Blood Biomarker Signatures for Slow Gait Speed in Older Adults: An Explainable Machine Learning Approach.

Maintaining physical function is crucial for independent living in older adults, with gait speed being a key predictor of health outcomes. Blood biomarkers may potentially monitor older adults' mobility, yet their association with slow gait speed still needs to be explored. This study aimed to investigate the relationship between blood biomarkers and gait speed using the Midlife in the United States (MIDUS) study biomarker dataset.

Pharmacokinetic validation of a new protocol of chronic oral administration of aripiprazole in male C57 Bl/6 mice through drinking solution.

Schizophrenia is a chronic mental illness, with a prevalence of about 1%. The symptoms are classified in three categories: positive symptoms, negative symptoms and deficits in cognitive function. Regarding the pharmacological treatment, current antipsychotics mainly improve positive symptoms while negative and cognitive symptoms remain inadequately treated.

Synthesis, in vitro and in vivo biological evaluation of novel dual compounds targeting both acetylcholinesterase and serotonergic 5-HT receptors with potential interest in the treatment of Alzheimer's disease.

In this work, we exemplified the "copride" family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT receptors, with anti-amnesiant and promnesiant activities in mice. Twenty-one analogs of donecopride, the first-in class representative of the series, were synthesized exploring the influence on the biological activities of the substituents (methoxy, amine and chlorine) carried by its phenyl ring. This work was the support of an intensive structure-activity relationship study and allowed to obtain some interesting derivatives of donecopride.

A new 2-hit model combining serine racemase deletion and maternal separation displays behavioral and cognitive deficits associated with schizophrenia.

Schizophrenia (SCZ) is a multifactorial psychotic disorder characterized by positive and negative symptoms as well as cognitive impairments. To advance the current treatments, it is important to improve animal models by considering the multifactorial etiology, thus by combining different risk factors. The objective of our study was to explore in a new mouse model, the impact of genetic deletion of serine racemase (genetic vulnerability) combined with an early stress factor induced by maternal separation (early environmental exposure) in the context of SCZ development.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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 D and D receptors.

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 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.

Serine Racemase Deletion Affects the Excitatory/Inhibitory Balance of the Hippocampal CA1 Network.

d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies.

Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT 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-HT receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors.

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.