Biology subjects

Ortega, J. E.

Publications and source records attributed to Ortega, J. E..

3 recordsLinked to original sources

bioRxiv2025

Behavioural and Physiological Signatures of Chronic Unpredictable Mild Stress Models in Mice

The chronic unpredictable mild stress (CUMS) paradigm is one of the most widely used preclinical models to investigate the role of stress in the neurobiology of depression and to evaluate potential antidepressant therapies, owing to its strong translational relevance. However, despite its extensive use, substantial discrepancies and concerns regarding the reproducibility of CUMS outcomes persist in the literature, with many studies reporting inconsistent or unreliable results. In the present comparative study, we implemented several CUMS protocols in mice that differed in the intensity and duration of stress exposure, and systematically evaluated the resulting pathophysiological and behavioural alterations associated with depressive- and anxiety-like phenotypes. We found that progressive escalation in stress intensity and frequency, as well as prolonged exposure, induced increasingly robust disease-related behavioural and physiological changes, including depression- and anxiety-like behaviours, adrenal hypertrophy, and reduced body weight gain.. Moreover, social isolation emerged as a major contributing factor exacerbating stress-induced deficits. Altogether, data suggest that a multidimensional assessment of the behavioural impairments is critical to reinforce the physiological changes indicative of a hyperactive hypothalamic-pituitary-adrenal axis (HPA). Differences in individual stress susceptibility, stressor intensity, frequency, and housing conditions are key determinants of CUMS outcomes. Therefore, precise, detailed, and transparent reporting of protocol parameters is critical to enhance reproducibility and enable meaningful comparisons across studies.

neuroscience↗

bioRxiv2025

Locus Coeruleus alpha-Synuclein Overexpression Induces Prodromal Parkinsonian Features in Mice

The locus coeruleus is one of the first brain regions to develop -synuclein pathology during the prodromal phase of Parkinsons Disease, contributing significantly to non-motor symptoms such as cognitive decline, mood alterations or sleep disturbances. However, the precise role of the locus coeruleus in the early stages of the disease remains unclear. To address this, we developed and characterized a novel mouse model based on the PRSx8-driven overexpression of human -synuclein in noradrenergic neurons of the locus coeruleus using an adeno-associated viral vector. Animals were assessed at 1 and 3 months post-injection using an integrated battery of histological, behavioural, neurochemical, and electrophysiological analyses. We observed robust accumulation of phosphorylated -synuclein in the locus coeruleus, along with widespread propagation to projection areas, including the hippocampus, prefrontal cortex, and dorsal raphe. Despite the absence of neuronal loss in the locus coeruleus, we identified reduced noradrenergic axonal integrity and marked decreases in both noradrenaline and serotonin levels, highlighting a disruption of neurochemical balance at an early stage. The electrophysiological data revealed transient alterations in the excitability and intrinsic properties of locus coeruleus neurons in a sex-dependent manner, suggesting that -synuclein pathology induces early functional disruption prior to overt neurodegeneration. Behavioural outcomes demonstrated selective cognitive deficits and mild anxiety-like behaviours, while other non-motor functions remained preserved. Importantly, although several pathological and functional alterations were evident in the initial phases, behavioural impairments were also maintained at later time points, indicating that locus coeruleus-driven pathology exerts long-lasting consequences. Interestingly, female mice exhibited colon shortening, providing evidence of a sex-specific pathological process at the level of the gut-brain axis. We believe that this model accurately replicates key prodromal features of Parkinsons disease, demonstrating that -synuclein-induced pathology in the locus coeruleus leads to functional circuit impairment and cognitive decline. Our findings emphasize the locus coeruleus as a critical site of early vulnerability in Parkinsons Disease and underscore the importance of sex as a biological variable influencing disease progression and therapeutic response.

neuroscience↗

bioRxiv2022

GLUT1 ablation in astrocytes paradoxically improves central and peripheral glucose metabolism via enhanced insulin-stimulated ATP release

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e. GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 ablation (GLUT11'GFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Importantly, GLUT11'GFAP mice did not present cognitive alterations. Mechanistically, we observed that GLUT1-ablated astrocytes exhibited increased insulin receptor-dependent ATP release, and both astrocyte insulin signalling and brain purinergic signalling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its ablation triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis and cognitive function.

neuroscience↗