Biology subjects

Gorgievski, V.

Publications and source records attributed to Gorgievski, V..

4 recordsLinked to original sources

bioRxiv2026

2-AG as a potential biomarker for predicting response to short-term fluoxetine treatment in a mouse model of depression

Major depressive disorder (MDD) is a complex psychiatric condition with significant individual and social impact and marked variability in treatment response. Identifying biomarkers that predict antidepressant efficacy remains a major challenge, and metabolomic approaches offer a powerful tool to uncover biochemical changes associated with depression and treatment outcome. The prefrontal cortex and the hippocampus are key brain regions involved in the pathophysiology of MDD and antidepressant response. Fluoxetine, one of the most commonly prescribed antidepressants, influences not only serotonergic signaling but also the endocannabinoid system. Accordingly, evaluating endocannabinoid levels in these brain regions might provide critical insight into their contribution to mood disorders and the effect of fluoxetine. To identify biomarkers associated with early antidepressant response, male mice were exposed for 5 weeks to the unpredictable chronic mild stress (UCMS) protocol, with fluoxetine treatment administered during the final week. Liquid chromatography-tandem mass spectrometry analyses of hippocampal and prefrontal cortex samples revealed that the depression-like phenotype induced by UCMS was associated with increased hippocampal anandamide (AEA) levels. Behavioral improvement following short-term fluoxetine treatment was accompanied by enhanced hippocampal 2-arachidonoylglycerol (2-AG), which was associated with reduced GABA and glutamate levels in the prefrontal cortex. These findings suggest that increased 2-AG levels may serve as a predictor of early response to fluoxetine.

neuroscience↗

bioRxiv2025

Role of oligodendroglial ADAM10 in oligodendrocyte maturation, myelination and myelin maintenance

In the central nervous system, oligodendrocytes extend their processes to wrap axons to form myelin sheaths, ensuring saltatory conduction of action potentials and providing trophic support for the axon. Our previous work demonstrated that pharmacological activation of -secretase promotes myelin protection and remyelination after both ex vivo and in vivo demyelination. Based on these findings, the present study aims to investigate the role of oligodendroglial ADAM10 (OLA10; a member of the a-secretase family) in myelin development and maintenance. Using an inducible knockout mouse model for OLA10 (KOOL-A10), we demonstrated that OLA10 deficiency results in delayed maturation of OPC in primary culture, and altered myelination in primary neuron/glia co-culture. Furthermore, an induction of OLA10 deficiency in adult mice was associated with an alteration of myelin sheath thickness and long-term motor and cognitive deficit in males but not in females. Overall, our study highlights the subtle but significant role of ADAM10 expressed by oligodendrocytes in the formation and maintenance of the myelin over time, while emphasizing a sexual dimorphism that carries important relevance for current research.

neuroscience↗

bioRxiv2024

A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the inherent complexity and heterogeneity of the disease and the "trial and error" approach in choosing the most effective antidepressant treatment for each patient, allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, to cross the blood-brain-barrier, and to be highly sensitive to changes in neuronal activity or activation of various neuronal receptors. Here we present evidence of a brain-enriched circRNA that is regulated by Serotonin 5-HT2A and Brain-Derived Neurotrophic Factor (BDNF) receptor activity and whose expression in the blood can predict response to SSRI treatment. We present data using circRNA-specific PCR in baseline whole blood samples from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) study, showing that before treatment this circRNA is differentially expressed between future responders and non-responders to sertraline. We further show that the expression of this circRNA is upregulated following sertraline treatment and that its trajectory of change post-treatment is associated with long-term remission. Furthermore, we show that the biomarker potential of this circRNA is specific to SSRIs, and not associated with prediction of response or remission after Placebo or Bupropion treatment. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting that the same circRNA is enriched in the brain and is regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.

neuroscience↗

bioRxiv2023

Behavioral and transcriptomic changes following brain-specific loss of noradrenergic transmission.

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific Vesicular Monoamine Transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the DBH gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the Synaptic Vesicle Glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat.

neuroscience↗