Biology subjects

Marcos, A.

Publications and source records attributed to Marcos, A..

10 recordsLinked to original sources

bioRxiv2026

Exploratory spatial peptidomic profiling during incubation of drug seeking following cocaine plus alcohol self-administration in young adult rats

BackgroundConcurrent cocaine and alcohol use is one of the most prevalent forms of polysubstance consumption and is associated with poorer clinical outcomes than cocaine use alone. However, the regional molecular adaptations induced by combined exposure remain poorly understood. Here, we used matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to characterize peptide/protein alterations in addiction-related brain regions following cocaine and cocaine-alcohol self-administration. MethodsYoung adult male and female Wistar rats underwent intravenous self-administration of saline, cocaine (1 mg/kg/infusion) or cocaine plus ethanol (1 mg/kg cocaine and 133 mg/kg ethanol per infusion), followed by extinction of drug-seeking behaviour. Coronal brain sections containing the anterior cingulate cortex (ACC) and ventral hippocampus (vHPC) were analysed by MALDI-IMS. Differential molecular features were identified using an exploratory statistical approach (FDR q < 0.20) and subsequently subjected to MS/MS analysis. ResultsThe ACC exhibited a substantially greater number of treatment-associated molecular alterations than the vHPC, suggesting a higher regional susceptibility to cocaine-induced molecular remodelling. Several molecular features were shared between the cocaine and cocaine-alcohol groups, indicating persistent cocaine-driven neuroadaptations. In contrast, additional signals were selectively associated with combined cocaine-alcohol exposure, while others present after cocaine alone were absent following alcohol co-exposure, supporting a modulatory effect of alcohol on specific cocaine-induced molecular responses. Overall, combined exposure generated a distinct regional molecular profile rather than simply reproducing the effects of cocaine alone. ConclusionsThis exploratory study demonstrates that MALDI-IMS enables the identification of region-specific peptide/protein alterations associated with cocaine and cocaine-alcohol exposure while preserving their spatial distribution within the brain. These findings highlight the ACC as a particularly responsive region and provide a framework for future studies aimed at validating molecular pathways involved in cocaine-alcohol polysubstance use.

neuroscience↗

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↗

bioRxiv2025

Transmission network for foot-and-mouth disease epidemic in Mar Chiquita - Argentina: A spatial modeling analysis

Foot-and-mouth disease (FMD) is a highly contagious viral disease with major implications for livestock production, food security, and economic stability. In this study, we investigate the transmission dynamics of the 2001 FMD outbreak in Mar Chiquita, Argentina, using a spatially explicit modeling framework. Transmission kernels based on inter-farm Euclidean distances are developed to estimate the probability of between-farm transmission and to reconstruct the likely transmission network. Several kernel formulations are evaluated, and parameters are estimated using maximum likelihood estimation techniques. We further assess the influence of isolation interventions by incorporating time-dependent kernel modifications that reflect reduced transmission risk following farm visits. Local transmission potential is quantified through farmspecific reproduction numbers, and transmission pathways are inferred using Markov Chain Monte Carlo (MCMC) simulations. Our results show that controlling geographic proximity alone does not reliably mitigate transmission risk and that delayed intervention can sustain epidemic spread. The reconstructed transmission network reveals spatial clusters of infections and temporal patterns consistent with field observations. These findings highlight the importance of timely isolation, active surveillance, and spatial risk assessment for effective outbreak control. HighlightsO_LISpatial transmission modeling captures FMD spread across 65 farms in Mar Chiquita, Argentina. C_LIO_LIDistance-based kernel functions estimated from epidemic data quantify between-farm infection risk. C_LIO_LIMCMC simulations reconstruct high-resolution farm-to-farm transmission networks. C_LIO_LIIntervention strategies (e.g., isolation) effectively reduce transmission probability and local R0. C_LI

ecology↗

bioRxiv2025

Alkalinized Filtered Water Induces Changes in the Gut Microbiome in Inflammatory Bowel Disease.

ObjectiveThis study evaluated the effects of filtered, alkalinized water on inflammation and intestinal dysbiosis in individuals with inflammatory bowel disease (IBD). MethodsWe conducted a three-month, two-arm, randomized intervention study involving 46 patients with IBD in remission. Participants were divided into two groups: one consumed filtered water from an active filtering device, and the control group consumed water from a mock device. Blood and stool samples were collected before and after the intervention. We assessed antioxidant capacity and circulating cytokine levels from plasma. Gene expression levels of inflammatory mediators were determined using mRNA from peripheral blood mononuclear cells (PBMCs). The microbial composition of fecal samples was characterized by qPCR analysis using primers targeting 16S rRNA genes. ResultsConsumption of alkalinized filtered water significantly reduced IL1B gene expression in PBMCs. Furthermore, subjects drinking alkalinized filtered water exhibited a consistent, albeit not statistically significant, decrease in circulating IL-1{beta} and significantly lower levels of IL-4 than controls. Microbiome analysis revealed that the levels of the Bacteroides fragilis Group were significantly lower in subjects consuming tap water than in those consuming filtered water. ConclusionThese changes suggest that consuming alkalinized water for three months leads to an improved inflammatory status compared with consuming tap water.

pathology↗

bioRxiv2025

Adolescent cannabinoid vapour exposure sex-dependently alters the relationship between vulnerability traits and ethanol self-administration and modifies naltrexone actions on ethanol intake in rats

BackgroundCannabis use during adolescence is common and may predispose individuals to substance use disorders. Animal studies have explored the gateway hypothesis, but data on ethanol consumption are limited. This study aimed to investigate the potential link between adolescent cannabis exposure and ethanol self-administration, as well as the relationship between predisposing behavioural traits and ethanol consumption. MethodsAdolescent rats were exposed to vapourised {Delta}9-tetrahydrocannabinol (THC) alone or with cannabidiol (CBD) at different ratios, or to a vehicle, from postnatal day (PND) 28 to 44, every other day. Behavioural assessments, including novelty and saccharin preference, goal-tracking, elevated plus maze, and ethanol self-administration (fixed and progressive ratio, punished seeking), were conducted from PND 70. Naltrexone was administered to assess its effects on ethanol intake. ResultsCannabinoid exposure did not significantly affect behavioural traits or ethanol self-administration. However, sex differences emerged, with females showing a more vulnerable pattern of ethanol consumption and seeking. In THC-exposed males, a negative correlation was observed between sucrose preference and compulsive ethanol seeking, which was absent in vehicle-exposed males. In females, THC exposure disrupted the correlation between novelty preference and ethanol intake and was associated with a negative correlation between goal-tracking and compulsive seeking. Naltrexone was most effective in reducing ethanol intake in THC-exposed rats. ConclusionsAdolescent cannabinoid exposure has limited effects on overall alcohol risk but may alter the psychological framework of alcohol-related behaviours and increase naltrexone potency. The observed sex differences highlight the need for personalised interventions.

neuroscience↗

bioRxiv2023

Dopamine alters the effect of brain stimulation on decision-making

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), show promise in treating cognitive and behavioural impairments in clinical conditions. However, optimisation of such clinical applications requires a better understanding of how tDCS alters cognition and behaviour. Existing evidence implicates dopamine in the way tDCS alters brain activity and plasticity, however, there is as yet no causal evidence for a role of dopamine in tDCS effects on cognition and behaviour. Here, in a preregistered, double-blinded study, we examined how pharmacologically manipulating dopamine altered the effect of tDCS on the speed-accuracy trade-off, which taps ubiquitous strategic cognitive processes. Cathodal tDCS was delivered over the left prefrontal cortex and the superior medial frontal cortex before participants completed a dot-motion task, deciding the direction of moving dots under instructions to emphasize speed, accuracy, or both. We leveraged computational modelling to uncover how our manipulations altered latent decisional processes driving the speed-accuracy tradeoff. We show that dopamine in combination with tDCS (but not tDCS alone, nor dopamine alone) not only impaired decision accuracy, but also impaired discriminability, which suggests that these manipulations altered the encoding or representation of discriminative evidence. This is, to the best of our knowledge, the first direct evidence implicating dopamine in the way tDCS affects cognition and behaviour. Significance statementTranscranial direct current stimulation (tDCS) can improve cognitive and behavioural impairments in clinical conditions, however better understanding of its mechanisms is required to optimise future clinical applications. Here, using a pharmacological approach to manipulate brain dopamine levels in healthy adults, we demonstrate a role for dopamine in the effects of tDCS in the speed-accuracy trade-off, a strategic cognitive process ubiquitous in many contexts. In doing so, we provide direct evidence implicating dopamine in the way tDCS affects cognition and behaviour.

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↗

bioRxiv2020

SARS-CoV-2 specific memory T lymphocytes from COVID-19 convalescent donors: identification, biobanking and large scale production for Adoptive Cell Therapy

SARS-CoV-2 is causing a second outbreak so the hope for its complete eradication is far from happening. In the absence of effective vaccines, it is mandatory to find effective treatments with low adverse effects able to treat hospitalized patients with COVID-19 disease. In this work, we determined the existence of SARS-CoV-2 specific T cells within the CD45RA- T memory cells from the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms. Also, CD45RA- memory T cells confer protection from other pathogens the donors encountered in their life. This is vital to clear other secondary infections usually developed in hospitalized COVID-19 patients. SARS-CoV-2 specific memory T cells were found within all the CD45RA- subsets CD3+, CD4+, CD8+, and in the central memory and effector memory subpopulations. The procedure to obtain the cells is feasible, easy to implement for small scale manufacture, quick and cost-effective involving minimal manipulation, and without GMP condition requirements. This biobank of specific SARS-CoV-2 memory T cells would be immediately available off-the-shelf to treat moderate/severe cases of COVID-19 increasing the therapeutic options available for these patients.

immunology↗