Publications by authors named "Rodrigo Grassi-Oliveira"

138 Publications

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

Behav Brain Res 2021 Mar 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2021.113237DOI Listing
March 2021

Cortical thickness and subcortical volume abnormalities in male crack-cocaine users.

Psychiatry Res Neuroimaging 2021 Apr 23;310:111232. Epub 2020 Nov 23.

Department of Neuroscience, Pontifical Catholic University of Rio Grande do Sul, 90619900, Porto Alegre, Brasil.

Crack-cocaine offers a higher risk of abuse than intranasal and intravenous use of cocaine. Yet, current treatments remain disappointing and our understanding of the mechanism of crack-cocaine neurotoxicity is still incomplete. Magnetic resonance images studies on brain changes of crack-cocaine addicts show divergent data. The present study investigated gray matter (GM) abnormalities in crack-cocaine dependents (n = 18) compared to healthy controls (n = 17). MRI data was analysed using FreeSurfer and voxel-based morphometry (VBM). FreeSurfer analysis showed that CD had decreased cortical thickness (CT) in the left inferior temporal cortex (lTC), left orbitofrontal cortex (lOFC) and left rostro frontal cortex (lRFC), enlargement in left inferior lateral ventricle, and smaller GM volume in right hippocampus and right ventral diencephalon. VBM analysis showed that CD had significantly decreased GM volume in left Putamen and left nucleus accumbens. Furthermore, we found a negative correlation between duration of crack-cocaine use and lTC CT. These results provide compelling evidence for GM abnormalities in CD and also suggest that duration of crack-cocaine use may be associated with CT alterations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pscychresns.2020.111232DOI Listing
April 2021

A behavioral economic risk aversion experiment in the context of the COVID-19 pandemic.

PLoS One 2021 19;16(1):e0245261. Epub 2021 Jan 19.

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

We investigated what degree of risk of infection with COVID-19 is necessary so that people intend to stay home, even when doing so means losing their salary. We conducted an online survey across Brazil during the initial outbreak, in which 8,345 participants answered a questionnaire designed to identify the maximum tolerated risk (k') necessary for them to disregard social distancing recommendations and guarantee their salaries. Generalized linear mixed models, path analysis structural equation, and conditional interference classification tree were performed to further understand how sociodemographic factors impact k' and to establish a predictive model for the risk behavior of leaving home during the pandemic. We found that, on average, people tolerate 38% risk of infection to leave home and earn a full salary, but this number decreased to 13% when the individual risk perception of becoming ill from severe acute respiratory syndrome coronavirus-2 is considered. Furthermore, participants who have a medium-to-high household income and who are older than 35 years are more likely to be part of the risk-taking group who leave home regardless of the potential COVID-19 infection level; while participants over 45 years old and with good financial health are more likely to be part of the risk-averse group, who stay home at the expense of any salary offered. Our findings add to the political and public debate concerning lockdown strategies by showing that, contrary to supposition, people with low socioeconomic status are not more likely to ignore social distancing recommendations due to personal economic matters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815159PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00221-020-05859-yDOI Listing
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00221-020-05859-yDOI Listing
September 2020

Gene expression changes associated with trajectories of psychopathology in a longitudinal cohort of children and adolescents.

Transl Psychiatry 2020 03 17;10(1):99. Epub 2020 Mar 17.

LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.

We aimed to identify blood gene expression patterns associated to psychopathological trajectories retrieved from a large community, focusing on the emergence and remission of general psychiatric symptoms. Hundred and three individuals from the Brazilian High-Risk Cohort Study (BHRCS) for mental disorders were classified in four groups according to Child Behavior Checklist (CBCL) total score at the baseline (w0) and after 3 years (w1): low-high (L-H) (N = 27), high-low (H-L) (N = 12), high-high (H-H) (N = 34) and low-low (L-L) groups (N = 30). Blood gene expression profile was measured using Illumina HT-12 Beadchips, and paired analyses comparing w0 and w1 were performed for each group. Results: 98 transcripts were differentially expressed comparing w0 and w1 in the L-H, 33 in the H-L, 177 in the H-H and 273 in the L-L. Of these, 66 transcripts were differentially expressed exclusively in the L-H; and 6 only in the H-L. Cross-Lagged Panel Models analyses revealed that RPRD2 gene expression at w1 might be influenced by the CBCL score at w0. Moreover, COX5B, SEC62, and NDUFA2 were validated with another technique and were also differentially regulated in postmortem brain of subjects with mental disorders, indicating that they might be important not only to specific disorders, but also to general psychopathology and symptoms trajectories. Whereas genes related to metabolic pathways seem to be associated with the emergence of psychiatric symptoms, mitochondrial inner membrane genes might be important over the course of normal development. These results suggest that changes in gene expression can be detected in blood in different psychopathological trajectories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-0772-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078305PMC
March 2020

Association of CHRNA5 Gene Variants with Crack Cocaine Addiction.

Neuromolecular Med 2020 09 10;22(3):384-390. Epub 2020 Mar 10.

Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Genome-wide studies provide increasing evidence of association of genetic variants with different behaviors. However, there is a growing need for replication and subsequent characterization of specific findings. In this sense, the CHRNA5 gene has been associated with nicotine (with genome-wide significance), alcohol and cocaine addictions. So far, this gene has not been evaluated in smoked (crack) cocaine. We aimed to analyze the influence of CHRNA5 variants in crack addiction susceptibility and severity. The sample includes 300 crack-addicted patients and 769 non-addicted individuals. The CHRNA5 SNPs evaluated were rs588765, rs16969968, and rs514743. Homozygosity for rs16969968 and rs588765 major alleles was nominally associated with a risk to crack addiction (GG, P = 0.032; CC, P = 0.036, respectively). Haplotype analyses reveal significant associations (rs588765|rs16969968|rs514743 p = 7.66 × 10) and suggest a substantial role for rs16969968. These findings corroborate previous reports in cocaine addiction-in line with the expected effects of cocaine in the cholinergic system-and in the opposite direction of significant GWAS findings for nicotine addiction susceptibility. These results are strengthened by the first report of an association of rs588765 with crack addiction and by the haplotype findings. In summary, our study highlights the relevance of the α5 subunit on crack cocaine addiction, replicating previous results relating CHRNA5 with the genetics and pathophysiology of addiction of different drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12017-020-08596-1DOI Listing
September 2020

Association Between Recent Cannabis Consumption and Withdrawal-Related Symptoms During Early Abstinence Among Females With Smoked Cocaine Use Disorder.

J Addict Med 2020 Jul/Aug;14(4):e37-e43

Pontifical Catholic University of Rio Grande do Sul (PUCRS), Developmental Cognitive Neuroscience Lab, Porto Alegre, RS, Brazil (TWV, LMR, JVNMP, CB, JPN, RG-O); Experimental and Clinical Pharmacopsychology Laboratory, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland (BK-S); Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, TX (JS); Pontifical Catholic University of Rio de Janeiro (PUC-Rio), Department of Psychology, Rio de Janeiro, RJ, Brazil (BS-V).

Background: The effects of cannabis on clinical outcomes of treatment services for other drug use disorders remains unclear. The primary aim of the current study was to investigate the effects of recent cannabis consumption on the severity of cocaine withdrawal and depressive symptoms during a 3-week inpatient treatment program for women with cocaine use disorder. The second goal of this study was to test the effect of recent alcohol or tobacco use on the aforementioned outcomes.

Methods: This was a longitudinal study with 2 assessment time points: at enrollment and upon discharge from a medically managed intensive inpatient unit. The sample was composed of 214 early abstinence females with cocaine use disorder. Cocaine withdrawal and depressive symptoms were measured using the Cocaine Selective Severity Assessment (CSSA) and the Beck Depressive Inventory (BDI-II). Recent substance use was evaluated using the Addiction Severity Index (ASI-6).

Results: Patients with cocaine use disorder and with frequent recent cannabis use reported higher severity of cocaine withdrawal and depressive symptoms after 3 weeks of inpatient treatment. Neither recent alcohol nor tobacco use was associated with increased CSSA or BDI outcomes, suggesting these substances play a minor role compared to recent cannabis use in affecting withdrawal-related symptoms.

Conclusions: The assessment of recent cannabis use may help identify patients in need of additional treatment to manage severe cocaine withdrawal symptoms and depressive symptoms during early abstinence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ADM.0000000000000599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358113PMC
July 2021

Exercise before pregnancy attenuates the effects of prenatal stress in adult mice in a sex-dependent manner.

Int J Dev Neurosci 2020 Apr 5;80(2):86-95. Epub 2020 Feb 5.

Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

The present study aimed to investigate the long-term effects of exercise before pregnancy on changes induced by prenatal stress. Female and male Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX + PNS). As adult, fear/anxiety behavior, corticosterone secretion, expression of hypothalamic-pituitary-adrenal (HPA)-related genes, as well as epigenetic modifications were evaluated. Exercise before gestation did not prevent the increased fear/anxiety behavior in PNS mice. A nearly significant (p = .06) basal corticosterone increase was observed in PNS males and the exercise before pregnancy reduced the stress-induced corticosterone increase in PNS females. In addition, an increase on prefrontal cortex (PFC) CRHR1 gene expression was observed in PNS females, which was attenuated by the exercise before gestation. We have also found a glucocorticoid receptor (GR) gene expression decrease in the prefrontal cortex in PNS males, as well as a histone H3 acetylation decrease (p = .06) close to the significance level. In conclusion, pregestational exercise may attenuate developmental changes induced by prenatal stress in a sex-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jdn.10001DOI Listing
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jdn.10004DOI Listing
February 2020

Are serum brain-derived neurotrophic factor concentrations related to brain structure and psychopathology in late childhood and early adolescence?

CNS Spectr 2020 Dec 17;25(6):790-796. Epub 2019 Dec 17.

National Institute of Developmental Psychiatry for Children and Adolescents (INCTCNPq), São Paulo, Brazil.

Objective: Mental disorders can have a major impact on brain development. Peripheral blood concentrations of brain-derived neurotrophic factor (BDNF) are lower in adult psychiatric disorders. Serum BDNF concentrations and BDNF genotype have been associated with cortical maturation in children and adolescents. In 2 large independent samples, this study tests associations between serum BDNF concentrations, brain structure, and psychopathology, and the effects of BDNF genotype on BDNF serum concentrations in late childhood and early adolescence.

Methods: Children and adolescents (7-14 years old) from 2 cities (n = 267 in Porto Alegre; n = 273 in São Paulo) were evaluated as part of the Brazilian high-risk cohort (HRC) study. Serum BDNF concentrations were quantified by sandwich ELISA. Genotyping was conducted from blood or saliva samples using the SNParray Infinium HumanCore Array BeadChip. Subcortical volumes and cortical thickness were quantified using FreeSurfer. The Development and Well-Being Behavior Assessment was used to identify the presence of a psychiatric disorder.

Results: Serum BDNF concentrations were not associated with subcortical volumes or with cortical thickness. Serum BDNF concentration did not differ between participants with and without mental disorders, or between Val homozygotes and Met carriers.

Conclusions: No evidence was found to support serum BDNF concentrations as a useful marker of developmental differences in brain and behavior in early life. Negative findings were replicated in 2 of the largest independent samples investigated to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1092852919001688DOI Listing
December 2020

An fMRI study of inhibitory control and the effects of exposure to violence in Latin-American early adolescents: alterations in frontoparietal activation and performance.

Soc Cogn Affect Neurosci 2019 10;14(10):1097-1107

School of Medicine, PUCRS-Pontifícia Universidade Catolica do Rio Grande do Sul, Porto Alegre, RS, Brazil, 90619-900.

We used functional magnetic resonance to investigate the effects of exposure to violence on early adolescent brain function in an inhibitory control task. We investigated the association among scores on self-reported exposure to violence, performance and brain activation. Thirty-seven early adolescents (ages 10-14) from a Latin-American urban region participated in the study. Results showed that recent and chronic exposure to violence was associated with less activation of a network of frontal regions, including the anterior cingulate gyrus and the superior frontal cortex; recent exposure to violence was also associated with less activation of the superior parietal lobe. Results also showed that less activation correlated with more prominent deterioration in the performance in the inhibitory control task (increased latency with time). The findings suggest that early adolescence exposure to violence is associated with differences in activation of a neural network commonly associated with executive function and control. The results underscore the urgency of addressing exposure to violence in adolescence, a period of high susceptibility to the environment, and are discussed in the light of the evidence of the effects of violence on adolescent brain function. Executive function training may be a candidate for targeted cognitive interventions aimed at mitigating these effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/scan/nsz092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036087PMC
October 2019

Cocaine Use Disorder Is Associated With Changes in Th1/Th2/Th17 Cytokines and Lymphocytes Subsets.

Front Immunol 2019 15;10:2435. Epub 2019 Oct 15.

Developmental Cognitive Neuroscience Lab, School of Medicine, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.

Cocaine is a psychostimulant drug with high addictive proprieties. Evidence suggests that cocaine use leads to critical changes in the immune system, with significant effects on T, B, and natural killer (NK) cells and influencing peripheral levels of cytokines. The presence of abstinence-related symptoms during detoxification treatment is known to influence the prognosis. Here, our aim was to investigate immune profiles in women with cocaine use disorder (CUD) according to withdrawal symptoms severity. Blood samples and clinical data were collected at onset of detoxification treatment of 50 women with CUD. The patients were stratified according to Cocaine Selective Severity Assessment (CSSA) scores in low withdrawal (L-W) and high withdrawal (H-W) categories. In addition, we also included a control group with 19 healthy women as reference to immune parameters. Peripheral blood was collected and lymphocyte subsets were phenotyped by multi-color flow cytometry (B cells, CD4 T, CD8 T, NK cells, and different stages of T-cell differentiation). PBMCs from patients and healthy controls were stimulated with phytohemagglutinin (1%) for 72 h to assess the production of Th1/Th2/Th17 cytokines. Following stimulation, lymphocytes from women with CUD produced increased levels of Th1/Th2/Th17 cytokines. However, higher levels of IL-2 and IL-17 were observed only in the L-W group, while higher levels of IL-6 were detected in the H-W group compared to controls. H-W group showed lower percentage of early-differentiated Th cells (CD4CD27CD28), elevated percentage of Th cells (CD3CD4), intermediate-differentiated Th cells (CD4CD27CD28), and B cells (CD3CD19). Both CUD groups showed decreased percentages of naïve T cells (CD3CD4CD45RA and CD3CD8CD45RA). Our data demonstrated that CUD can lead to increased production of Th1/Th2/Th17 cytokines and lymphocyte changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843068PMC
October 2020

Association between spontaneous activity of the default mode network hubs and leukocyte telomere length in late childhood and early adolescence.

J Psychosom Res 2019 12 30;127:109864. Epub 2019 Oct 30.

Center of Mathematics, Computing and Cognition, Universidade Federal do ABC, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil. Electronic address:

The impact of early life stress on mental health and telomere length shortening have been reported. Changes in brain default mode network (DMN) were found to be related to a myriad of psychiatric conditions in which stress may play a role. In this context, family environment and adverse childhood experiences (ACEs) are potential causes of stress. This is a hypothesis-driven study focused on testing two hypotheses: (i) there is an association between telomere length and the function of two main hubs of DMN: the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC); (ii) this association is modulated by family environment and/or ACEs. To the best of our knowledge, this is the first study investigating these hypotheses. Resting-state functional magnetic resonance imaging data and blood sample were collected from 389 subjects (6-15 age range). We assessed DMN fractional amplitude of low-frequency fluctuations (fALFF) and leukocyte telomere length (LTL). We fitted general linear models to test the main effects of LTL on DMN hubs and the interaction effects with Family Environment Scale (FES) and ACEs. The results did not survive a strict Bonferroni correction. However, uncorrected p-values suggest that LTL was positively correlated with fALFF in PCC and a FES interaction between FES and LTL at mPFC. Although marginal, our results encourage further research on the interaction between DMN hubs, telomere length and family environment, which may play a role on the biological embedding of stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychores.2019.109864DOI Listing
December 2019

Hair cortisol levels and mental health problems in children and adolescents exposed to victimization.

Stress 2020 09 15;23(5):546-555. Epub 2019 Nov 15.

School of Medicine, Graduate Program of Medicine, Neurosciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Youths who experience multiple forms of victimization are at a heightened risk for psychopathology across the lifespan. The hypothalamic-pituitary-adrenal (HPA) axis is a key target for the investigation of neurobiological changes induced by chronic stress and violence exposure. The measurement of hair cortisol concentration allows the investigation of long-term HPA activity and its association with victimization. The present study investigated the impact of exposure to polyvictimization in Latin-American children and adolescents on hair cortisol levels. We investigated association among cortisol, mental health problems and victimization. The study included 83 youths (mean age 10.84 years-old) from southern Brazil. We assessed self-reported victimization scores (Juvenile Victimization Questionnaire - JVQ-R2), mental health problems (Child Behavior Checklist - CBCL/6-18), and hair cortisol concentrations for the previous 30 days. The results showed an association between exposure to multiple forms of victimization and higher concentrations of hair cortisol; the results also showed that cortisol levels and mental health problems were associated with the severity of polyvictimization. These findings suggest that preadolescent victimization is associated with hyperactivation of HPA axis and with increased risk of mental health issues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10253890.2019.1690448DOI Listing
September 2020

Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths.

Clin Epigenetics 2019 10 21;11(1):146. Epub 2019 Oct 21.

Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu 740, Ed. Leitão da Cunha, Vila Clementino, Sao Paulo, SP, Brazil.

Background: Psychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time.

Methods: We selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n = 48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature.

Results: We identified 663 differentially methylated positions (DMPs) and 90 differentially methylated regions (DMRs) associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood; among these, we found a correlation between the DNA methylation and mRNA levels of RB1CC1 and a correlation between the CBCL and mRNA levels of KMT2E. Of the DMRs, three genes were differentially expressed: ASCL2, which is involved in neurogenesis; HLA-E, which is mapped to the MHC loci; and RPS6KB1, the gene expression of which was correlated with an increase in the CBCL between the time points.

Conclusions: We observed that changes in DNA methylation and, consequently, in gene expression in the peripheral blood occurred concurrently with the emergence of dimensional psychopathology in youths. Therefore, epigenomic modulations might be involved in the regulation of an individual's development of psychopathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0740-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805541PMC
October 2019

Association between cognitive performance and SYT1-rs2251214 among women with cocaine use disorder.

J Neural Transm (Vienna) 2019 12 27;126(12):1707-1711. Epub 2019 Sep 27.

Developmental Cognitive Neuroscience Lab, School of Medicine, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Avenida Ipiranga 6691 - Predio 11, sala 926, Jardim Botânico, Porto Alegre, RS, Brazil.

The SNP rs2251214 of the SYT1 gene was recently associated with externalizing phenotypes, including ADHD and cocaine use disorder (CUD). Here, we investigated whether SYT1-rs2251214 could also be implicated with cognitive performance variations among women with CUD. Results showed that G homozygous (n = 146) have lower cognitive performance in the Stroop, Trail Making and Matrix Reasoning tests compared with A-allele carriers (n = 64), suggesting that rs2251214 may influence the severity of cognitive impairments in CUD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-019-02086-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858578PMC
December 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2019.112221DOI Listing
December 2019

Genetic risk for Alzheimer's disease and functional brain connectivity in children and adolescents.

Neurobiol Aging 2019 10 6;82:10-17. Epub 2019 Jul 6.

Departamento de Psiquiatria e Medicina Legal, Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Section on Negative Affect and Social Processes, Porto Alegre, Brazil; National Institute of Developmental Psychiatry (INPD, CNPq), São Paulo, Brazil. Electronic address:

Research suggested accumulation of tau proteins might lead to the degeneration of functional networks. Studies investigating the impact of genetic risk for Alzheimer's disease (AD) on early brain connections might shed light on mechanisms leading to AD development later in life. Here, we aim to investigate whether the polygenic risk score for Alzheimer's disease (AD-PRS) influences the connectivity among regions susceptible to tau pathology during childhood and adolescence. Participants were youth, aged 6-14 years, and recruited in Porto Alegre (discovery sample, n = 332) and São Paulo (replication sample, n = 304), Brazil. Subjects underwent genotyping and 6-min resting state funcional magnetic resonance imaging. Connections between the local maxima of tau pathology networks were used as dependent variables. The AD-PRS was associated with the connectivity between the right precuneus and the right superior temporal gyrus (discovery sample: β = 0.180, p = 0.036; replication sample: β = 0.202, p = 0.031). This connectivity was also associated with inhibitory control (β = 0.157, p = 0.035) and moderated the association between the AD-PRS and both immediate and delayed recall. These findings suggest the AD-PRS may affect brain connectivity in youth, which might impact memory performance and inhibitory control in early life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658444PMC
October 2019

Cocaine use disorder in females is associated with altered social decision-making: a study with the prisoner's dilemma and the ultimatum game.

BMC Psychiatry 2019 07 5;19(1):211. Epub 2019 Jul 5.

Pontifical Catholic University of Rio Grande do Sul (PUCRS), Developmental Cognitive Neuroscience Lab, Avenida Ipiranga 6690 - Prédio 63, Jardim Botânico, Porto Alegre, RS, Brazil.

Background: Chronic cocaine use is associated with cognitive deficits, including poor performance on neuropsychological tasks of memory, executive functions, theory of mind and decision-making. However, the relationship between cocaine use disorder and social decision-making remains unclear. This is particularly relevant given the fact that many cocaine abusers present impairments in social functioning. In this sense, game theory paradigms have been helping to comprehend the behavior of psychiatric patients when they directly engage in social situations, which may better approximate many of their real-life choices.

Methods: The present study investigated social decision-making in individuals with or without cocaine use disorder, examining their behavior in the Prisoner's Dilemma and in the Ultimatum Game. Thus, 129 females diagnosed with cocaine use disorder and 55 females with no history of substance abuse were recruited and performed both social decision-making tasks. Additional assessments included information about demographics, patterns of substance consumption and executive function performance.

Results: Females with cocaine use disorder opted more often to not defect in the Prisoner's Dilemma, while in the Ultimatum Game they frequently chose to accept the first and unfair offer as responders. These effects were more pronounced within females with long-term history of cocaine use. Associations between cocaine use disorder and altered social decision-making were independent from demographic and executive function variables.

Conclusions: The influence of cocaine use disorder on social decision-making was detected in both game paradigms, resulting in more cooperative behavior in the Prisoner's Dilemma and higher acceptance rate of unfair offers in the Ultimatum Game. Further studies should focus on investigating these associations to shed light on the putative biopsychosocial factors underlying the observed effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12888-019-2198-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612218PMC
July 2019

Hair cortisol concentration, cognitive, behavioral, and motor impairment in multiple sclerosis.

J Neural Transm (Vienna) 2019 09 27;126(9):1145-1154. Epub 2019 Jun 27.

Instituto de Psicologia, Laboratório de Psicologia Experimental, Neurociências e Comportamento (LPNeC), Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600, Sala 116, Santa Cecilia, Porto Alegre, RS, 90035-003, Brazil.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that is characterized by the demyelinated inflammatory processes that occur within the central nervous system. Hypothalamus-pituitary-adrenal axis (HPA axis) dysfunctions have been associated with the triggering or increase in MS symptoms. We thus aimed at evaluating motor and behavioral functions, planning skills, processing speed, and their relationship with stress through measuring hair cortisol concentration from patients with MS. The sample was composed of 40 volunteers that were clinically diagnosed with MS, along with 33 healthy adults. Evaluations included: Clinical Evaluation Form, Mini-Mental State Exam, Hamilton Depression Rating Scale, Multiple Sclerosis Functional Composite Measure, Expanded Disability Status Scale, Berg Balance Scale, Perceived Stress Scale, Zoo Map task, and a hair sample to analyze cortisol levels in the last 30 days. MS patients showed highly elevated hair cortisol levels in comparison to the control group (p = 0.048). All groups presented some degree of depressive and anxiety symptoms, aside from considerable perceived stress levels. The MS group presented deficits in gait, balance, manual skills and processing speed, and this was particularly so in individuals with moderate impairments when compared to control group (p < 0.001). Individuals with MS spent less time planning on ZooMap1 (p = 0.024) and made more mistakes (p < 0.001). No correlation was found between hair cortisol and the symptoms we assessed. However, depressive symptoms and anxiety were related to perceived stress, and higher hair cortisol suggests a change in levels in the HPA axis in MS. Nevertheless, future studies will be necessary to further understand how basal hair cortisol is related to MS symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-019-02040-wDOI Listing
September 2019

Sex-based differences in multidimensional clinical assessments of early-abstinence crack cocaine users.

PLoS One 2019 21;14(6):e0218334. Epub 2019 Jun 21.

Developmental Cognitive Neuroscience Lab, School of Health Sciences, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

Crack cocaine use disorder (CUD) has been related to sex differences. This work aimed to compare the severity of drug use and the severity of other negative related outcomes in males and females with CUD. A total of 1344 inpatients (798 males and 546 females) with crack cocaine use disorder (CUD) were evaluated by a detailed multidimensional clinical assessment, including addiction severity and trauma exposure. Linear regression predicted higher drug use severity (β = 0.273, p < 0.001) and more problems in domains related to childcare issues (β = 0.321), criminal involvement (β = 0.108), work-related problems (β = 0.281) and social support impairments (β = 0.142) for females, all with p < 0.001. Alcohol problems were predicted to be higher in males (β = -0.206, P < 0.001). Females had higher rates of other mental disorders, particularly trauma and stress-related disorders (OR: 3.206, CI: 2.22, 4.61). Important sex differences also emerged in trauma history and HIV infection prevalence. CUD has a more severe clinical presentation among females facing early abstinence. Sex differences in the CUD course indicate the need for consideration of sex-specific interventions and research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218334PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588218PMC
February 2020

Childhood maltreatment and health outcomes.

Braz J Psychiatry 2019 May-Jun;41(3):193

Graduate Program of Medicine and Medical Sciences: Neuroscience, Instituto do Cérebro (InsCer), Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/1516-4446-2019-4103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794127PMC
July 2019

Effect of alcohol use disorder on cellular aging.

Psychopharmacology (Berl) 2019 Nov 3;236(11):3245-3255. Epub 2019 Jun 3.

National Institute on Drug Abuse, Bethesda, National Institutes of Health, Bethesda, MD, USA.

Rationale: Human telomeres consist of tandem repeats at chromosome ends which protect chromosomal DNA from degradation. Telomere shortening occurs as part of natural aging; however, life stressors, smoking, drug use, BMI, and psychiatric disorders could disrupt cell aging and affect telomere length (TL). In this context, studies have evaluated the effects of alcohol consumption on TL; however, results have been inconsistent, which may reflect diverse drinking cut-offs and categorizations.

Objectives: To help clarify this, the present study addresses the association of TL with alcohol use disorder (AUD), drinking behaviors, lifetime stress, and chronological age.

Methods: TL was quantified as the telomere to albumin ratio (T/S ratio) obtained from peripheral blood DNA using the quantitative PCR assay, from 260 participants with AUD and 449 non-dependent healthy controls (HC) from an existing National Institute on Alcohol Abuse and Alcoholism (NIAAA) database.

Results: AUD participants showed shorter TL compared to HC with both, age, and AUD, as independent predictors as well as a significant AUD with age interaction effect on TL. TL was also associated with impulsiveness in AUD participants. We did not observe an association between TL and chronicity of alcohol use, alcohol doses ingested, or childhood trauma exposures in either AUD or HC, although very few HC reported a history of childhood trauma.

Conclusion: Our results support previous findings of telomere shortening with chronic alcohol exposures and show both an effect of AUD on TL that is independent of age as well as a significant AUD by age interaction on TL. These findings are consistent with accelerated cellular aging in AUD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-019-05281-5DOI Listing
November 2019

The association between SYT1-rs2251214 and cocaine use disorder further supports its role in psychiatry.

Prog Neuropsychopharmacol Biol Psychiatry 2019 08 3;94:109642. Epub 2019 May 3.

ADHD Outpatient Program, Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

Synaptotagmin-1 is an essential regulator of synaptic vesicle exocytosis, and its encoding gene (SYT1) is a genome and transcriptome-wide association hit in cognitive performance, personality and cocaine use disorder (CUD) studies. Additionally, in candidate gene studies the specific variant rs2251214 has been associated with attention-deficit/hyperactivity disorder (ADHD), antisocial personality disorder and other externalizing phenotypes in adults with ADHD, as well as with response to methylphenidate (MPH) treatment. In this context, we sought to evaluate, in an independent sample, the association of this variant with CUD, a phenotype that shares common biological underpinnings with the previously associated traits. We tested the association between SYT1-rs2251214 and CUD susceptibility and severity (addiction severity index) in a sample composed by 315 patients addicted to smoked cocaine and 769 non-addicted volunteers. SYT1-rs2251214 was significantly associated with susceptibility to CUD, where the G allele presented increased risk for the disorder in the genetic models tested (P = 0.0021, OR = 1.44, allelic; P = 0.0012, OR = 1.48, additive; P = 0.0127, OR = 1.41, dominant). This is the same allele that was associated with increased risk for ADHD and other externalizing behaviors, as well as poor response to MPH treatment in previous studies. These findings suggest that the neurotransmitter exocytosis pathway might play a critical role in the liability for psychiatric disorders, especially externalizing behaviors and CUD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2019.109642DOI Listing
August 2019

Peripheral blood microRNA levels in females with cocaine use disorder.

J Psychiatr Res 2019 07 2;114:48-54. Epub 2019 Apr 2.

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

Background: There is growing emphasis in the field of psychiatry on the need to identify candidate biomarkers to aid in diagnosis and clinical management of addictive disorders. MicroRNAs (miRNAs) are small nucleotide sequences with the ability to regulate gene expression at the transcriptomic level. However, the role of miRNAs as potential biomarkers for addiction is still underexplored. Based on translational and clinical findings, we compared the expression levels of microRNA-124 (miR-124), microRNA-181 (miR-181), and microRNA-212 (miR-212) between a group of females with cocaine use disorder (CUD; n = 30) and a group of healthy female controls (HC; n = 20).

Methods: Blood expression levels of miR-124, miR-181, and miR-212 in the HC and CUD group were determined by qPCR, using two miRNAs as endogenous controls (miR-24 and miR-126). Substance use behavior was assessed by self-report using the Addiction Severity Index (ASI-6) and depressive symptoms severity was measured using the Beck Depressive Inventory (BDI-II). Urine screen test was performed to detect cocaine metabolites.

Results: Mir-124 and miR-181 were upregulated in the CUD group (p > 0.01). Furthermore, increased cognitive/affective depression symptoms were identified among a CUD subgroup with the higher miR-181 expression levels (p > 0.05). No significant difference in expression levels was found for miR-212.

Conclusions: MiR-124 and miR-181 show promise as biomarkers for CUD when assessed in the peripheral blood. Further investigation is needed to elucidate the molecular mechanisms underlying these associations and to validate target genes regulated by these miRNAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2019.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546503PMC
July 2019

The DNA modification N6-methyl-2'-deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction.

Nat Neurosci 2019 04 18;22(4):534-544. Epub 2019 Feb 18.

Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.

DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of chemical modifications on other nucleobases in the brain. Here we report that in adult mice trained in fear extinction, the DNA modification N6-methyl-2'-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression. The accumulation of m6dA is associated with transcriptional activation at the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV messenger RNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as an epigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-019-0339-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462436PMC
April 2019