Biology subjects

Moreno-Fernandez, M.

Publications and source records attributed to Moreno-Fernandez, M..

5 recordsLinked to original sources

bioRxiv2026

Maternal immune activation and peripubertal stress differentially disrupt glutamatergic, endocannabinoid, and neuromodulatory signalling in the adult rat dorsal hippocampus: implications for excitatory-inhibitory balance

Disruptions in excitatory-inhibitory (E/I) balance during neurodevelopment have been implicated in a range of psychiatric conditions, yet the neurochemical alterations associated to early-life insults and their potential contribution to E/I imbalance remain poorly understood. Using a "two-hit" rat model combining maternal immune activation (MIA; lipopolysaccharide -LPS- on gestational days 15-16) and peripubertal unpredictable stress (PUS; postnatal days 28-38), we examined the long-term effects of these insults, alone and in combination, on the adult dorsal hippocampus. Assessments included gene and/or protein expression of glutamatergic and GABAergic markers, endocannabinoid system enzymes, neuromodulatory amino acid level and prepulse inhibition (PPI) of the acoustic startle response. MIA increased GluN1 protein expression, while PUS reduced the Grin2a/Grin2b mRNA ratio, indicating incomplete NMDA receptor subunit maturation. GABA levels and GABA-A{gamma}2 expression were unchanged, suggesting deficient inhibitory compensation in the face of heightened excitatory tone. PUS increased Mgll gene expression, whereas a trend towards reduced Dagla expression was observed exclusively in non-stressed LPS-exposed animals, suggesting that MIA may suppress 2-AG synthesis only in the absence of subsequent stress. MIA and PUS displayed interactive effects on taurine levels, with elevation observed only in the double-hit condition; glycine was elevated by MIA independently of PUS. These findings support a model in which MIA and PUS converge on hippocampal E/I balance through complementary adaptations -- excitatory upregulation, incomplete synaptic maturation, and reduced endocannabinoid tone -- inadequately counterbalanced by inhibitory systems. Taurine and glycine emerge as potential markers of homeostatic compensation in response to early neurochemical dysregulation.

neuroscience↗

bioRxiv2025

Specific and converging modulation of the CRH and noradrenergic systems across drug classes and natural rewards in an incubation of seeking paradigm

Stress is known to play a critical role in relapse to drug use as well as in food craving. Craving itself is a key determinant of relapse, and cue-induced drug craving has been shown to increase, or incubate, over time for certain drugs such as cocaine and nicotine, though this effect is less consistent for others such as opiates. However, the modulations of stress-related biochemical systems after early or protracted withdrawal that could contribute to this incubation phenomenon have not yet been systematically examined in animal models, nor has the specificity of these mechanisms been tested across different drug classes or reinforcers. To address this gap, we analysed brains from male Lewis rats that self-administered cocaine (0.75 mg/kg, i.v.), heroin (0.075 mg/kg, i.v.), or saline, and subsequently assessed changes in plasma corticosterone, ornithine and other stress-related amines, alongside central gene and protein expression CRH, CRH2 receptor, and - and {beta}-adrenergic receptor subunits -Adra1, Adra2a and Adrb1) in cortico-striato-amygdalar nodes (after 1 or 30 days of withdrawal). A parallel experiment was conducted using sucrose as a reinforcer. Our findings indicate that although most effects were reinforcer-specific, convergent adaptations were also observed, particularly within noradrenergic systems and the basolateral amygdala, expanding our knowledge about the neurochemical rearrangements occurring during withdrawal.

neuroscience↗

bioRxiv2024

A hidden mark of a troubled past: neuroimaging and transcriptomic analyses reveal interactive effects of maternal immune activation and adolescent THC exposure in the absence of overt behavioural disruptions

Maternal exposure to infections during gestation has been shown to predispose individuals to the development of schizophrenia. Additionally, clinical data suggest that cannabis use could trigger the onset of schizophrenia in vulnerable individuals. However, the direction of causality remains unclear. To elucidate this issue, we utilised a rat model of maternal immune activation, combined with exposure to increasing doses of THC during adolescence, in both male and female rats. We investigated several behaviours in adulthood that resemble specific symptoms of schizophrenia, including impairments in working memory, deficits in sensorimotor gating, alterations in social behaviour, anhedonia, and potential changes in implicit learning (conditioned taste aversion). Furthermore, we conducted a longitudinal positron emission tomography (PET) study to identify affected brain regions and subsequently collected brain samples from one of these regions (the orbitofrontal cortex) for RNA sequencing analyses. These analyses were also performed on peripheral blood mononuclear cells to identify peripheral biomarkers. Notably, while no overt behavioural disruptions were observed, our PET scans revealed several brain alterations dependent on the combination of both exposures. Additionally, the transcriptomic studies demonstrated that maternal immune activation affected glutamatergic and serotoninergic genes, with the combination of both exposures shifting the expression from down-regulation to up-regulation. In peripheral cells, interactive effects were observed on inflammatory pathways, and some genes were proposed as biomarkers of the disease. These results suggest that the combination of these two vulnerability factors leaves a lasting mark on the body, potentially predisposing individuals to the disease even before behavioural alterations manifest.

neuroscience↗

bioRxiv2023

LACK OF INTERACTIONS BETWEEN PRENATAL IMMUNE ACTIVATION AND delta9-TETRAHYDROCANNABINOL EXPOSURE DURING ADOLESCENCE IN BEHAVIOURS RELEVANT TO SYMPTOM DIMENSIONS OF SCHIZOPHRENIA IN RATS

The causality in the association between cannabis use and the risk of developing schizophrenia has been the subject of intense debate in the last years. The development of animal models recapitulating several aspects of the disease is crucial for shedding light on this issue. Maternal infections are a known risk for schizophrenia. Here, we used the maternal immune activation (MIA) model combined with THC exposure during adolescence to examine several behaviours in rats (working memory in the Y maze, sociability in the three-chamber test, sucrose preference as a measure, prepulse inhibition and formation of incidental associations) that are similar to the different symptom clusters of the disease. To this end, we administered LPS to pregnant dams and when the offspring reached adolescence, we exposed them to a mild dose of THC to examine their behaviour in adulthood. We also studied several parameters in the dams, including locomotor activity in the open field, elevated plus maze performance and their response to LPS, that could predict symptom severity of the offspring, but found no evidence of any predictive value of these variables. In the adult offspring, MIA was associated with impaired working memory and sensorimotor gating, but surprisingly, it increased sociability, social novelty and sucrose preference. THC, on its own, impaired sociability and social memory, but there were no interactions between MIA and THC exposure. These results suggest that, in this model, THC during adolescence does not trigger or aggravate symptoms related to schizophrenia in rats.

neuroscience↗

bioRxiv2021

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome.

Substance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to 5 episodes of unpredictable stress every other day during adolescence (from postnatal day 28 to 38). When rats reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, conditioning processes and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration while PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and reversed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted Pavlovian or instrumental conditioning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. MIA+PUS altered the structure and function of the dorsal striatum increasing its volume and interfering with glutamatergic dynamics. MIA did not affect the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the restored cocaine intake. PUS had a profound effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction.

neuroscience↗