Biology subjects

Valverde, O.

Publications and source records attributed to Valverde, O..

15 recordsLinked to original sources

bioRxiv2025

Prenatal alcohol exposure dysregulates the expression of clock genes and alters rhythmic behaviour in mice

Foetal Alcohol Spectrum Disorders (FASD) refer to a range of adverse physical, behavioural, and cognitive effects caused by perinatal alcohol exposure. While cognitive impairments are well-documented, FASD has also been associated with sleep disturbances and circadian rhythm disruptions. This study aimed to examine the effects of perinatal alcohol exposure on circadian rhythms at behavioural and gene expression levels across two developmental stages (adolescence and adulthood) in both, male and female mice. Using a validated prenatal and lactation alcohol exposure (PLAE) protocol, we assessed circadian patterns of locomotor activity under free-running conditions and spatial memory performance during adolescence and adulthood. Additionally, we evaluated the impact of PLAE on circadian expression of clock and non-circadian genes involved in neurotransmission across key brain regions, including the medial prefrontal cortex and hippocampus. PLAE altered circadian rhythmicity and impaired spatial memory. Gene expression analyses revealed disrupted oscillatory patterns in clock genes and in genes related to plasticity and cognition, including those from the expanded endocannabinoid system (e.g. Cnr1, Dagla, Faah) and other neurotransmitter systems (e.g. Oprm1, Slc17a8, Drd1, Gabra1). These findings underscore the impact of early alcohol exposure on biological rhythms and neurobehavioral function, highlighting circadian dysregulation as a contributing factor to FASD.

neuroscience↗

bioRxiv2024

Chronic circadian disruption in adolescent mice impairs hippocampal memory disrupting gene expression oscillations

Chronodisruption, the misalignment of internal biological systems with external environmental changes, leads to adverse health effects. Particularly, Social Jet Lag (SJL) is defined as the discrepancy between social and biological time and it exemplifies this misalignment, affecting a large part of the young population and impacting cognitive function. Despite its prevalence, our understanding of how developmental chronodisruption ultimately translates into morbidity is limited. To address this, we implemented a chronic chronodisruption protocol in adolescent mice consisting of light/dark cycle manipulation. We employed a comprehensive battery of established behavioral tests alongside an in-depth analysis of the oscillatory expression of the molecular clock and other genes involved in relevant physiological function. Our results show that chronic circadian disruption during adolescence induces impairments in short-term, social, and spatial memory without prompting anxiety-like behavior. Additionally, we report altered gene expression patterns of circadian clock genes per1, per2, cry2 and npas2 in the hypothalamus and the hippocampus. Lastly, we observed a disruption of hippocampal gene expression oscillations which may underlie the hippocampal memory impairments. Overall, this work underscores the critical role of adolescent circadian rhythms in maintaining cognitive function, the relevance of circadian control of hippocampal homeostasis, and the importance of further research into the mechanisms of chronodisruption, particularly during adolescence, to better understand its long-term implications for cognitive function and overall health.

neuroscience↗

bioRxiv2024

Irregular light schedules induce alterations on daily rhythms and gene expression in mice

Synchronization of internal biological rhythms with external light-dark cycles is crucial for proper function and survival of the organisms, however modern life often imposes irregular light exposure, disrupting these internal clocks. This study investigated the effects of short-term shifted light-dark cycles on mice rhythmicity, and whether these alterations trigger molecular or behavioral changes. We evaluated locomotor activity, different behavioral domains and gene expression in the hypothalamus and medial prefrontal cortex. Despite non prominent behavioral impairments, such as anxiety or cognitive deficits, we observed a notable simplification in the locomotor activity patterns of the mice subjected to disrupted light-dark cycles. Molecular alterations included dysregulations in oscillations of core clock genes (Cry2, Per2) and disruptions in expression of genes involved in neuroplasticity, motivation, and stress responses, including GluA1, Crhr2, and Vip in both studied brain areas. Our study reveals that even brief light cycle shifts can disrupt circadian regulation at the molecular level, despite minimal behavioral changes. This molecular-behavioral discrepancy may suggest a complex adaptive response to drastic short-term light perturbations. Understanding the complex interplay between external light cues and internal biological rhythms regulation is crucial for mitigating the negative consequences of irregular light exposure on physiological processes and overall well-being.

neuroscience↗

bioRxiv2024

Lack of rhythmicity in Bmal1 deficient mice impairs motivation towards natural stimuli.

Maintaining appropriate circadian rhythmicity is essential for coordinating the activity of biological functions in mammalian organisms. A variety of physiological and behavioral changes have been associated with disturbances of this complex clock mechanism. In the present study, we delve into the consequences of circadian arrhythmia using the Bmal1-knockout (KO) mouse line aiming to explore potential behavioral and motivational implications. We were able to identify the intricate activity patterns that define circadian disturbance in Bmal1-KO mice by utilizing a new analysis model based on entropy divergence. Alterations in locomotor activity were accompanied by disruptions of circadian expression patterns in various clock genes as revealed by gene expression analysis. Additionally, we found a dysregulated gene expression profile in Bmal1-KO mice regarding genes related to circadian control in various brain nuclei. Specifically, the ventral striatum exhibited a dysregulation in the expression levels of genes modulating reward and motivation. Further investigation revealed that BMAL1 deficient mice showed a sustained rise in motivation and seeking behavior for food and water reinforcers in the self-administration paradigm, independently of the caloric content of the reward. Together, our data reveal that disruptions in circadian rhythmicity, induced by alterations in the molecular clock, also impact the gene expression regulating the reward system. This, in turn, can lead to altered seeking behavior and motivation for natural rewards. In summary, the present study contributes to our understanding of how reward processing is under the regulation of circadian clock machinery.

neuroscience↗

bioRxiv2023

Cocaine-induced loss of LTD and social impairments are restored by fatty acid amide hydrolase inhibition

BackgroundA single usage of a drug of abuse can have lasting effects on both the brain and behavior, continuing even after the drug has been metabolized and eliminated from the body. A single dose of cocaine can abolish endocannabinoid-mediated long-term depression (eCB-LTD) in the nucleus accumbens (NAc) within 24 hours of administration. However, it is uncertain whether this altered neuroplasticity entails a behavioral deficit. MethodsOur study employed adult male mice to investigate the effects of a single dose of cocaine (20 mg/kg) on eCB-LTD, saccharin preference, and social interactions 24 hours after administration. We also examined the gene expression in components of the eCB system. The pharmacological increase of anandamide was evaluated using the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 mg/kg). ResultsAfter a single dose of cocaine, mice displayed altered plasticity, social interactions, and preference for saccharin and a reduction in mRNA levels of the anandamide-catabolizing enzyme NAPE-PLD. We discovered that the FAAH inhibitor URB597 (1 mg/kg) successfully reversed the cocaine-induced loss of eCB-LTD in the NAc and restored normal social interaction in cocaine-exposed mice, but it did not affect their saccharin preference. ConclusionsOverall, this research underlines the neuroplastic changes and subsequent behavioral alterations that occur after the initial use of cocaine, while also suggesting a potential role for anandamide in the early impairments caused by cocaine. The findings highlight the importance of understanding the mechanisms underlying the initiation of drug use and offer a potential therapeutic target.

neuroscience↗

bioRxiv2023

The FAAH inhibitor URB597 reduces cocaine seeking during conditioned punishment and withdrawal

The endocannabinoid system is prominently implicated in the control of cocaine reinforcement due to its relevant role in synaptic plasticity and neurotransmitter modulation in the mesocorticolimbic system. The inhibition of fatty acid amide hydrolase (FAAH), and the resulting increase in anandamide and other N-acylethanolamines, represents a promising strategy for reducing drug seeking. In the present study, we aimed to assess the effects of the FAAH inhibitor URB597 (1 mg/kg) on crucial features of cocaine addictive-like behaviour in mice. Therefore, we tested the effects of URB597 on acquisition of cocaine (0.6 mg/kg/inf) self-administration, compulsive-like cocaine intake and cue-induced drug-seeking behaviour during withdrawal. URB597 reduced cocaine intake under conditioned punishment while having no impact on acquisition. This result was associated to increased cannabinoid receptor 1 gene expression in the ventral striatum and medium spiny neurons activation in the nucleus accumbens shell. Moreover, URB597 reduced cue-induced drug-seeking behaviour during prolonged abstinence and prevented the withdrawal-induced increase in FAAH gene expression in the ventral striatum. In this case, URB597 decreased activation of medium spiny neurons in the nucleus accumbens core. Our findings evidence the prominent role of endocannabinoids in the development of cocaine addictive-like behaviours and support the potential of FAAH inhibition as a therapeutical target for the treatment of cocaine addiction.

neuroscience↗

bioRxiv2023

PPAR-γ is a promising therapeutic target for memory deficits induced by early alcohol exposure.

BackgroundPatients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates of these deficits remain unclear. Here, we studied the participation of the expanded endocannabinoid system (ECS), which is known to be affected by alcohol in other life periods, and it is involved in memory impairments of neurodevelopmental disorders. MethodsC57BL/6 female mice were exposed to a time-limited access to either water or alcohol to model prenatal and lactation alcohol exposure (PLAE). The expanded ECS was analyzed in the prefrontal cortex and the hippocampus of the offspring at post-partum day (PD) 25 and 70. Then, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase N-acylethanolamines (NAEs), and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) antagonist; ii) pioglitazone, a PPAR-{gamma} agonist. Finally, we used a viral approach to upregulate astrocytic PPAR-{gamma} in the hippocampus to restore memory deficits. ResultsWe report that PLAE causes a hippocampal reduction of NAEs and PPAR-{gamma} at PD25. Moreover, URB597 suppresses PLAE-induced memory deficits through PPAR-{gamma}, since its effects are prevented by GW9662. Direct PPAR-{gamma} activation, using pioglitazone, also ameliorates memory impairments. Lastly, we demonstrate that the upregulation of PPAR-{gamma} in hippocampal astrocytes is sufficient to rescue PLAE-induced memory deficits. ConclusionOur data reveal a bidirectional link between memory deficits and expanded ECS alterations in the context of early alcohol exposure. Furthermore, we proved that PPAR-{gamma} in hippocampal astrocytes represents a specific therapeutic target for memory deficits in FASD.

neuroscience↗

bioRxiv2022

A novel mouse model of postpartum depression and the neurobiological effects of fast-acting antidepressant treatments

postpartum depression (PPD) is a severe psychiatric disorder that affects up to 15% of mothers and impairs mother-infant bonding with devastating consequences on the child development and the mother health. Several studies indicate a possible dysregulation of glutamatergic and GABAergic signalling in the corticolimbic system, as well as a downregulation of the allopregnanolone levels in serum of PPD patients. Although brexanolone, an allopregnanolone-based treatment, has recently emerged as fundamental PPD treatment, there is scarce evidence on its neurobiological action mechanism. Moreover, ketamine appears to be a promising antidepressant treatment preventing PPD, nevertheless whether it might be a more effective than allopregnanolone for some patients remain unknown. Therefore, the present study is aimed to evaluate the depressive-like phenotype of postpartum females undergoing maternal separation with early weaning (MSEW) protocol, as well as to compare the effectiveness of ketamine and allopregnanolone treatments. MSEW dams show increased despair-like behaviour, anhedonia and disrupted maternal behaviour. Moreover, lower allopregnanolone serum levels, reduction of vesicular transporters for GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex, as well as decreased hippocampal cellular proliferation are found in MSEW females. As for the antidepressant treatments, both drugs prevent despair-like behaviour, whereas only ketamine reverts anhedonia present in MSEW females. In addition, both treatments induce pro-neurogenic effects in the dorsal hippocampus but only allopregnanolone increases the VGAT and VGLUT1, without altering the excitatory/inhibitory ratio. Altogether, we propose a new mice model that recapitulates the core symptomatology and alterations in glutamatergic and GABAergic systems shown in PPD patients, which allows us to investigate the therapeutic mechanisms of allopregnanolone and ketamine.

neuroscience↗

bioRxiv2022

Bmal1-knockout mice exhibit reduced cocaine-seeking behaviour and cognitive impairments

Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Recently, its function has also been associated with alterations in mood, and reward processing. We investigated the behavioural and neurobiological impact of Bmal1 gene deletion in mice, as well as how these alterations affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations in Bmal1-KO mice including changes in locomotor activity with impaired habituation to environments as well as short term memory and social recognition impairments. In addition, Bmal1-KO mice experienced reduced cocaine-induced sensitization and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore, Bmal1 deletion influenced the expression of other clock-related genes in the mPFC and striatum as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterization of Bmal1-KO animals. We suggest that reduced cocaines rewarding effects in these mutant mice might be related to Bmal1 role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.

neuroscience↗

bioRxiv2021

Cannabidiol attenuates cognitive deficits and neuroinflammation induced by early alcohol exposure in a mice model.

Foetal alcohol spectrum disorder (FASD) is the umbrella term used to describe the physical and mental disabilities induced by alcohol exposure during development. Early alcohol exposure induces cognitive impairments resulting from damage to the central nervous system (CNS). The neuroinflammatory response accompanied by neurodegenerative mechanisms contribute to those detrimental alterations. Cannabidiol (CBD) has recently emerged as an anti-inflammatory drug that might be useful to treat several neuropsychiatric disorders. In our study, we assessed the effects of CBD on long-lasting cognitive deficits induced by early alcohol exposure. Furthermore, we analysed long-term pro-inflammatory and apoptotic markers within the prefrontal cortex and hippocampus. To model alcohol binge drinking during gestational and lactation periods, we used pregnant C57BL/6 female mice with time-limited access to 20% v/v alcohol solution. Following the prenatal and lactation alcohol exposure (PLAE), we treated the male and female offspring with CBD from post-natal day (PD) 25 until PD34, and we evaluated their cognitive performance at PD60. Our results showed that CBD treatment during peri-adolescence period ameliorates cognitive deficits observed in our FASD-like mouse model, without sex differences. Moreover, CBD restores the PLAE-induced increased levels of TNF and IL-6 in the hippocampus. Thus, our study provides new insights for CBD as a therapeutic agent to counteract cognitive impairments and neuroinflammation caused by early alcohol exposure.

neuroscience↗

bioRxiv2020

Cannabidiol effects on cocaine-seeking behaviour and incubation of craving in mice.

Background and PurposeTo remain abstinent represents one of the major challenges for the treatment of cocaine use disorder. Cocaine seeking elicited by drug-associated cues progressively intensifies during abstinence in a process termed incubation of craving, representing an aggravating factor for relapse. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-seeking behaviour, although its effects on cocaine-craving incubation have never been elucidated. Experimental ApproachWe developed a mouse model of behavioural economic analysis of demand curves and incubation of cue-induced cocaine craving. Changes in the protein expression of AMPAR subunits and ERK1/2 phosphorylation were analysed. We also assessed the effects of cannabidiol (20 mg{middle dot}kg-1) administered either during acquisition of cocaine self-administration or abstinence. Key ResultsMice efficiently performed the demand task and incubation of cocaine craving. Besides, changes in GluA1 and GluA2 protein levels were found along the abstinence in prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK1/2 phosphorylation in ventral striatum. Cannabidiol reduced ongoing cocaine intake when administered during the acquisition phase of the self-administration, but failed to alter the subsequent demand task performance and incubation of cocaine craving. No effects were found when cannabidiol was administered during the abstinence period. Conclusion and ImplicationsWe provide here a novel model of behavioural economic analysis of demand curves and cue-induced incubation of cocaine-seeking behaviour for mice. Moreover, we show that cannabidiol exerts differential effects on the current model depending on the self-administration phase in which it was administered. What is already knownO_LIBehavioural economics and incubation of cocaine craving are well-stablished paradigms to evaluate cocaine seeking in rats. C_LIO_LICBD reduces cocaine-seeking and cocaine-taking behaviours. C_LI What this study addsO_LIA mouse model of behavioural economic analysis of demand curves and incubation of cue-induced cocaine craving. C_LIO_LICBD reduces cocaine self-administration and has no effect over demand task and cocaine-craving incubation. C_LI Clinical significanceO_LIA new behavioural model for studying cocaine addiction in mice. C_LIO_LICBD exerts differential effects depending on when it was administered in the addictive process. C_LI TO_SCPLOWABLESC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWOFC_SCPLOW LO_SCPLOWINKSC_SCPLOW O_TBL View this table: org.highwire.dtl.DTLVardef@654e3aorg.highwire.dtl.DTLVardef@f2d37aorg.highwire.dtl.DTLVardef@1a0396org.highwire.dtl.DTLVardef@1e19d1dorg.highwire.dtl.DTLVardef@1121b7b_HPS_FORMAT_FIGEXP M_TBL C_TBL

neuroscience↗

bioRxiv2020

Behavioural and transcriptomic characterization of the comorbidity between Alzheimer s disease and Major Depression

Major Depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimers disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown. In this regard, we investigated the cognitive and emotional responses in 3- and 6-month-old in APP/PSEN1-Tg mutant mice, before {beta}-amyloid plaques were detected. Then, we studied the deregulation of genes and pathways in prefrontal cortex, striatum, hippocampus and amygdala, using transcriptomic and functional data analysis. The results demonstrated that depressive-like and anxiety-like behaviours, as well as memory impairments are already present at 3-month-old together with the deregulation of several genes and gene sets, including components of the circadian rhythms, electronic transport chain and neurotransmission. Finally, DisGeNET GSEA provides translational support for common depregulated gene sets related to MD and AD. Altogether, the results demonstrate that MD could be an early manifestation of AD.

neuroscience↗

bioRxiv2020

BEHAVIOURAL AND MOLECULAR EFFECTS OF CANNABIDIOLIC ACID IN MICE

ABSTRACTAims Cannabidiolic acid (CBDA) is one of the most abundant phytocannabinoid acids in the Cannabis Sativa plant. It has been shown it is able to exert some therapeutic effects such as antiemetic, anti-inflammatory, anxiolytic or antidepressant, although some of them remain under debate. In the present study we aim to assess the potential effects of CBDA on different behaviours and on the modulation of neuroinflammatory markers in the prefrontal cortex (PFC).Main methods the effects of acute and/or chronic CBDA (0.001-1 mg/kg i.p.) treatment were evaluated on cognitive, emotional, motivational and nociceptive behaviours in male CD1 mice. For this, Y-maze and elevated plus maze paradigms, spontaneous locomotor activity, social interaction, hot-plate, formalin and tail suspension tests were used. We also studied the effects of CBDA on the rewarding responses of cocaine in the conditioned place preference (CPP) paradigm. PFC was dissected after acute and chronic CBDA treatments to evaluate inflammatory markers.Key findings acute CBDA treatment induced antinociceptive responses in the hot-plate test. A 10-day chronic CBDA treatment reduced despair-like behaviour in the tail suspension test. CBDA did not alter the remaining behavioural tests assayed, including cocaine-induced reward in the CPP. Regarding the biochemical analysis, chronic CBDA treatment diminished peroxisome proliferator-activated receptor gamma (PPAR-γ) and increased interleukin-6 (IL-6) protein levels in PFC.Significance these results show that CBDA has limited in vivo effects modulating mice behaviour, highlighting the current disagreement regarding its therapeutic potential.Competing Interest StatementThe authors have declared no competing interest.Abbreviations5-HT1ASerotonin receptor 1ACBDCannabidiolCBDACannabiodiolic acidCOX-2Ciclooxigenase-2CPPConditioned place preferenceEPMElevated plus mazeIL-6Interleukin-6PFCPrefrontal cortexPPARProliferator-activated receptorTRPA1Transient receptor potential cation channel ankyrin 1TRPM8Transient receptor potential cation channel melastatin 8TRPV1Transient receptor potential cation channel vanilloid 1TSTTail suspension testView Full Text

pharmacology and toxicology↗

bioRxiv2020

COCAINE-INDUCED IMPULSIVITY IS DIFFERENTIALLY EXPRESSED IN MALE AND FEMALE MICE EXPOSED TO MATERNAL SEPARATION AND IS ASSOCIATED WITH ALTERATIONS IN AMPA RECEPTORS SUBUNITS.

Impulsivity is a key trait in the diagnosis of major depressive disorder (MDD) and substance use disorder (SUD). MDD is a chronic illness characterized by sadness, insomnia, and loss of interest. SUD is a chronic and relapsing disorder characterized by the consumption of drugs despite their negative consequences. Among drugs of abuse, cocaine is the most consumed psychostimulant. Animal studies demonstrated that increased impulsivity predicts predisposition to acquire cocaine self-administration (SA) behaviour with an increased cocaine-intake. Moreover, early-life stress represents a vulnerability factor to develop depressive disorders and drug addiction. Maternal separation with early weaning (MSEW) is an animal model that allows examining the impact of early-life stress on cocaine abuse. In this study, we aimed to explore changes in MSEW-induced impulsivity to determine potential associations between depression-like and cocaine-seeking behaviours in male and female mice. We also evaluated possible alterations in the AMPA receptors (AMPArs) composition and glutamatergic neurotransmission. We exposed mice to MSEW and the behavioural tests were performed during adulthood. Moreover, GluA1, GluA2 mRNA and protein expression were evaluated in the medial Prefrontal Cortex (mPFC). Results showed higher impulsive cocaine-seeking in females, independently the MSEW, as well as an increase in GluA1 and GluA2 protein expression. Moreover, MSEW induced downregulation of Gria2 and increased the GluA1/GluA2 ratio, only in male mice. In conclusion, female mice expressed higher mPFC glutamatergic function, which potentiated their impulsivity during cocaine SA. Also, data indicated that MSEW alters glutamatergic function in mPFC of male mice, increasing the glutamatergic excitability.

neuroscience↗

bioRxiv2020

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113.

Cocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8-12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates extinction burst responding after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism. Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.

neuroscience↗