Biology subjects

Orihuel, J.

Publications and source records attributed to Orihuel, J..

4 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↗

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↗

bioRxiv2020

Testing The Role Of Δ9-Tetrahydrocannabinol During Adolescence As A Gateway Drug: Behavioural, Brain Imaging And Transcriptomic Studies

Cannabis is widely consumed by adolescents, and is also a potential prior step leading to the use of other drugs later in life (Gateway Hypothesis); however, the evidence for this hypothesis is controversial. This work aimed to increase our understanding of the long-term consequences of adolescent exposure to {Delta}9-tetrahydrocannabinol (THC) and to test the Gateway Hypothesis, experimentally. We exposed rats of both sexes to THC and studied its effects on reward-related processes, brain morphology (MRI), metabolism (1H-MRS), function (PET) and the transcriptomic profiles of the nucleus accumbens (RNASeq). Lastly, we studied cocaine-induced cellular activation (c-Fos) and cocaine addiction-like behaviours. THC exposure increased Pavlovian to instrumental transfer in males, goal-tracking (regardless of the sex) and impulsivity, but did not affect habit formation. Adolescent THC reduced striatal volume (in females), commissural integrity and ventricular volume. Also, there were lower levels of choline compounds in the cortex of THC-exposed rats and cerebellar hypoactivation in THC-females. THC also modified some of the gene expression programs of the nucleus accumbens, which could contribute to the behavioural features observed. Lastly, THC exposure increased cocaine-induced c-Fos levels in cortical and hypothalamic areas and increased the motivation for cocaine, followed by a higher rebound of use in THC-females after reestablishing low-effort conditions. Critically, acquisition of cocaine self-administration, compulsive seeking, intake under extended access or the incubation of seeking were unaltered. These results suggest that adolescent THC exposure alters psychological and brain development and that the Gateway Hypothesis does not entirely pass the test of preclinical enquiry.

neuroscience↗

bioRxiv2019

Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of schizophrenia-related alterations: effects of prenatal immune activation and peripubertal stress.

Prenatal infections are environmental risk factors for neurodevelopmental disorders. In addition, traumatic experiences during adolescence in individuals exposed to infections during gestation could increase the risk of schizophrenia. Given the tremendous burden that these diseases pose on societies when they fully manifest, it is of the most crucial importance to discover potential markers of the disease in its early stages or even before its onset, so that therapeutic strategies may be implemented. In the present study, we combined a well-characterized two-hit model of schizophrenia-related symptoms with proton magnetic resonance spectroscopy to discover potential biomarkers. To this end, we i.p. injected 100 g/kg/ml of lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to five episodes of stress or handling on alternate days during postnatal days (PND) 28 to 38. Once the animals reached adulthood (PND70), we evaluated prepulse inhibition (PPI). At PND90, we performed an ex vivo proton magnetic resonance spectroscopy study in the cortex and striatum. While we did not detect alterations in PPI at the age tested, we found neurochemical disturbances induced by LPS, stress or (more interestingly) their interaction. LPS decreased glucose levels in the cortex and striatum and altered glutamate, glutamine and N-acetylaspartate levels. Glutamate and glutamine levels in the left (but not right) striatum were differentially affected by prenatal LPS exposure in a manner that depended on stress experiences. These results suggest that alterations in the glutamate cycle in the striatum may predate the full emergence of disorders of the schizophrenic spectrum and could be used as early markers of the disease.

neuroscience↗