurobiological mechanisms remain unknown. This study aims to determine whether chronic (6 h/day, 3 times/week) and long-lasting (4-8 months) music exposure, initiated at middle age in rats (15 months old), can influence behavioral parameters sensitive to age effects and reduce age-related spatial memory decline in rats. Spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior as well as spatial working and reference memory were assessed in 14-month-old rats and then after 4 and 8 months of music exposure (19 and 23 months old, respectively). Spatial learning and reference memory data were followed up by considering cognitive status of animals prior to music exposure (14 months old) given by K-means clustering of individual Z-score. Hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) level in the hippocampus and frontal cortex were measured. Results show that music exposure differentially rescues age-related deficits in spatial navigation tasks according to its duration without affecting spontaneous locomotor, circadian rhythmic activity, and anxiety-like behavior. Hippocampal cell proliferation as well as hippocampal and frontal cortex BDNF levels was not affected by music across aging. Cognitive improvement by music in aging rats may require distinct neurobiological mechanisms than hippocampal cell proliferation and BDNF.

A new 3-hit mouse model of schizophrenia built on genetic, early and late factors.

Whether the etiology of schizophrenia remains unknown, its multifactorial aspect is conversely now well admitted. However, most preclinical models of the disease still rely on a mono-factorial construction and do not allow discover unequivocal treatments, particularly for negative and cognitive symptoms. The main interaction factors that have been implicated in schizophrenia are a genetic predisposition and unfavorable environmental factors. Here we propose a new animal model combining a genetic predisposition (1st hit: partial deletion of MAP-6 (microtubule-associated protein)) with an early postnatal stress (2nd hit: 24 h maternal separation at post-natal day 9), and a late cannabinoid exposure during adolescence (3rd hit: tetrahydrocannabinol THC from post-natal day 32 to 52; 8 mg/kg/day). The 2-hit mice displayed spatial memory deficits, decreased cortical thickness and fractional anisotropy of callosal fibers. The 3-hit mice were more severely affected as attested by supplementary deficits such a decrease in spontaneous activity, sociability-related behavior, working memory performances, an increase in anxiety-like behavior, a decrease in hippocampus volume together with impaired integrity of corpus callosum fibers (less axons, less myelin). Taken together, these results show that the new 3-hit model displays several landmarks mimicking negative and cognitive symptoms of schizophrenia, conferring a high relevance for research of new treatments. Moreover, this 3-hit model possesses a strong construct validity, which fits with gene x environment interactions hypothesis of schizophrenia. The 2-hit model, which associates maternal separation with THC exposure in wild-type mice gives a less severe phenotype, and could be useful for research on other forms of psychiatric diseases.

Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer's disease.

Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 µM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.