Biology subjects

Miczan, V.

Publications and source records attributed to Miczan, V..

5 recordsLinked to original sources

bioRxiv2026

An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine neuron inputs following prenatal cannabinoid exposure

Dynamic regulation of midbrain dopamine neuron activity is necessary for diverse processes including motivation, novelty detection, reinforcement learning, and cognitive flexibility. By setting the strength of synaptic inputs to dopaminergic neurons, endocannabinoid signaling is essential for regulating dopaminergic activity. Prenatal exposure to {Delta}9-tetrahydrocannabinol (THC), the main psychoactive substance in cannabis, is known to induce abnormal dopaminergic activity and increased susceptibility to psychopathology. However, how prenatal cannabinoid exposure (PCE) affects endocannabinoid-mediated synaptic plasticity of dopamine neurons remains largely unknown. Here, we use a rat model of PCE to directly determine this. We found that endocannabinoid-mediated synaptic plasticity at excitatory synapses on dopamine neurons of the ventral tegmental area (VTA) was absent in PCE male rat offspring, where the presynaptic nanoscale architecture of excitatory afferents onto VTA dopamine neurons was reorganized to impair the control of type-1 cannabinoid receptors on glutamate release. We demonstrate that, in response to postsynaptic depolarization, PCE dopamine cells switch to nitric oxide (NO) rather than endocannabinoid signaling to induce opposing forms of synaptic plasticity at inhibitory and excitatory inputs. We disclosed a NO-dependent long-term potentiation of GABAA-receptor-mediated synaptic transmission, and a long-term depression of glutamatergic synapses requiring presynaptic activation of GABAB-receptors. These PCE-induced reciprocal forms of synaptic plasticity reshape the balance of excitatory and inhibitory control over dopamine neurons, potentially contributing to increased vulnerability to psychiatric disorders.

neuroscience↗

bioRxiv2025

Nanoscale synaptic remodeling at corticostriatal circuits predicts flexible action control

Synaptic plasticity is a fundamental substrate of behavioral adaptation, yet the underlying molecular dynamics remain poorly defined. We tested the hypothesis that, within striatal circuits, flexibility relies on nanoscale remodeling of synaptic machinery coupling anterograde glutamatergic transmission to retrograde endocannabinoid signaling, a process disrupted in states of rigidity and aging. In the dorsolateral striatum, we found cell-type-specific facilitation of metabotropic glutamate receptor 5 (mGlu5)-dependent, endocannabinoid-mediated long-term depression at cortico-striatal synapses of indirect pathway neurons in flexible goal-directed behavior, but not after training promoting inflexibility. Stochastic Optical Reconstruction Microscopy (STORM) super-resolution imaging revealed that behavioral adaptation, but not rigidity, is accompanied by increased postsynaptic abundance of mGlu5 and diacylglycerol lipase- (DAGL), an endocannabinoid-synthesizing enzyme, and presynaptic CB1 cannabinoid receptors. In parallel, the nanoscale distance between mGlu5 and DAGL is reduced in postsynaptic spine heads. These nanoscale changes emerged within the time window required for behavioral updating. Intriguingly, the molecular densities of mGlu5, DAGL, and CB1 receptors predict the strength of behavioral adaptation. In aging mice, these nanoscale changes were absent in association with behavioral rigidity. These findings identify a nanoscale synaptic remodeling mechanism that enables behavioral flexibility and reveal how its failure contributes to rigidity, including that observed in aging.

neuroscience↗

bioRxiv2025

Subphase-Labeled Mitotic Dataset for AI-powered Cell Division Analysis

Mitosis detection represents a critical task in the field of digital pathology, as determination of the mitotic index (MI) plays an important role in the tumor grading and prognostic assessment of patients. Manual determination of MI is a labor-intensive and time-consuming task for practitioners with rather high interobserver variability, thus, automation has become a priority. There has been substantial progress towards creating robust mitosis detection algorithms in recent years, primarily driven by the Mitosis Domain Generalization (MIDOG) challenges. In parallel, there has been growing interest in the molecular characterization of mitosis with the goal of achieving a more comprehensive understanding of its underlying mechanisms in a subphase-specific manner. Here, we introduce a new mitotic figure dataset annotated with subphase information based on the MIDOG++ dataset as well as a previously unrepresented tumor domain to enhance the diversity and applicability of the dataset. We envision a new perspective for domain generalization by improving the performance of models with subtyping mitotic cells into the 5 main stages of normal mitosis, complemented with an atypical mitotic class. We believe that our work broadens the horizon in digital pathology: subtyping information could provide useful help for mitosis detection, while also providing promising new directions in answering biological questions, such as molecular analysis of the subphases on a single cell level.

bioinformatics↗

bioRxiv2025

A Morpho-Proteomic Atlas of Mitosis at Sub-Minute Resolution

Precise spatiotemporal protein organization is critical for fundamental biological processes including cell division1,2. Indeed, aberrant mitosis and mitotic factors are involved in diverse diseases, including various cancers3,4, Alzheimers disease5, and rare diseases6. During mitosis, complex spatial rearrangements and regulation ensure the accurate separation of replicated sister chromatids to produce genetically identical daughter cells7-9. Previous studies employed high-throughput methodologies to follow specific proteins during mitosis10-15. Still a temporally refined systems-level approach capable of monitoring morphological and proteomic changes throughout mitosis has been lacking. Here, we achieved unprecedented resolution by phenotypically decomposing mitosis into 40 subsections of a regression plane for proteomic analysis using deep learning and regression techniques. Our deep visual proteomics (DVP) workflow16, revealed rapid, dynamic proteomic changes throughout mitosis. We quantified 4,350 proteins with high confidence, demonstrating that 147 show significant dynamic abundance changes during mitotic progression. Clustering revealed coordinated patterns of protein regulation, while network analysis uncovered tight regulation of core cell cycle proteins and a link between cell cycle and cancer-linked mutations. Immunofluorescence validated abundance changes and linked previously uncharacterised proteins, like C19orf53, to mitosis. To facilitate data navigation, we developed Mito-Omix, a user-friendly online platform that integrates intricate morphological and molecular data. Our morphological and proteomic dataset spans mitosis at high resolution, providing a rich resource for understanding healthy and aberrant cell division.

cell biology↗

bioRxiv2019

ABHD4-dependent developmental anoikis protects the prenatal brain from pathological insults

In light of the astronomical number of cell divisions taking place in restricted neurogenic niches, brain malformations caused by ectopic proliferation of misplaced progenitor cells are surprisingly rare. Here, we show that a process we term developmental anoikis distinguishes the abnormal detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. By using in vivo gain-of-function, loss-of-function, and rescue manipulations together with correlated confocal and super-resolution imaging, we identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of abnormally detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults.

developmental biology↗