Biology subjects

Castro-Zavala, A.

Publications and source records attributed to Castro-Zavala, A..

6 recordsLinked to original sources

bioRxiv2025

A persistent increase in gut permeability correlates with emotional dysregulation following maternal separation in male and female mice.

Early life stress (ELS) can significantly influence vulnerability to the development of psychiatric disorders in adulthood. One of the most widely used preclinical models for investigating ELS is maternal separation with early weaning (MSEW), which mimics early-life neglect. The objective of this study was to evaluate the impact of ELS induced by MSEW on the emotional behaviour of male and female mice, as well as its relationship with intestinal permeability and neuroinflammatory markers in the hippocampus. Our results show that MSEW leads to increased anxiety-like behaviours in the adulthood, particularly in females, and exacerbates depression-like behaviours and anhedonia in both sexes. Notably, increased intestinal permeability was observed, which correlated with higher anxiety and depression-like responses, suggesting that gut health plays a crucial role in emotional regulation. These alterations in intestinal permeability were long-lasting, indicating persistent effects on gut function following ELS. Additionally, we observed that MSEW animals showed higher BDNF expression in the hippocampus, particularly in males. However, we did not find significant differences in the long-term survival of adult-born hippocampal cells, as measured by BrdU+ labeling. Furthermore, upon exposure to MSEW, both sexes showed increased NF-{kappa}B protein levels. However, only MSEW male mice exhibited changes in TNF- and BDNF levels, suggesting a sex-specific regulatory mechanism in response to chronic stress. The novel contribution of this study is its exploration of intestinal permeability as a mechanism linking ELS to emotional and behavioural dysregulation, particularly anxiety and depression. By showing a long-lasting increase in intestinal permeability and its correlation with mood disorders, our study extends the gut-brain axis hypothesis to ELS. Additionally, the inclusion of both male and female mice offers a more comprehensive understanding of the sex-specific effects of early stress, often overlooked in other studies. These findings suggest that intestinal permeability could serve as a biomarker for stress-related psychiatric conditions. HIGHLIGHTSO_LIMSEW increases anxiety and depression-like behaviours, especially in females. C_LIO_LIMaternal separation leads to long-lasting gut permeability changes into adulthood. C_LIO_LIIncreased gut permeability directly correlates with anxiety and anhedonia-like responses. C_LIO_LINeuroinflammation via NF-kB may link gut permeability to mood disorders. C_LIO_LIDifferential regulation of early-life stress is observed between males and females. C_LI

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

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↗

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↗

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↗