Biology subjects

Miranda, R.

Publications and source records attributed to Miranda, R..

8 recordsLinked to original sources

bioRxiv2026

Prenatal alcohol and cannabinoid co-exposure increases ethanol-seeking in adult offspring and produces sex-dependent medial prefrontal cannabinoid receptor 1 expression.

Background: Alcohol and cannabinoids are frequently used during pregnancy, however their combined effects on offspring outcomes are currently under-investigated. In this study, co-exposure was compared to single-drug and drug-free exposures for influences on adult alcohol-seeking and cannabinoid system proteomics. Methods: Pregnant C57BL/6J mice received ethanol vapor (ALC), CP-55,940 (0.75 mg/kg; CB), both (ALC+CB), or neither on gestational days 12-15. Beginning on Postnatal Day 200, male and female offspring underwent home-cage ethanol drinking (N=108) and operant self-administration, progressive-ratio, extinction, and reinstatement testing (N=96). CNR1 and CNRIP1 protein abundance was quantified in the medial prefrontal cortex (mPFC) and dorsomedial striatum (N=57) and compared to within-subject drinking behaviors. Results: Prenatal CB exposure increased cumulative home-cage ethanol intake, primarily in males. At 40% ethanol under progressive-ratio schedules, ALC+CB males consumed more than all other male groups, whereas all exposed female groups consumed more than controls. ALC+CB males also showed greater extinction responding than all other male groups and greater reinstatement intake relative to baseline than CON and ALC males. ALC+CB increased mPFC CNR1 in males relative to all other groups, whereas CB and ALC+CB reduced mPFC CNR1 in females. Higher mPFC CNR1 was associated with fixed-ratio and 40% progressive-ratio intake, extinction, and reinstatement exclusively in males. Conclusions: Prenatal co-exposure produced a persistent male phenotype of enhanced ethanol seeking that was distinct from either exposure alone and accompanied by elevated mPFC CNR1. This behavioral and molecular convergence justifies future investigations manipulating corticostriatal cannabinoid signaling to attenuate exposure-induced ethanol consumption in late adulthood.

developmental biology↗

bioRxiv2026

Do anglers take the bait? Anglers' perceptions about fluvial barriers in three river basins in Northern Spain

Removing river barriers - such as dams or weirs - is an increasingly used strategy for restoring freshwater ecosystems. In Europe, these actions are key for achieving the goal of 25,000 kilometers of free-flowing rivers that the recent regulation on nature restoration establishes for 2030. However, social acceptance remains uneven, and local opposition--often related to cultural attachments, poor ecological awareness, and misinformation--may influence or even impede restoration efforts. Among stakeholders, anglers play a particularly influential role, yet their perceptions and knowledge remain poorly documented. This study addresses how anglers from three river basins in Northern Spain perceive river barriers, their removal, and their ecological impacts, and contrasts their attitudes to those of other residents. We carried out a telephone survey of 1,200 adult residents in the target basins. We assessed perceptions, misconceptions, and self-reported knowledge of river barriers, and collected various sociodemographic parameters. We selected 180 self-identified anglers and compared their answers to those from a subsample of 180 non-anglers with similar demographic characteristics. Despite reporting significantly higher self-perceived knowledge and more polarised responses, anglers showed lower awareness of the ecological impacts of fluvial barriers. They were more likely to underestimate their negative effects compared to the control group. In addition to falling for the main misconceptions surrounding the issue, their responses displayed a degree of bimodality, suggesting that the type of fishing practised may influence their attitudes. Our findings reaffirm the importance of strengthening awareness-raising efforts among relevant stakeholders about the impacts of river barriers and the benefits of their removal when planning specific interventions. It is essential to engage local communities--particularly key groups such as anglers--to strengthen the social acceptance of such actions and improve environmental governance.

ecology↗

bioRxiv2025

Prenatal Alcohol Exposure Impairs Striatal Cholinergic Function and Cognitive Flexibility in Adult Offspring

Fetal Alcohol Spectrum Disorder (FASD), caused by prenatal alcohol exposure (PAE), is characterized by significant cognitive impairments, including reduced cognitive flexibility. Despite the critical role of cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) for cognitive and behavioral flexibility, their contribution to neurobehavioral deficits in FASD remains unclear. To address this gap, this research explored the impact of PAE on CIN populations and activity, cognitive flexibility, and compulsive drinking behaviors in adult offspring. Using ChAT-Cre;Ai14-tdTomato mice combined with ChAT staining, we found substantial reductions in CIN number within the striatum of adult PAE offspring. Functional assessments revealed that PAE markedly decreased CIN firing activity and reduced acetylcholine (ACh) release in the DMS, as measured by electrophysiology recordings and live-tissue confocal imaging using a genetically encoded ACh sensor. Behaviorally, PAE-exposed offspring exhibited a significant deficit in adapting to reversed action-outcome contingencies despite intact initial learning capabilities. Moreover, PAE-exposed mice exhibited compulsive alcohol drinking behavior, characterized by elevated consumption and preference for quinine-adulterated alcohol. These findings collectively highlight the critical role of impaired cholinergic signaling in the cognitive and behavioral deficits observed following PAE. Understanding this cholinergic dysfunction provides valuable insights necessary for developing targeted interventions aimed at mitigating cognitive and behavioral consequences associated with FASD. HighlightsPAE reduces the number of CINs, their firing rate and ACh release in the DMS. PAE impaired instrumental reversal learning, known to be mediated by CINs. PAE increased compulsive-like drinking of quinine adulterated alcohol.

neuroscience↗

bioRxiv2025

Early Life Outcomes of Prenatal Exposure to Alcohol and Synthetic Cannabinoids in Mice

This study explores the effects of prenatal co-exposure to alcohol and synthetic cannabinoids on offspring viability, physical development, and neurobehavioral outcomes in young adulthood. The aim is to identify distinct outcomes of co-exposure compared to single-drug exposures and to examine potential sex-specific vulnerabilities in motor coordination and exploratory behaviors. Pregnant C57Bl/6J mice were assigned to one of four treatment groups: Control, Alcohol-exposed, Cannabinoid-exposed, or Alcohol+Cannabinoid-exposed, with drug administration occurring between Gestational Days 12-15. Offspring were first evaluated at birth for survival, physical malformations, and developmental delays. Subsequently, young adult offspring were assessed for motor coordination using rotarod tests and exploratory behavior using open field tests. Our results indicate that alcohol and cannabinoid co-exposure significantly reduced offspring survival and litter sizes compared to controls. Non-viable offspring displayed craniofacial abnormalities, limb malformations, and developmental delays. Behavioral assessments in young adulthood demonstrated that all forms of prenatal drug exposure impaired motor coordination in males, while alcohol and cannabinoid exposures independently produced impairments in females. In the open field test, co-exposed male offspring exhibited reduced center exploration, indicative of anxiety-like behavior. Co-exposed offspring, regardless of sex, demonstrated hyperactivity, characterized by increased speed and distance traveled. Together, these findings underscore the heightened risks associated with prenatal polysubstance exposure, which exacerbates offspring mortality and induces sex-specific neurobehavioral deficits. This study highlights the distinct outcomes associated with prenatal co-exposure, and the need for future research to investigate underlying mechanisms driving these developmental disruptions and sex-specific susceptibilities. Structured AbstractO_ST_ABSPurposeC_ST_ABSThis study investigates the effects of prenatal co-exposure to alcohol and synthetic cannabinoids on offspring viability, physical development, and neurobehavioral outcomes in young adulthood. The goal of this investigation is to determine whether prenatal co-exposure produces distinct outcomes from single-drug exposures, including sex-specific vulnerabilities in motor coordination and exploratory behaviors. MethodsPregnant C57Bl/6J mice were randomly assigned to one of four treatment groups: drug-free controls, alcohol (ALC)-exposed, cannabinoid (CP-55,940, CB)-exposed or ALC+CB-exposed, with drug exposure occurring between Gestational Days 12-15. Offspring viability, physical malformations, and developmental delays were first assessed at birth. Then, behavioral evaluations, including rotarod and open field tests, were conducted on young adult offspring (Postnatal Days 100-120). ResultsALC+CB exposure significantly decreased litter survival (p = 0.006) and offspring viability compared to controls. Non-viable offspring exhibited craniofacial abnormalities, limb malformations, and developmental delays. Assessments of rotarod performance revealed that all exposures reduced motor coordination in males compared to controls (p < 0.05), while ALC and CB exposures alone produced this outcome in females. Open field tests indicated that ALC+CB exposure reduced time in the center of the arena in male offspring exclusively, while this same exposure increased hyperactivity compared to single-drug and control groups, independent of sex (p < 0.05). ConclusionsPrenatal co-exposure to alcohol and synthetic cannabinoids exacerbates offspring mortality and induces sex-specific deficits in neurobehavioral motor outcomes. These findings highlight the distinct risks of polysubstance exposure during pregnancy and underscore the need for targeted interventions to mitigate the effects of prenatal polysubstance exposure on offspring health outcomes. HighlightsO_LIAlcohol and cannabinoid co-exposure significantly reduces offspring survival. C_LIO_LIReduced survival is associated with offspring craniofacial and limb malformations. C_LIO_LIPrenatal exposures produce sex-specific impairments in motor coordination. C_LIO_LICo-exposed offspring display hyperactivity in young adulthood. C_LI

animal behavior and cognition↗

bioRxiv2023

WRN Inhibition Leads to its Chromatin-Associated Degradation Via the PIAS4-RNF4-p97/VCP Axis

Synthetic lethality, the concept in which the co-occurrence of two genetic events leads to cell death while either single event alone does not, is an attractive strategy for targeted cancer therapies. A recent example of synthetic lethality as a therapeutic paradigm is the observation that cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) RecQ helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics are not fully understood. In this study, we used our single molecule tracking (SMT) platform in combination with a recently disclosed WRN inhibitor to gain insights into WRNs dynamic localization within the nuclei of live cancer cells. We observe that WRN inhibition results in the helicase becoming trapped on chromatin, requiring p97/VCP for extraction and shuttling to the proteasome for degradation. Interestingly, this sequence of events resulting in WRN degradation appears to be MSI-H dependent. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation and show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells. Taken together, our work elucidates a novel regulatory mechanism for WRN. Gaining a deeper understanding into this regulatory pathway for WRN can aid in the identification of new high value targets for targeted cancer therapies.

molecular biology↗

bioRxiv2023

Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking

Social isolation profoundly alters motivation and increases vulnerability to alcohol misuse in humans, yet the underlying neural mechanisms remain unclear. Here we show that isolation escalates alcohol drinking in male mice but suppresses it in females. Whole-cell recordings revealed that neurons in the basolateral amygdala projecting to the medial prefrontal cortex (BLA-mPFC) track alcohol intake in both sexes. Isolation increased BLA-mPFC excitability in males but decreased it in females, mirroring their opposite behavioral adaptations. Given this divergence, we focused subsequent mechanistic studies on males to isolate neural pathway-level drivers of escalated alcohol intake. Cellular-resolution calcium imaging showed that activity in BLA-mPFC neurons encodes and predicts alcohol drinking, and optogenetic activation of this pathway increased alcohol intake. Simultaneous optogenetics and calcium imaging revealed that BLA-mPFC stimulation enhanced mPFC neuronal responses to alcohol, mimicking isolation-induced activity patterns, while photoinhibition reduced drinking in isolated mice. Together, these findings identify a BLA-mPFC pathway mechanism through which social isolation reconfigures prefrontal processing to promote alcohol intake.

neuroscience↗

bioRxiv2022

Climate change will redefine taxonomic, functional, and phylogenetic diversity patterns of Odonata in space and time

Climate change is rearranging the mosaic of biodiversity on our planet. These broad-scale species re-distributions will affect the structure of communities across multiple biodiversity facets (taxonomic, phylogenetic, and functional diversity). The current challenges to understand such effects involve focusing on organisms other than vertebrates and considering the signature of species redistribution on phylogenetic and functional diversity in addition to species composition. Using European dragonflies and damselflies (Odonata), we asked: i) how climate change will redefine taxonomic, phylogenetic, and functional diversity at continental scales; ii) which traits will mediate species response to global change; and iii) whether this response will be conserved across the phylogeny. First, we constructed stacked species distribution models for 107 species of Odonata under current and future climate conditions. Then, we quantified the temporal variation of taxonomic, functional and phylogenetic components, forecasting alpha and beta diversity changes through our geographical grid. Lastly, we used phylogenetic comparative models to test the influence of phylogeny and traits on range shifts. We observed broad latitudinal and altitudinal rearrangements in community composition driven by climate change. Given the high dispersal ability of Odonata, changes are predicted to be rapid, especially in areas experiencing faster climate change rates. According to our predictions, changes in species composition cascade to affect functional and phylogenetic diversity, determining broad turnovers in traits and evolutionary lineages. There was no clear phylogenetic signal in the range-shift response of European Odonata to climate change. According to our phylogenetic regression models, only body size and flight period can be partly correlated with observed range shifts. By considering all three primary facets of biodiversity, our results support the design of inclusive management and conservation strategies, accounting not only for the diversity of species, but also the services they provide and the phylogenetic heritage they carry in a targeted ecosystem.

ecology↗

bioRxiv2019

Sleep, regional grey matter volumes, and psychological functioning in adolescents

Changing sleep rhythms in adolescents often lead to sleep deficits and increased variability in sleep schedules. The adolescent brain, and in particular the rapidly developing structures involved in emotional control, are vulnerable to external and internal factors. In our previous study in adolescents at age 14, we observed a strong relationship between weekend sleep schedules and regional medial prefrontal cortex grey matter volumes. Here, we aimed to assess whether this relationship remained in this group of adolescents of the general population at the age of 16 (n=101; mean age 16.8 years; 55% girls). We further examined grey matter volumes in the hippocampi and the amygdalae, calculated with voxel-based morphometry. In addition, we investigated the relationship between regional grey matter volumes with psychological functioning. Sleep was assessed with self-reports and psychological functioning with the Strengths and Difficulties Questionnaire and tests on working memory and impulsivity. Later weekend wake-up times were associated with smaller grey matter volumes in the medial prefrontal cortex and the amygdalae, and greater weekend delays in wake-up time were associated with smaller grey matter volumes in the right hippocampus and amygdala. The medial prefrontal cortex region mediated the correlation between weekend wake up time and both externalising and internalising symptoms. Paying attention to regular sleep habits during adolescence could act as a protective factor against the emergence of psychopathology via enabling favourable brain development.

neuroscience↗