Biology subjects

Koutroulis, I.

Publications and source records attributed to Koutroulis, I..

4 recordsLinked to original sources

bioRxiv2026

Developmental Arrest Associated with Altered Cerebellar Metabolism in Sudden Infant Death Syndrome

BackgroundEffective autoresuscitation during hypoxic stress demands the cerebellum integrate autonomic and arousal responses. It remains unknown if the SIDS cerebellum possesses the metabolic stability and developmental maturity to sustain this function. We aimed to define if cerebellar dysfunction constitutes a silent failure point within the central respiratory network. MethodsWe performed multi-omic integration of RNA-sequencing, targeted metabolomics, and quantitative histology on postmortem cerebellar tissue from SIDS infants and age-matched controls. Cross-omic concordance analysis mapped the relationship between metabolite abundance and the transcriptional directionality of corresponding metabolic enzymes. ResultsThe SIDS cerebellum revealed a distinct profile defined by neuroinflammation and altered GABA and glutamate metabolism. Targeted metabolomics confirmed a metabolic imbalance with significantly elevated glutamate and GABA (P < 0.05). Quantitative histology exposed concurrent developmental arrest; persistent external granule layers highlighted morphological immaturity, explaining the failure to mount effective compensatory responses. ConclusionsMetabolic pathology in the SIDS cerebellum is intrinsically linked to structural immaturity. This developmental arrest creates a compromised environment lacking the metabolic competence to support neural homeostasis, preventing critical arousal responses required for survival. ImpactO_LIMulti-omic and neuropathological analysis reveal that structural immaturity in SIDS cerebellum is directly linked to neuroinflammation and metabolic excitotoxicity. C_LIO_LIDevelopmental arrest leaves the tissue metabolically incompetent to support the neural homeostasis required for infant survival during hypoxic stress. C_LIO_LIThis study shifts the focus of SIDS pathology beyond traditional brainstem mechanisms by establishing the cerebellum as a critical, point of failure within the central respiratory network, providing a direct link between morphological delay and functional neurochemical disruption C_LIO_LIThese findings offer translatable paradigm for understanding SIDS vulnerability and identify specific metabolic targets for future diagnostic risk screening and therapeutic interventions. C_LI

neuroscience↗

bioRxiv2025

Intrinsic Gestational Timing Governs Human Cerebellar Development After Preterm Birth

Intrinsic programs shape brain maturation, yet which are perturbed by prematurity, and the molecular pathways involved remain unknown. The human cerebellum serves as a paradigm of extrauterine development; its accelerated growth and circuit formation align with the third trimester, a period disrupted by preterm delivery. Through multimodal datasets encompassing in vivo neuroimaging and neurodevelopmental outcomes with postmortem spatial-transcriptomic and histopathological profiling, we show that prematurity diverts the cerebellar developmental trajectory. Cerebellar growth and functional outcomes scaled with gestational age, despite modifying perinatal exposures. Spatially resolved developmental programs underlying macroscopic trajectories were marked by incomplete granule cell maturation and impaired Purkinje cell structural refinement, indicating lineage-specific developmental asynchrony. Thus, prematurity constitutes biologically displaced maturation, in which infants of equivalent post-menstrual age occupy divergent developmental states.

neuroscience↗

bioRxiv2025

Prematurity Reprograms Cerebellar Development and Long-Term Behavior

Preterm survivors often develop motor and socio-cognitive impairments that implicate altered cerebellar development, yet the underlying mechanisms remain poorly understood. A key challenge is that prematurity involves overlapping perinatal insults that converge on the developing brain, making their individual effects difficult to disentangle. Here, we model two major prematurity-associated insults, maternal immune activation (MIA) and neonatal hypoxia (Hx), in mice. By controlling timing and sequence, we define how these insults shape cerebellar assembly during rapid maturation. Comparative analysis with human tissue confirmed that these insults recapitulate key features of the human preterm cerebellum, establishing the translational validity of this model for dissecting insult-specific outcomes. Behavioral and kinematic profiling revealed divergent motor and social phenotypes, which we traced to insult-specific cerebellar remodelling. Hypoxia compromised both granule cell maturation in the internal granule layer and the principal excitatory afferents to Purkinje cells, a circuit state that manifested as impaired motor execution and stereotyped, sensory-disengaged social investigation. Maternal immune activation, by contrast, expanded the granule cell progenitor layer and reduced Purkinje cell dendritic complexity, a phenotype that preserved social preference but reorganized the kinematic structure of social investigation. When hypoxia followed maternal immune activation, it acted on this primed substrate to produce a distinct state in which the features established by prior inflammation were compounded by granule cell proliferative arrest, progressive mitochondrial dysfunction, and aberrant, hyper-interactive social investigation. Together, these findings reframe prematurity-associated insults as cerebellar reprogramming events shaped by both the identity and sequence of insults, linking distinct mechanistic substrates to divergent neurodevelopmental outcomes.

neuroscience↗

bioRxiv2025

Cerebellum and Plasma Metabolomics Identify Sepsis Biomarkers and MSC-sEV-Mediated Rescue

Septic encephalopathy (SE) is a severe complication of sepsis, characterized by neuroinflammation and metabolic dysfunction, with the cerebellum among the most vulnerable brain regions. Advances in the field have been constrained by the lack of reliable biomarkers for SE detection, incomplete mapping of cerebellar metabolic alterations in SE, and limited insight into the therapeutic mechanisms of human mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) therapy. To overcome these challenges, we used a murine sepsis model and conducted integrated metabolomic analyses of cerebellar tissue and plasma, with and without MSC-sEV administration. Cross-compartment analyses identified six plasma metabolites with strong diagnostic potential in mice, three of which (n-acetylputrescine, aspartic acid, and cystathionine) were also observed in the plasma of human septic patients, supporting their promise as translatable biomarker candidates. Sepsis triggered profound cerebellar metabolic dysfunction, suppression of oxidative energy metabolism, and redox imbalance. MSC-sEVs attenuated these disturbances via their bioactive cargo, restoring cellular energetics and reestablishing antioxidant balance. Collectively, these results highlight cross-species plasma biomarkers for SE diagnosis, delineate key cerebellar metabolic mechanisms in SE, and demonstrate therapeutic modulation by human MSC-sEVs.

neuroscience↗