Biology subjects

Bobic-Rasonja, M.

Publications and source records attributed to Bobic-Rasonja, M..

3 recordsLinked to original sources

bioRxiv2026

Mild perinatal hypoxia uncouples excitatory-inhibitory circuit maturation and reprograms neocortical organization

Perinatal hypoxia is a major contributor to neurodevelopmental disorders; however, the consequences of mild-to-moderate perinatal hypoxia (MPH) remain insufficiently characterized. Here, we investigated cortical plasticity following MPH using a multimodal approach that combines behavioral assessment, histological analysis, and in vivo magnetic resonance imaging (MRI). Fifty-six Wistar Han rats were exposed to hypoxia or normoxia at postnatal day 1 (P1). Neurodevelopmental assessment from P3 to P14 revealed impaired rooting and vibrissae-placing reflexes in hypoxic rats. Histological analysis demonstrated: altered expression of microtubule-associated protein-2, apical dendrite bundling, reduced neurofilament-H expression, and decreased dendritic arbor complexity in large pyramidal neurons, indicating disrupted maturation of excitatory circuits. Increased parvalbumin expression, higher interneuron density, and its enhanced neurite elaboration indicated precocious development of inhibitory circuits, consistent with a compensatory response. MRI at P15, combined with whole-brain voxel-wise analysis, revealed a significant increase in fractional anisotropy in the anterior cingulate cortex (ACC). Convergent behavioral, histological, and imaging findings identified the ACC as the most vulnerable region following MPH, followed by the somatosensory cortex. These findings reveal early cytoarchitectural and MRI detectable correlates of a single episode of MPH, which, together with previous findings from this model, support the neurodevelopmental origin of persistent alterations in cortical structure and circuit function, characterized by an excitatory-inhibitory imbalance. The study identifies and defines a framework for understanding region-specific vulnerability and plasticity in the immature brain, with implications for improving the early detection of subtle perinatal brain injury, as a prerequisite for timely therapeutic intervention.

neuroscience↗

bioRxiv2022

Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephalic cortical malformation

Actins are structural cytoskeletal proteins playing crucial roles in multiple cellular processes. Mutations in the ACTB and ACTG1 genes, encoding the ubiquitous beta- and gamma- cytoskeletal actin isoforms, respectively, cause a broad spectrum of neurodevelopmental disorders, with microcephaly as the most frequent one. Here we used patient-derived cerebral organoids to gain insight into the pathogenesis underlying this cortical malformation. Cerebral organoids from induced pluripotent stem cells (iPSCs) of patients with the Baraitser-Winter- CerebroFrontoFacial syndrome (BWCFF-S), expressing either an ACTB or an ACTG1 missense mutation, are reduced in size, showing a thinner ventricular zone (VZ). This decrease in VZ progenitors is in turn associated with a striking change in the orientation of their cleavage plane from predominantly vertical (control) to predominantly horizontal (BWCFF-S), which is incompatible with increasing VZ progenitor abundance. Various cytoskeletal and morphological irregularities of BWCFF-S VZ progenitors, notably in the apical region of these cells, seemingly contribute to their predominantly horizontal cleavage plane orientation. Our results provide insight into the cell biological basis of the microcephaly associated with BWCFF-S caused by actin mutations.

neuroscience↗

bioRxiv2020

Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

The choroid plexus (ChP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the ChP epithelium (ChPe) arises from the Wnt-expressing cortical hem. Embryonic mouse and human ChPe both express nuclear {beta}-CATENIN, a canonical Wnt signaling pathway effector, indicating that this pathway is active during ChPe development. Point mutations in human {beta}-CATENIN result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of ChPe identity and an apparent transformation of the ChPe to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. The ChPe is also disrupted when {beta}-Catenin is conditionally inactivated in the mouse. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal ChPe development in the mammalian brain.

developmental biology↗