Publications by authors named "Luís Eduardo Wearick-Silva"

22 Publications

  • Page 1 of 1

Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation.

Front Cell Dev Biol 2021 1;9:653384. Epub 2021 Jun 1.

Laboratory of Psychopharmacology and Molecular Psychiatry, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.

Epidemiological studies have shown that environmental insults and maternal stress during pregnancy increase the risk of several psychiatric disorders in the offspring. Converging lines of evidence from humans, as well as from rodent models, suggest that prenatal stress (PNS) interferes with fetal development, ultimately determining changes in brain maturation and function that may lead to the onset of neuropsychiatric disorders. From a molecular standpoint, transcriptional alterations are thought to play a major role in this context and may contribute to the behavioral phenotype by shifting the expression of genes related to excitatory and inhibitory (E/I) transmission balance. Nevertheless, the exact neurophysiological mechanisms underlying the enhanced vulnerability to psychopathology following PNS exposure are not well understood. In the present study, we used a model of maternal stress in rats to investigate the distal effects of PNS on the expression of genes related to glutamatergic and GABAergic neurotransmissions. We inspected two critical brain regions involved in emotion regulation, namely, the prefrontal cortex (PFC) and the amygdala (AMY), which we show to relate with the mild behavioral effects detected in adult rat offspring. We observed that PNS exposure promotes E/I imbalance in the PFC of adult males only, by dysregulating the expression of glutamatergic-related genes. Moreover, such an effect is accompanied by increased expression of the activity-dependent synaptic modulator gene specifically in the PFC parvalbumin (PV)-positive interneurons, suggesting an altered regulation of synapse formation promoting higher PV-dependent inhibitory transmission and increased overall circuit inhibition in the PFC of males. In the AMY, PNS more evidently affects the transcription of GABAergic-related genes, shifting the balance toward inhibition. Collectively, our findings suggest that the E/I dysregulation of the PFC-to-AMY transmission may be a long-term signature of PNS and may contribute to increase the risk for mood disorder upon further stress.
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http://dx.doi.org/10.3389/fcell.2021.653384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204112PMC
June 2021

Prenatal stress and KCl-induced depolarization modulate cell death, hypothalamic-pituitary-adrenal axis genes, oxidative and inflammatory response in primary cortical neurons.

Neurochem Int 2021 Jul 5;147:105053. Epub 2021 May 5.

Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. Electronic address:

Maternal stress has been described as an important component in the offspring's cerebral development, altering the susceptibility to diseases in later life. Moreover, the postnatal period is essential for the development and integration of several peripheral and central systems related to the control of homeostasis. Thus, this study aimed to evaluate the effects of prenatal stress on the activation of cortical neurons, by performing experiments both under basal conditions and after KCl-induced depolarization. Female mice were divided in two groups: control and prenatal restraint stress. Cortical neurons from the offspring were obtained at gestational day 18. The effects of prenatal stress and KCl stimulations on cellular mortality, autophagy, gene expression, oxidative stress, and inflammation were evaluated. We found that neurons from PNS mice have decreased necrosis and autophagy after depolarization. Moreover, prenatal stress modulated the HPA axis, as observed by the increased GR and decreased 5HTr1 mRNA expression. The BDNF is an important factor for neuronal function and results demonstrated that KCl-induced depolarization increased the gene expression of BDNF I, BDNF IV, and TRκB. Furthermore, prenatal stress and KCl treatment induced significant alterations in oxidative and inflammatory markers. In conclusion, prenatal stress and stimulation with KCl may influence several markers related to neurodevelopment in cortical neurons from neonate mice, supporting the well-known long-term effects of maternal stress.
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http://dx.doi.org/10.1016/j.neuint.2021.105053DOI Listing
July 2021

Early environmental enrichment rescues memory impairments provoked by mild neonatal hypoxia-ischemia in adolescent mice.

Behav Brain Res 2021 Jun 31;407:113237. Epub 2021 Mar 31.

Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Brain Institute (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address:

Hypoxia-ischemia (HI) is a consequence of a lack of oxygen and glucose support to the developing brain, which causes several neurodevelopmental impairments. Environmental enrichment (EE) is considered an option to recover the alterations observed in rodents exposed to HI. The aim of this study was to investigate the impact of early EE on memory, hippocampal volume and brain-derived neurotrophic factor (Bbnf) and glucocorticoid receptor (Nr3c1) gene expression of mice exposed to HI. At P10, pups underwent right carotid artery permanent occlusion followed by 35 min of 8% O hypoxic environment. Starting at P11, animals were reared in EE or in standard cage (HI-SC or SHAM-SC) conditions until behavioral testing (P45). SHAM pups did not undergo carotid ligation and hypoxic exposure. Memory performance was assessed in the Y-maze, Novel object recognition, and Barnes maze. Animals were then sacrificed for analysis of hippocampal volume and Bdnf and Nr3c1 gene expression. We observed that animals exposed to HI performed worse in all three tests compared to SHAM animals. Furthermore, HI animals exposed to EE did not differ from SHAM animals in all tasks. Moreover, HI decreased hippocampal volume, while animals reared in early EE were not different compared to SHAM animals. Animals exposed to HI also showed upregulated hippocampal Bdnf expression compared to SHAM animals. We conclude that early EE from P11 to P45 proved to be effective in recovering memory impairments and hippocampal volume loss elicited by HI. Nevertheless, Bdnf expression was not associated with the improvements in memory performance observed in animals exposed to EE after a hypoxic-ischemic event.
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http://dx.doi.org/10.1016/j.bbr.2021.113237DOI Listing
June 2021

Maternal Separation Combined With Limited Bedding Increases Anxiety-Like Behavior and Alters Hypothalamic-Pituitary-Adrenal Axis Function of Male BALB/cJ Mice.

Front Behav Neurosci 2020 12;14:600766. Epub 2020 Nov 12.

Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Early life stress (ELS) is considered a risk factor for the development of psychiatric conditions, including depression and anxiety disorder. Individuals that live in adverse environments are usually exposed to multiple stressors simultaneously, such as maternal neglect, maltreatment, and limited resources. Nevertheless, most pre-clinical ELS models are designed to explore the impact of these events separately. For this reason, this study aims to investigate the effects of a combined model of ELS on anxiety-like behavior and hypothalamic-pituitary-adrenal (HPA) axis related targets. From PND 2 to PND 15 BALB/cJ mice were exposed simultaneously to maternal separation (MS; 3 h per day) and limited bedding (LB; ELS group) or left undisturbed (CT group). Maternal behavior was recorded in intercalated days, from PND 1 to PND 9. Male offspring were tested for anxiety-like behavior from PND 53 to PND 55 in the open field test (OF), elevated plus-maze (EPM), and light/dark test (LD). After behavioral testing, animals were euthanized, and glucocorticoid receptor (, corticotrophin-releasing hormone (), and its receptor type 1 () gene expression in the hypothalamus were measured. Moreover, plasma corticosterone levels were analyzed. We observed that ELS dams presented altered quality of maternal care, characterized by a decrease in arched-back nursing, and an increase in passive nursing. Stressed dams also showed an increase in the number of exits from the nest when compared to CT dams. Furthermore, ELS animals showed increased anxiety-like behavior in the OF, EPM, and LD. Regarding gene expression, we identified an increase in hypothalamus levels of ELS group when compared to CT animals, while no differences in and expression were observed. Finally, stressed animals showed decreased levels of plasma corticosterone when compared to the CT group. In conclusion, we observed an alteration in maternal behavior in ELS dams. Later in life, animals exposed to the combined model of ELS showed increased levels of anxiety-like behavior. Moreover, the central and peripheral HPA measures observed could indicate a dysregulation in HPA function provoked by ELS exposure.
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http://dx.doi.org/10.3389/fnbeh.2020.600766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693708PMC
November 2020

Corticotropin-releasing factor infusion in the bed nucleus of the stria terminalis of lactating mice alters maternal care and induces behavioural phenotypes in offspring.

Sci Rep 2020 11 17;10(1):19985. Epub 2020 Nov 17.

Developmental Cognitive Neuroscience Lab, Brain Institute of Rio Grande Do Sul (InsCer), Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Jardim Botânico, Porto Alegre, RS, Brazil.

The peripartum period is accompanied by numerous physiological and behavioural adaptations organised by the maternal brain. These changes are essential for adequate expression of maternal behaviour, thereby ensuring proper development of the offspring. The corticotropin-releasing factor (CRF) plays a key role in a variety of behaviours accompanying stress, anxiety, and depression. There is also evidence that CRF contributes to maladaptations during the peripartum period. We investigated the effects of CRF in the bed nucleus of the stria terminalis (BNST) of lactating mice during maternal care and analysed locomotor activity and anxiety-like behaviour in the offspring. The BNST has been implicated in anxiety behaviour and regulation of the stress response. The effects of intra-BNST CRF administration were compared with those induced by the limited bedding (LB) procedure, a model that produces altered maternal behaviour. BALB/cJ dams were exposed to five infusions of CRF or saline into the BNST in the first weeks after birth while the LB dams were exposed to limited nesting material from postnatal days (P) 2-9. Maternal behaviour was recorded in intercalated days, from P1-9. Offspring anxiety-like behaviour was assessed during adulthood using the open-field, elevated plus-maze, and light/dark tests. Both intra-BNST CRF and LB exposure produced altered maternal care, represented by decreased arched-back nursing and increased frequency of exits from the nest. These changes in maternal care resulted in robust sex-based differences in the offspring's behavioural responses during adulthood. Females raised by CRF-infused dams exhibited increased anxiety-like behaviour, whereas males presented a significant decrease in anxiety. On the other hand, both males and females raised by dams exposed to LB showed higher locomotor activity. Our study demonstrates that maternal care is impaired by intra-BNST CRF administrations, and these maladaptations are similar to exposure to adverse early environments. These procedures, however, produce distinct phenotypes in mice during young adulthood and suggest sex-based differences in the susceptibility to poor maternal care.
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http://dx.doi.org/10.1038/s41598-020-77118-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672063PMC
November 2020

Maternal separation induces long-term oxidative stress alterations and increases anxiety-like behavior of male Balb/cJ mice.

Exp Brain Res 2020 Sep 12;238(9):2097-2107. Epub 2020 Jul 12.

Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Avenida Ipiranga, 6681, prédio 11, sala 936-Partenon, Porto Alegre, RS, 90619-900, Brazil.

Early life stress (ELS) exposure is a well-known risk factor for the development of psychiatric conditions, including anxiety disorder. Preclinical studies show that maternal separation (MS), a classical model of ELS, causes hypothalamic-pituitary-adrenal (HPA) axis alterations, a key contributor to the stress response modulation. Given that HPA axis activation has been shown to induce oxidative stress, it is possible to hypothesize that oxidative stress mediates the relationship between chronic ELS exposure and the development of several disorders. Here, we investigate the effects of MS in the oxidative status [plasma and brain reduced glutathione, catalase and thiobarbituric acid reactive substances (TBARS)], metabolism (glucose, triglycerides and cholesterol) and anxiety-like behaviors in adult Balb/cJ mice. In short, we found that MS increased anxiety-like behaviors in the open field, light/dark test but not in the elevated-plus maze. Animals also presented increased circulating cholesterol, increased TBARS in the plasma and decreased catalase in the hippocampus. Our findings suggest that MS induces long-term alterations in oxidative stress and increased anxiety-like behaviors.
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http://dx.doi.org/10.1007/s00221-020-05859-yDOI Listing
September 2020

Vulnerable and resilient cognitive performance related to early life stress: The potential mediating role of dopaminergic receptors in the medial prefrontal cortex of adult mice.

Int J Dev Neurosci 2020 Feb 23;80(1):13-27. Epub 2020 Jan 23.

Graduate Program in Psychology, School of Health and Life Sciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Rationale: Exposure to early life stress (ELS) is known to have pronounced effects on the prefrontal cortex (PFC). However, not all individuals exposed to ELS manifest the same neurobiological and cognitive phenotypes when adults. Dopamine signaling could be a key factor in understanding the effects of stress on PFC-related cognitive function.

Objectives: We aimed to investigate the differential effects of ELS on cognitive performance of adult mice and the dopaminergic receptors expression in the PFC.

Methods: BALB/c males were exposed to the maternal separation (MS) procedure and their cognitive performance on the eight-arm radial maze (8-RAM) were assessed during adulthood. For molecular-level assessments, we performed mRNA expression analyses for dopamine receptors-DRD1, DRD2, DRD3-and Hers1 expression in the medial PFC.

Results: While MS produced an overall impairment on 8-RAM, the stressed animals could be divided in two groups based on their performance: those with impaired cognitive performance (vulnerable to maternal separation, V-MS) and those without any impairment (resilient to maternal separation, R-MS). V-MS animals showed increased DRD1 and DRD2 expression in comparison with other groups. Errors on 8-RAM were also positively correlated with DRD1 and DRD2 mRNA expression.

Conclusions: Our findings suggest a potential role of the dopaminergic system in the programming mechanisms of cognitive vulnerability and resilience related to ELS.
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http://dx.doi.org/10.1002/jdn.10004DOI Listing
February 2020

How Early Life Stress Impact Maternal Care: A Systematic Review of Rodent Studies.

Front Behav Neurosci 2019 28;13:197. Epub 2019 Aug 28.

Developmental Cognitive Neuroscience Lab (DCNL), School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Maternal care refers to the behavior performed by the dam to nourish and protect her litter during its early development. Frequent and high-quality performance of such maternal behaviors is critical for the neurodevelopment of the pups. Maternal exposure to stress during early development can impair maternal care and amplify the deleterious effects of poor maternal caregiving and neglect. As such, a thorough understanding of the effects caused by several models of early life stress on maternal care may yield more insights into the relationship between stress and maternal behavior. A systematic review was performed to identify and address the effects of early life stress on maternal behavior. The search was conducted using three online databases: PUBMED, Embase, and Web of Science. To provide clear evidence of the impact of stress on maternal care, in every study, the stress group was always compared to a control group. Outcomes were categorized into eight different behaviors: (1) licking/grooming; (2) arched-back nursing; (3) blanket-nursing/passive nursing; (4) nest building; (5) contact with pups; (6) harmful/adverse caregiving; (7) no contact; (8) nest exits. Additionally, the methodological quality of the studies was evaluated. A total of 12 different early life stress protocols were identified from the 56 studies included in this systematic review. Our data demonstrate that different stress models can promote specific maternal patterns of behavior. Regarding the maternal separation protocol, we observed an overall increase in nursing and licking/grooming behaviors, which are essential for pup development. An increase in the number of nest exits, which represents a fragmentation of maternal care, was observed in the limited bedding protocol, but the total amount of maternal care appears to remain similar between groups. Each stress protocol has unique characteristics that increase the difficulty of rendering comparisons of maternal behavior. The increase in maternal care observed in the maternal separation protocol may be an attempt to overcompensate for the time off-nest. Fragmented maternal care is a key component of the limited bedding protocol. Moreover, the methodological approaches to evaluate maternal behavior, such as time, duration, and behavior type should be more homogeneous across studies.
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http://dx.doi.org/10.3389/fnbeh.2019.00197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724664PMC
August 2019

Acute neuroinflammation elicited by TLR-3 systemic activation combined with early life stress induces working memory impairments in male adolescent mice.

Behav Brain Res 2019 12 9;376:112221. Epub 2019 Sep 9.

Pontifical Catholic University of Rio Grande do Sul (PUCRS), Brain Institute, Developmental Cognitive Neuroscience Lab, Porto Alegre, RS, Brazil. Electronic address:

Toll-like Receptors (TLRs) are implicated with the pathogenesis of cognitive impairment induced by inflammation. Early life stress is associated with altered trajectories of neuroimmune signaling with implications for cognitive development. However, effects of TLR-3 activation on early life stress-related cognitive outcomes are understudied. We investigated the effects of maternal separation (MS) during postnatal development and a viral immune challenge during adolescence on working memory performance. BALB/c mice exposed to MS were separated from their dams daily for 180-min from postnatal day (PND) 2 to 15. At PND 45, animals were challenged with a single i.p. injection of either Poly (I:C) or sterile saline, and then subjected to a spatial working memory test in a Y-maze apparatus. Gene expression was determined by qPCR. Protein levels of oxidative stress markers were also assessed. A single peripheral administration of a TLR-3 agonist was able to induce working memory impairments in adolescent mice exposed to MS. At a molecular level, exposure to MS was associated with lower mRNA levels of Tlr3 in the medial prefrontal cortex (mPFC). However, when MS animals were exposed to Poly (I:C), a more robust activation of Tlr3, Il6 and Nfkb1 gene transcription was observed in these mice compared with control animals. These modifications did not result in oxidative stress. Finally, higher mRNA levels of Nfkb1 in the mPFC were correlated with lower working memory performance, suggesting that altered NF-κB signaling might be related with poor cognitive functioning. These results have implications for how ELS affects neuroimmune signaling in the mPFC.
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http://dx.doi.org/10.1016/j.bbr.2019.112221DOI Listing
December 2019

Postnatal impoverished housing impairs adolescent risk-assessment and increases risk-taking: A sex-specific effect associated with histone epigenetic regulation of Crfr1 in the medial prefrontal cortex.

Psychoneuroendocrinology 2019 01 26;99:8-19. Epub 2018 Aug 26.

Pontifical Catholic University of Rio Grande do Sul (PUCRS), Brain Institute (InsCer), Developmental Cognitive Neuroscience Lab, Porto Alegre, RS, Brazil. Electronic address:

While increasing evidence posits poor decision-making as a central feature of mental disorders, very few studies investigated the effects of early-life stress (ELS) on specific components of reward-related choice behaviors. Risk-taking (RT) involves the exposure to some danger, or negative consequences, in order to achieve a goal-directed behavior. Such behaviors are likely to be preceded by risk-assessment (RA), which is a dynamic cognitive process involving the acquisition of information in potentially dangerous situations. Here, we investigated the effects of being raised in impoverished housing conditions during early life (P2-P9) on RT, RA and dopaminergic and corticotrophinergic gene expression of adolescent male and female mice. Phenotypes were assessed by two protocols: the elevated plus-maze (EPM) and the predator-odor risk-taking (PORT). We found decreased RA in mice exposed to impoverished housing in the absence of a reward (EPM), with a more pronounced effect among females. Moreover, when exposed to a predatory olfactory cue, increased RT was observed in these females in a reward-related task (PORT), as well as decreased HPA axis responsivity. This sex-specific behavioral effect was associated with increased Crfr1 mRNA expression in the medial prefrontal cortex (mPFC) and higher levels of the histone mark H3R2, a histone modification known to be involved in transcriptional activation, within the promoter of the Crfr1 gene. These findings revealed that ELS exposure can impair the acquisition of environmental information in dangerous situations and increase RT in reward-related scenarios among females, with an important role regarding epigenetic regulation of the Crfr1 gene.
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http://dx.doi.org/10.1016/j.psyneuen.2018.08.032DOI Listing
January 2019

Maternal behavior of the mouse dam toward pups: implications for maternal separation model of early life stress.

Stress 2018 01 18;21(1):19-27. Epub 2017 Oct 18.

a Developmental Cognitive Neuroscience Laboratory (DCNL), Brain Institute (InsCer) , Pontifical Catholic University of Rio Grande do Sul (PUCRS) , Porto Alegre , Brazil.

Maternal care is essential for an adequate pup development, as well as for the health of the dam. Exposure to stress in early stages of life can disrupt this dam-pup relationship promoting altered neurobiological and behavioral phenotypes. However, there is a lack of consensus regarding the effects of daily maternal separation (MS) on the pattern of maternal behavior. The aim of this study is to compare the patterns of maternal behavior between mice exposed to MS and controls. BALB/c mice were subjected to MS for a period of 180 min/day from postnatal day 2-7 (n = 17) or designated to be standard animal facility reared (AFR) controls (n = 19). Maternal behaviors were computed as frequency of nursing, licking pups and contact with pups, and nonmaternal behaviors were computed as frequency of actions without interaction with pups and eating/drinking. A total of 18 daily observations of maternal behavior were conducted during these six days, and considering the proportion of maternal and nonmaternal behaviors, an index was calculated. There was no difference when comparing the global index of maternal behavior between the AFR and MS animals by the end of the observed period. However, the pattern of maternal behavior between groups was significantly different. While MS dams presented low frequency of maternal behavior within the first couple days of the stress protocol, but increasing over time, AFR dams showed higher maternal behavior at the beginning, reducing over time. Together, our results indicate that MS alters the maternal behavior of the dams toward pups throughout the first week of the stress protocol and provoked some anxiety-related traits in the dams. The inversion of maternal behavior pattern could possibly be an attempt to compensate the low levels of maternal care observed in the first days of MS.
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http://dx.doi.org/10.1080/10253890.2017.1389883DOI Listing
January 2018

NFκB1 and NFκB2 gene expression in the prefrontal cortex and hippocampus of early life stressed mice exposed to cocaine-induced conditioned place preference during adolescence.

Neurosci Lett 2017 Sep 18;658:27-31. Epub 2017 Aug 18.

Developmental Cognitive Neuroscience Lab (DCNL), Brain Institute of Rio Grande do Sul (InsCer), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil; Graduate Program in Psychology, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil; Graduate Program in Pediatrics and Child Health, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil. Electronic address:

Neuro-immune pathways contribute to the onset and maintenance of cocaine-seeking behaviors, particularly through activation of NFκB signaling in the brain. However, the molecular mechanisms of this relationship are still not completely understood, especially considering the effects of early life stress, a major risk factor to cocaine addiction. The goal of this study was to investigate NFκB1 and NFκB2 gene expression in the prefrontal cortex (PFC) and hippocampus of mice exposed to early life stress and cocaine-induced conditioned place preference (CPP) within adolescence. Male BALB/c mice were randomly assigned to one of four groups: animal facility reared (AFR) with or without CPP training; maternal separation (MS) with our without CPP training. The MS animals were subjected to daily 3-h maternal separation from postnatal day (PND) 2 to 15. CPP was performed following three sequential phases: habituation (PND 34), conditioning (PND 35 to PND 44) and post-conditioning test (PND 45). Gene expression was determined by qPCR. NFκB1 mRNA levels were decreased in the PFC of animals exposed to CPP compared to drug-naïve animals, while no difference was detected regarding rearing conditions. NFκB2 expression was upregulated in the PFC of animals exposed to CPP when compared to drug-naïve animals, particularly in animals exposed to MS with higher CPP scores. No significant effects were detected in the hippocampus. Cortical NFκB2 up-regulation may be involved with the enhanced motivational salience for cocaine-paired cues observed in animals exposed to MS during adolescence.
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http://dx.doi.org/10.1016/j.neulet.2017.08.032DOI Listing
September 2017

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice.

Neurobiol Learn Mem 2017 May 20;141:157-167. Epub 2017 Apr 20.

Graduate Program in Pediatrics and Child Health, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil; Developmental Cognitive Neuroscience Lab (DCNL), Graduate Program in Psychology, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil. Electronic address:

In rodents, disruption of mother-infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long-term neurobiological consequences. Particularly stress-induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex-dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related β -catenin (β -Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH-2 and CDH-8 mRNA levels, as well as an upregulation of CDH-1 in the prefrontal cortex in both males and females. MS-reared female mice presented lower CDH-1 mRNA levels in the hippocampus. In addition, hippocampal CDH-1 mRNA levels were positively correlated with recognition memory performance in females. MS-reared male mice exhibited higher β -Cat mRNA levels in the hippocampus. Considering sex-specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH-1, β -Cat, and CDH-6 in the hippocampus, as well as CDH-1, CDH-8 and CDH-11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.
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http://dx.doi.org/10.1016/j.nlm.2017.04.006DOI Listing
May 2017

MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice.

Biol Psychiatry 2017 06 26;81(12):979-989. Epub 2016 Dec 26.

Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck. Electronic address:

Background: MicroRNA (miRNA)-mediated control of gene expression suggests that miRNAs are interesting targets and/or biomarkers in the treatment of anxiety- and trauma-related disorders, where often memory-associated gene expression is adversely affected.

Methods: The role of miRNAs in the rescue of impaired fear extinction was assessed using the 129S1/SvlmJ (S1) mouse model of impaired fear extinction. miRNA microarray analysis, reverse transcription polymerase chain reaction, fluorescent in situ hybridization, lentiviral overexpression, and Luciferase reporter assays were used to gain insight into the mechanisms underlying miRNA-mediated normalization of deficient fear extinction.

Results: Rescuing impaired fear extinction via dietary zinc restriction was associated with differential expression of miRNAs in the amygdala. One candidate, miR-144-3p, robustly expressed in the basolateral amygdala, showed specific extinction-induced, but not fear-induced, increased expression in both extinction-rescued S1 mice and extinction-intact C57BL/6 (BL6) mice. miR-144-3p upregulation and effects on subsequent behavioral adaption was assessed in S1 and BL6 mice. miR-144-3p overexpression in the basolateral amygdala rescued impaired fear extinction in S1 mice, led to enhanced fear extinction acquisition in BL6 mice, and furthermore protected against fear renewal in BL6 mice. miR-144-3p targets a number of genes implicated in the control of plasticity-associated signaling cascades, including Pten, Spred1, and Notch1. In functional interaction studies, we revealed that the miR-144-3p target, PTEN, colocalized with miR-144-3p in the basolateral amygdala and showed functional downregulation following successful fear extinction in S1 mice.

Conclusions: These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders.
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http://dx.doi.org/10.1016/j.biopsych.2016.12.021DOI Listing
June 2017

Running during adolescence rescues a maternal separation-induced memory impairment in female mice: Potential role of differential exon-specific BDNF expression.

Dev Psychobiol 2017 03 3;59(2):268-274. Epub 2016 Nov 3.

Graduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil.

Exposure to early life stress has been associated with memory impairments related to changes in brain-derived neurotrophic factor (BDNF) signaling. However, the potential impact of physical exercise to reverse these effects of maternal separation has been under investigated. Mice were subjected to maternal separation during the first 2 weeks of life and then exposed to a 3-week running protocol during adolescence. The spontaneous object recognition task was performed during adolescence followed by analysis of hippocampal expression of exons I, IV, and IX of the BDNF gene. As expected, maternal separation impaired recognition memory and this effect was reversed by exercise. In addition, running increased BDNF exon I expression, but decreased expression of BDNF exon IV in all groups, while exon IX expression increased only in MS animals exposed to exercise. Our data suggest that memory deficits can be attenuated by exercise and specific transcripts of the BDNF gene are dynamically regulated following both MS and exercise.
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http://dx.doi.org/10.1002/dev.21487DOI Listing
March 2017

Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2.

Psychopharmacology (Berl) 2016 Sep 9;233(17):3279-88. Epub 2016 Jul 9.

Postgraduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Rationale: Early life stress is a major risk factor for cocaine addiction; however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors.

Objectives: We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex.

Methods: Male BALB/c mice subjected to MS (3 h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment.

Results: MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS.

Conclusions: Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.
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http://dx.doi.org/10.1007/s00213-016-4373-zDOI Listing
September 2016

Brain-Derived Neurotrophic Factor and Delayed Verbal Recall in Crack/Cocaine Dependents.

Eur Addict Res 2015 28;21(5):273-8. Epub 2015 May 28.

Programa de Pós-Graduação em Pediatria e Saúde da Criança, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil.

Background/aims: Considering the role of brain-derived neurotrophic factor (BDNF) in memory processes and its peripheral response during the detoxification of cocaine, the aim of this study was to investigate whether plasma BDNF levels could be related to memory performance in women with crack/cocaine dependence.

Methods: Twenty-five abstinent female crack/cocaine users (CCD) and 25 unmedicated healthy women (HW), carefully matched for age and years of formal education, were assessed regarding memory performance. Logical Memory was used to assess the immediate verbal recall (IVR), delayed verbal recall (DVR) and memory retention. Plasma BDNF levels were measured by Elisa immunoassay. Beck Depression Inventory was used to assess the severity of depressive symptoms, and the Cocaine Selective Severity Assessment the severity of cocaine abstinence symptoms.

Results: The CCD group had lower DVR scores and higher plasma BDNF levels when compared to HW group. In addition, a linear regression model showed that BDNF levels predicted DVR scores within CCD group independently of depressive symptoms (R = 0.51; R(2) = 0.26; t(22) = 4.025, p = 0.03).

Conclusion: Despite higher plasma BDNF levels, crack users exhibited memory impairments when compared to healthy women. Specifically, peripheral BDNF levels predicted better cognitive performance only within individuals who already had cognitive impairment.
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http://dx.doi.org/10.1159/000430436DOI Listing
May 2016

Long-term cannabis abuse and early-onset cannabis use increase the severity of cocaine withdrawal during detoxification and rehospitalization rates due to cocaine dependence.

Drug Alcohol Depend 2014 Nov 16;144:153-9. Epub 2014 Sep 16.

Centre of Studies and Research in Traumatic Stress, Pontifical Catholic University of Rio Grande do Sul, Av. Ipiranga, 6681, prédio 11, sala 928, 90619-900 Porto Alegre, RS, Brazil. Electronic address:

Background: Long-term and early-onset cannabis consumption are implicated in subsequent substance- related problems. The aim of this follow-up study was to investigate whether these patterns of cannabis use could impact cocaine withdrawal severity and cocaine craving intensity during detoxification. In addition, we investigated their impact in the rehospitalization rates due to cocaine dependence 2.5 years after detoxification assessment.

Methods: The sample was composed of 93 female cocaine-dependent inpatients who were enrolled in an inpatient detoxification unit. Cocaine withdrawal symptoms were measured at the 4th, 9th and 14th days of detoxification using the cocaine selective severity assessment (CSSA). Data on the age of first years of drug use - alcohol, cannabis and cocaine - and the years of substance abuse were obtained using the Addiction Severity Index (ASI-6). Other relevant clinical variables were also investigated, including a 2.5 years follow-up assessment of number of rehospitalization due to cocaine dependence.

Results: Early-onset cannabis use and long-term cannabis abuse were associated with an increase instead of a reduction in the severity of cocaine withdrawal symptoms and craving intensity during detoxification. In addition, long-term cannabis abuse predicted higher number of rehospitalization due to cocaine dependence after 2.5 years of the first detoxification assessment.

Conclusions: Early-onset cannabis use and long-term cannabis abuse are associated with a worse detoxification treatment response. Our findings may help to identify patients who will struggle more severely to control cocaine withdrawal syndrome during early drug abstinence, and indicate that cannabis use prior to cocaine withdrawal should be considered an adverse factor.
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http://dx.doi.org/10.1016/j.drugalcdep.2014.09.003DOI Listing
November 2014

Dual-memory processes in crack cocaine dependents: The effects of childhood neglect on recall.

Memory 2015 24;23(7):955-71. Epub 2014 Jul 24.

a Centre of Studies and Research in Traumatic Stress (NEPTE) , Pontifical Catholic University of Rio Grande do Sul , Porto Alegre , RS , Brazil.

Exposure to adversities during sensitive periods of neurodevelopment is associated with the subsequent development of substance dependence and exerts harmful, long-lasting effects upon memory functioning. In this study, we investigated the relationship between childhood neglect (CN) and memory using a dual-process model that quantifies recollective and non-recollective retrieval processes in crack cocaine dependents. Eighty-four female crack cocaine-dependent inpatients who did (N = 32) or did not (N = 52) report a history of CN received multiple opportunities to study and recall a short list composed of familiar and concrete words and then received a delayed-recall test. Crack cocaine dependents with a history of CN showed worse performance on free-recall tests than did dependents without a history of CN; this finding was associated with declines in recollective retrieval (direct access) rather than non-recollective retrieval. In addition, we found no evidence of group differences in forgetting rates between immediate- and delayed-recall tests. The results support developmental models of traumatology and suggest that neglect of crack cocaine dependents in early life disrupts the adult memory processes that support the retrieval of detailed representations of events from the past.
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http://dx.doi.org/10.1080/09658211.2014.938084DOI Listing
May 2016

Mothers who were sexually abused during childhood are more likely to have a child victim of sexual violence.

Trends Psychiatry Psychother 2014 Jun 30;36(2):119-22. Epub 2014 May 30.

Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Introduction: Recurrent exposure to childhood sexual abuse (CSA) seems to be higher among victims of sexual abuse. In this sense, experiences related to sexual violence can perpetuate within the family context itself in various ways. Here, we investigate the association between being exposed to CSA and having a child victim of sexual abuse.

Method: We used a sample with 123 mothers, who were divided into 2 groups: one consisting of 41 mothers of sexually abused children and another consisting of 82 mothers of non-sexually abused children. History of exposure to CSA was evaluated by means of the Childhood Trauma Questionnaire - Short Form (CTQ) and we used a logistic regression model to estimate the prediction values regarding having or not a child exposed to sexual violence.

Results: Mothers of sexually abused children had significantly higher scores on CTQ, especially on the sexual abuse subscale (SA). According to our logistic regression model, higher scores on the CTQ significantly predicted the status of being a mother of children exposed to sexual violence in our sample (Wald = 7.074; p = 0.008; Exp(B) = 1.681). Years of formal education reduced the likelihood of having a child victim of sexual violence (Wald = 18.994; p = 0.001; Exp(B) = 0.497).

Conclusion: Our findings highlight the importance of a possible intergenerational effect of sexual abuse. Family intervention and prevention against childhood maltreatment should take this issue in account.
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http://dx.doi.org/10.1590/2237-6089-2013-0054DOI Listing
June 2014

Early life stress and tumor necrosis factor superfamily in crack cocaine withdrawal.

J Psychiatr Res 2014 Jun 2;53:180-6. Epub 2014 Mar 2.

Centre of Studies and Research in Traumatic Stress, Pontifical Catholic University of Rio Grande do Sul, Av. Ipiranga, 6681 Prédio 11 Sala 936, Porto Alegre, RS 90619-900, Brazil; Laboratory of Immunosenescence, Institute of Biomedical Research, Pontifical Catholic University of Rio Grande do Sul, Av. Ipiranga, 6690/2° floor, Porto Alegre, RS 90610-000, Brazil. Electronic address:

Background: Both early life stress (ELS) and substance abuse, especially cocaine, have robust effects on the inflammatory system. Considering the role of the tumor necrosis factor system in inflammatory signaling and its association with ELS, the aim of the study was to compare plasma levels of TNF-alpha, its soluble receptors and ligands during early abstinence of crack cocaine.

Methods: This study included 24 crack cocaine-dependent women with (CRACK-ELS) and 20 without (CRACK) a history of ELS. A healthy control group (HC), containing 25 participants, was included to provide reference values. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history of patients. Plasma levels of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), soluble receptors TNFRI (sTNFRI) and TNFRII (sTNFRII) were assessed on the 18th day of treatment.

Results: The CRACK-ELS group had higher TNF-alpha and lower TWEAK levels compared to the CRACK and HC groups. sTNFRII was increased, but only in comparison with the crack cocaine group and the controls. TRAIL levels were slightly higher in the CRACK-ELS group, while no differences were found for sTNFRI levels. Also, TNF-alpha plasma level was positively predicted by abstinence severity and childhood maltreatment severity, and TWEAK was negatively predicted by childhood maltreatment severity.

Conclusions: This is the first study to evaluate the newly secreted tumor necrosis factor superfamily ligands, TWEAK and TRAIL, during crack cocaine abstinence, supporting the association between early life stress and peripheral pro-inflammatory levels.
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http://dx.doi.org/10.1016/j.jpsychires.2014.02.017DOI Listing
June 2014

Revised Reading the Mind in the Eyes Test (RMET) - Brazilian version.

Braz J Psychiatry 2014 Jan-Mar;36(1):60-7. Epub 2013 Dec 17.

Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Center for Studies and Research in Traumatic Stress, Graduate Program in Psychology, Porto AlegreRS, Brazil, Center for Studies and Research in Traumatic Stress, Graduate Program in Psychology, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.

Objective: To translate and adapt to Brazilian Portuguese the Revised Reading the Mind in the Eyes Test (RMET), in both paper-and-pencil and computerized versions. The RMET is a well-accepted instrument for assessment of Theory of Mind (ToM), an important component of social cognition.

Methods: Following a guideline for translation of material for clinical populations, this study had three main phases: 1) formal translation and semantic adaptation to Brazilian Portuguese; 2) an acceptability trial with health professionals as judges evaluating picture-word matching; and 3) a trial using the paper-and-pencil and computerized versions (experiments built in E-Prime 2.0.10 software) with healthy participants to test whether the instrument has similar outputs to those expected in versions in other languages.

Results: RMET was adequately adapted to Brazilian Portuguese. This version showed acceptability and outputs similar to versions of the instrument in other languages, including the original one. We kept the same number of images as the original English version.

Conclusions: Considering the scarcity of cognitive assessment instruments adequately adapted to Portuguese and the importance of social cognition in many psychiatric disorders, this work adds an important resource to Brazilian research and is administrable in both paper-and-pencil and computerized versions.
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http://dx.doi.org/10.1590/1516-4446-2013-1162DOI Listing
September 2014