Tumoroid-On-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening.

Employing three-dimensional (3D) in vitro models, including tumor organoids and spheroids, stands pivotal in enhancing cancer therapy. These models bridge the gap between two-dimensional (2D) cell cultures and complex in vivo environments and offer versatile tools for comprehensive studies into cancer progression, drug responses, and tailored therapies. This study introduces the Tumoroid-on-a-Plate (ToP) device, an innovative ope-surface microfluidic platform designed to create predictive 3D models of solid tumors.

A single intravenous reelin injection restores corticosterone-induced neurochemical and behavioral alterations in dams during the post-partum period.

Introduction: Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD).

Methods: This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD.

Chronic corticosterone exposure in rats induces sex-specific alterations in hypothalamic reelin fragments, MeCP2, and DNMT3a protein levels.

Women are disproportionately affected by stress-related disorders like depression. In our prior research, we discovered that females exhibit lower basal hypothalamic reelin levels, and these levels are differentially influenced by chronic stress induced through repeated corticosterone (CORT) injections. Although epigenetic mechanisms involving DNA methylation and the formation of repressor complexes by DNA methyl-transferases (DNMTs) and Methyl-CpG binding protein 2 (MeCP2) have been recognized as regulators of reelin expression in vitro, there is limited understanding of the impact of stress on the epigenetic regulation of reelin in vivo and whether sex differences exist in these mechanisms.

Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress.

There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose.

Molecular Mechanisms of Reelin in the Enteric Nervous System and the Microbiota-Gut-Brain Axis: Implications for Depression and Antidepressant Therapy.

Current pharmacological treatments for depression fail to produce adequate remission in a significant proportion of patients. Increasingly, other systems, such as the microbiome-gut-brain axis, are being looked at as putative novel avenues for depression treatment. Dysbiosis and dysregulation along this axis are highly comorbid with the severity of depression symptoms.

Reelin Rescues Behavioral, Electrophysiological, and Molecular Metrics of a Chronic Stress Phenotype in a Similar Manner to Ketamine.

Over the past decade, ketamine, an NMDA receptor antagonist, has demonstrated fast-acting antidepressant effects previously unseen with monoaminergic-based therapeutics. Concerns regarding psychotomimetic effects limit the use of ketamine for certain patient populations. Reelin, an extracellular matrix glycoprotein, has shown promise as a putative fast-acting antidepressant in a model of chronic stress.

Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress.

Reelin, an extracellular matrix protein with putative antidepressant-like properties, becomes dysregulated by chronic stress. Improvement in cognitive dysfunction and depression-like behavior induced by chronic stress has been reported with both intrahippocampal and intravenous Reelin treatment but the mechanisms responsible are not clear. To determine if treatment with Reelin modifies chronic stress-induced dysfunction in immune organs and whether this relates to behavioral and/or neurochemical outcomes, spleens were collected from both male (n = 62) and female (n = 53) rats treated with daily corticosterone injections for three weeks that received Reelin or vehicle.

A Scoping Review of Rodent Studies Investigating the Epigenetic Mechanisms in the Brain Underlying the Effects of Diet on Depressive-like Behaviour.

A healthy diet has been highly associated with a decreased risk for mental health problems such as major depression. Evidence from human studies shows that diet can influence mood but there is a poor understanding of the molecular mechanisms behind these effects, especially the role of epigenetic alterations in the brain. Our objective was to use the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) format to gather all recent studies using animal models that investigate direct or indirect (on the offspring) effects of diet on depressive symptoms, including studies that assess epigenetic mechanisms in the brain.

Sex differences in basal reelin levels in the paraventricular hypothalamus and in response to chronic stress induced by repeated corticosterone in rats.

Repeated exposure to the stress hormone corticosterone results in depressive-like behaviours paralleled by the downregulation of hippocampal reelin expression. Reelin is expressed in key neural populations involved in the stress response, but whether its hypothalamic expression is sex-specific or involved in sex-specific vulnerability to stress is unknown. Female and male rats were treated with either daily vehicle or corticosterone injections (40 mg/kg) for 21 days.

Reelin has antidepressant-like effects after repeated or singular peripheral injections.

Chronic stress is a significant risk factor for depression onset. The effects of chronic stress can be studied preclinically using a corticosterone (CORT)-administration paradigm that results in a phenotype of depressive-like behavior associated with neurochemical abnormalities in brain regions like the hippocampus. We have recently shown that intrahippocampal infusions of Reelin have a fast effect in normalizing CORT-induced behavioral and neurochemical alterations.

The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression.

Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. MeCP2 has mainly been studied for its role in neurodevelopmental disorders, but alterations in MeCP2 are also present in stress-related disorders such as major depression.

Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road.

Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development.

Patient oriented research in mental health: matching laboratory to life and beyond in Canada.

As patient-oriented research gains popularity in clinical research, the lack of patient input in foundational science grows more evident. Research has shown great utility in active partnerships between patient partners and scientists, yet many researchers are still hesitant about listening to the voices of those with lived experience guide and shape their experiments. Mental health has been a leading area for patient movements such as survivor-led research, however the stigma experienced by these patients creates difficulties not present in other health disciplines.

Altered acoustic startle, prepulse facilitation, and object recognition memory produced by corticosterone withdrawal in male rats.

The symptoms of human depression often include cognitive deficits. However, cognition is not frequently included in the behavioral assessments conducted in preclinical models of depression. For example, it is well known that repeated corticosterone (CORT) injections in rodents produce depression-like behavior as measured by the forced swim test, sucrose preference test, and tail suspension test, but the cognitive impairments produced by repeated CORT have not been thoroughly examined.

Severe life stress, mitochondrial dysfunction, and depressive behavior: A pathophysiological and therapeutic perspective.

Mitochondria are responsible for providing our cells with energy, as well as regulating oxidative stress and apoptosis, and considerable evidence demonstrates that mitochondria-related alterations are prevalent during chronic stress and depression. Here, we discuss how chronic stress may induce depressive behavior by potentiating mitochondrial allostatic load, which ultimately decreases energy production, elevates the generation of harmful reactive oxygen species, damages mitochondrial DNA and increases membrane permeability and pro-apoptotic factor release. We also discuss how mitochondrial insults can exacerbate the immune response, contributing to depressive symptomology.

Ketamine Rescues Hippocampal Reelin Expression and Synaptic Markers in the Repeated-Corticosterone Chronic Stress Paradigm.

Depression is the leading cause of disability worldwide, which necessitates novel therapeutics and biomarkers to approach treatment of this neuropsychiatric disorder. To assess potential mechanisms underlying the fast-acting antidepressant actions of ketamine we used a repeated corticosterone paradigm in adult male rats to assess the effects of ketamine on reelin-positive cells, a protein largely implicated in the pathophysiology of depression. We also assessed the effects of reelin and ketamine on hippocampal and cerebellar synpatosomes, and on serotonin transporter clustering in peripheral lymphocytes to determine reelin and ketamine's impact at the synaptic and peripheral levels.

Cyclical administration of corticosterone results in aggravation of depression-like behaviors and accompanying downregulations in reelin in an animal model of chronic stress relevant to human recurrent depression.

Depression is recognized as a highly chronic and recurrent disorder. Each successive episode increases susceptibility to future relapses. The current study aimed to develop an animal model of chronic stress relevant to human recurrent depression in order to examine possible neurobiological mechanisms behind this increased vulnerability.

Fast-acting antidepressant-like effects of Reelin evaluated in the repeated-corticosterone chronic stress paradigm.

The present report examines the effects of repeated or single intrahippocampal Reelin infusions on measures of depressive-like behavior, cognition, and hippocampal neurogenesis in the repeated-corticosterone (CORT) paradigm. Rats received subcutaneous injections of CORT for 3 weeks and Reelin was infused through an inserted canula in the left hippocampus on days 7, 14, and 21, or only on day 21 of CORT injections. CORT increased immobility in the forced-swim test and impaired object-location memory.

Patterns of Membrane Protein Clustering in Peripheral Lymphocytes as Predictors of Therapeutic Outcomes in Major Depressive Disorder.

There is an utmost necessity of developing novel biomarkers of depression that result in a more efficacious use of current antidepressant drugs. The present report reviews and discusses a recent series of experiments that focused on analysis of membrane protein clustering in peripheral lymphocytes as putative biomarkers of therapeutic efficacy for major depressive disorder. This review recapitulates how the ideas were originated, and the main findings demonstrated that analysis of serotonin transporter and serotonin 2 A receptor clustering in peripheral lymphocytes of naïve depression patients resulted in a discrimination of two subpopulations of depressed patients that showed a differential response upon 8 weeks of antidepressant treatment.