Sex differences in sensitivity to fentanyl effects in mice: Behavioral and molecular findings during late adolescence.

PURPOSE: Sex differences play a crucial role in understanding vulnerability to opioid addiction, yet there have been limited preclinical investigations of this effect during the transition from adolescence to adulthood. The present study compared the behaviors of male and female rodents in response to fentanyl treatment and targeted molecular correlates in the striatum and medial prefrontal cortex. MATERIALS AND METHODS: Thirty adolescent C57BL/6J mice underwent a 1-week fentanyl treatment with an escalating dose. In addition to evaluating locomotor activity and anxiety-related parameters, we also assessed naloxone-induced fentanyl acute withdrawal jumps. We employed real-time quantitative PCR (qPCR) to assess overall gene expression of dopaminergic receptors (Drd1, Drd2, Drd4 and Drd5) and the µ-opioid receptor Oprm1. The levels of epigenetic base modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were assessed on CpG islands of relevant genes. RESULTS: Females had higher locomotor activity than males after chronic fentanyl treatment, and they exhibited higher fentanyl withdrawal jumping behavior induced by naloxone. Females also presented lower Drd4 gene expression and DNA methylation (5mC + 5hmC) in the striatum. We found that locomotor activity and fentanyl withdrawal jumps were negatively correlated with Drd4 methylation and gene expression in the striatum, respectively. CONCLUSIONS: The findings suggested that female mice displayed heightened sensitivity to the effects of fentanyl treatment during the transition from adolescence to adulthood. This effect may be associated with molecular alterations related to the Drd4 gene.

Prenatal cocaine exposure and its influence on pediatric epigenetic clocks and epigenetic scores in humans.

The investigation of the effects of prenatal cocaine exposure (PCE) on offspring has been inconsistent, with few studies investigating biological outcomes in humans. We profiled genome-wide DNA methylation (DNAm) of umbilical cord blood (UCB) from newborns with (n = 35) and without (n = 47) PCE. We used DNAm data to (1) assess pediatric epigenetic clocks at birth and (2) to estimate epigenetic scores (ES) for lifetime disorders. We generated gestational epigenetic age estimates (DNAmGA) based on Knight and Bohlin epigenetic clocks. We also investigated the association between DNAmGA and UCB serum brain-derived neurotrophic factor (BDNF) levels. Considering the large-scale DNAm data availability and existing evidence regarding PCE as a risk for health problems later in life, we generated ES for tobacco smoking, psychosis, autism, diabetes, and obesity. A gene ontology (GO) analysis on the CpGs included in the ES with group differences was performed. PCE was associated with lower DNAmGA in newborns, and this effect remained significant when controlling for potential confounders, such as blood cell type composition predicted by DNAm and obstetric data. DNAmGA was negatively correlated with BDNF levels in the serum of UCB. Higher tobacco smoking, psychosis, and diabetes ES were found in the PCE group. The GO analysis revealed GABAergic synapses as a potential pathway altered by PCE. Our findings of decelerated DNAmGA and ES for adverse phenotypes associated with PCE, suggest that the effects of gestational cocaine exposure on the epigenetic landscape of human newborns are detectable at birth.

Cocaine-use disorder and childhood maltreatment are associated with the activation of neutrophils and increased inflammation.

BACKGROUND: Cocaine-use disorder (CUD) has been associated with early life adversity and activated cellular immune responses. Women are most vulnerable to complications from chronic substance disorders, generally presenting an intense feeling of abstinence and consuming significant drug amounts. Here, we investigated neutrophil functional activities in CUD, including the formation of neutrophil extracellular traps (NETs) and related intracellular signalling. We also investigated the role of early life stress in inflammatory profiles. METHODS: Blood samples, clinical data, and history of childhood abuse or neglect were collected at the onset of detoxification treatment of 41 female individuals with CUD and 31 healthy controls (HCs). Plasma cytokines, neutrophil phagocytosis, NETs, intracellular reactive oxygen species (ROS) generation, and phosphorylated protein kinase B (Akt) and mitogen-activated protein kinases (MAPK)s were assessed by flow cytometry. RESULTS: CUD subjects had higher scores of childhood trauma than controls. Increased plasma cytokines (TNF-α, IL-1ß, IL-6, IL-8, IL-12, and IL-10), neutrophil phagocytosis, and production of NETs were reported in CUD subjects as compared to HC. Neutrophils of CUD subjects also produced high levels of intracellular ROS and had more activated Akt and MAPKs (p38/ERK), which are essential signalling pathways involved in cell survival and NETs production. Childhood trauma scores were significantly associated with neutrophil activation and peripheral inflammation. CONCLUSION: Our study reinforces that smoked cocaine and early life stress activate neutrophils in an inflammatory environment.

Cocaine use disorder effects on blood oxytocin levels and OXTR DNA methylation.

Substance use disorders have been associated with alterations in the oxytocinergic system, but few studies have investigated both the peptide and epigenetic mechanisms potentially implicated in the regulation of oxytocin receptor. In this study, we compared plasma oxytocin and blood DNA methylation in the OXTR gene between people with and without cocaine use disorder (CUD). We measured the oxytocin levels of 51 people with CUD during acute abstinence and of 30 healthy controls using an enzyme immunoassay. The levels of DNA methylation in four CpG sites at exon III of the OXTR gene were evaluated in a subsample using pyrosequencing. The Addiction Severity Index was used to assess clinical characteristics. We found higher oxytocin levels in men with CUD (56.5 pg/mL; 95% CI: 48.2-64.7) than in control men (33.6 pg/mL; 95% CI: 20.7-46.5), while no differences between women with and without CUD were detected. With a moderate effect size, the interaction effect between group and sex remained significant when controlling for height, weight and age data. A positive correlation in the CUD sample was found between oxytocin levels and days of psychological suffering prior to treatment enrollment. No group differences were observed regarding DNA methylation data. This suggests that CUD is associated with higher peripheral oxytocin levels in men during acute abstinence. This finding may be considered in future studies that aim at using exogenous oxytocin as a potential treatment for cocaine addiction.

A cross-sectional study of the association between exposure to violence, intelligence, and executive function in Brazilian youths.

We carried out an exploratory study of the association between exposure to violence, intelligence, and executive functions in Brazilian preadolescents. The study included 56 participants (31 males) aged 8 to 14 years old (mean = 11.3, SD = 1.0). We administered neuropsychological tests to evaluate executive functions and the Juvenile Victimization Questionnaire (JVQ) to evaluate exposure to violence. We used the following neuropsychological instruments: Wechsler Abbreviated Scale of Intelligence (WASI), Stroop Color-Word Interference task, digits subtest of the Wechsler Intelligence Scale for Children, and an N-back task. We generated a composite score from neuropsychological test scores and investigated the association of that score, and individual test scores, with exposure to violence and socioeconomic status (SES). Results suggest, first, that exposure to violence is associated with a 0.5-point lower intelligence quotient score for every reported victimization event in the Juvenile Victimization Questionnaire. Results also show that the digits backward subtest scores showed a significant negative correlation with exposure to violence (JVQ; rho = -0.29, p < 0.05); both analyses were adjusted for the level of schooling of parents or guardians, which was also found to be significantly associated with lower intelligence quotient scores. We discuss results in the light of the existing literature on the effects of exposure to violence on adolescent development, and the amounting evidence that suggests an association of exposure to violence, and of victimization, with tests that evaluate constructs of executive functions. The study struggled with low compliance from participants, and we underscore the challenges of carrying out empirical studies aimed at better understanding the development of underrepresented youths, such as those from Central and Latin America.

Decision-making under risk and theory of mind in adolescent offenders in provisional deprivation of liberty.

INTRODUCTION: Delinquent behaviors are risky behaviors that increase during puberty and reach their highest peak in late adolescence. It has been proposed that poor decision-making and theory of mind (ToM) are key cognitive processes implicated with delinquency during adolescence, affecting evaluation of risks and impairing appreciation of social norms. Nevertheless, it is not yet clear whether adolescent offenders who are subjected to provisional deprivation of liberty due to conflict with the law (adolescents in conflict with the law [ACL]) might, in fact, present a specific profile with regard to these cognitive processes. OBJECTIVES: To assess deliberative decision-making and ToM among adolescents in conflict with the law and adolescents not in conflict with the law. METHODS: The sample comprised 62 participants: ACL (n = 29) and a control group (CG) (n = 33). ToM was assessed with the Reading the Mind in the Eyes Test (RMET) and decision-making was assessed with the Columbia Card Task (CCT). Substance use, callous-unemotional traits, childhood maltreatment, and intelligence quotient (IQ) were also assessed. RESULTS: ACL had more ToM errors for negative mental states in comparison to CG, but not for error rates concerning neutral and positive mental states. With regards to decision-making, our results suggest that ACL group members did not vary their behavior based on the available information and that the risk information had an opposite effect on the number of cards chosen (risk-taking behavior) when compared to CG. CONCLUSION: These findings have important implications for development of interventions for these adolescents, suggesting that they tend to learn little from negative outcomes and have reduced capacity to process negative emotions.

Validation of the Brazilian Portuguese version of the Quick Inventory of Depressive Symptomatology and Self-Report (QIDS-SR16) for the Brazilian population.

OBJECTIVES: To evaluate the psychometric properties of the Quick Inventory of Depressive Symptomatology (QID-SR16), a self-report instrument based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria that assesses the severity of depression symptoms, in the Brazilian population. METHODS: Participants were 4,400 Brazilians over the age of 15 years recruited for an online survey assessing depressive symptoms during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Brazil. The internal consistency, construct validity, and convergent and discriminant validity of the QIDS-SR16 were evaluated. RESULTS: The model tested was considered an adequate fit to the data (comparative fit index [CFI] = 0.947, Tucker-Lewis index [TLI] = 0.927, and root-mean-square error of approximation [RMSEA] = 0.051) and its internal consistency was good, with a Cronbach's alpha of 0.71 and an average item correlation of 0.23. The correlations between the total QIDS-SR16 score and the total scores of the Patient Health Questionnaire (PHQ-9) instruments (r = 0.67, p < 0.001), the Posttraumatic Symptoms Checklist (PCL-5) (r = 0.61, p < 0.001), and the Patient-Reported Outcomes Measurement Information System (PROMIS) (r = 0.60, p < 0.001) indicate good concurrent and convergent validity. CONCLUSION: The QIDS-SR16 has robust psychometric properties in terms of its internal consistency, construct validity, and convergent and discriminant validity. The Portuguese version of the QIDS-SR16 is an adequate instrument for assessment of depressive symptoms in the context of an online survey.

Effects of substance use disorder on oxidative and antioxidative stress markers: A systematic review and meta-analysis.

Recently, it has been suggested that central and peripheral toxicities identified in persons with substance use disorder (SUD) could be partially associated with an imbalance in reactive oxygen species and antioxidant defenses. We conducted a systematic review and meta-analysis to investigate whether SUD is associated with oxidative stress and to identify biomarkers possibly more affected by this condition. We have included studies that analysed oxidant and antioxidant markers in individuals with SUD caused by stimulants, alcohol, nicotine, opioids, and others (cannabis, inhalants, and polysubstance use). Our analysis showed that persons with SUD show higher oxidant markers and lower antioxidant markers than healthy controls. SUD was associated specifically with higher levels of oxidant markers malondialdehyde, thiobarbituric acid reactive substances and lipid peroxidation. Conversely, the antioxidant superoxide dismutase and the total antioxidant capacity/status were lowered in the SUD group. A meta-regression analysis revealed that persons with alcohol use disorder had higher oxidative stress estimates than those with stimulant use disorder. Moreover, individuals evaluated during abstinence showed smaller antioxidant effect sizes than non-abstinent ones. Our findings suggest a clear oxidative imbalance in persons with SUD, which could lead to cell damage and result in multiple associated comorbidities, particularly accelerated aging.

Proposing an integrative, dynamic and transdiagnostic model for addictions: dysregulation phenomena of the three main modes of the predostatic mind.

Several theories have been proposed to explain the complex diagnostic aspects related to addiction disorders and their development. Recent frameworks tend to focus on dimensional perspectives of symptoms rather than categorical systems, since substance use disorders are frequently comorbid with other psychiatric and especially personality disorders. However, useful transdiagnostic models that could integrate clinical evaluation derived from neuroscientific theories are lacking. In the present manuscript, the authors propose a model based on a new paradigm, in an attempt to better explain this complex, multifaceted phenomenon. The new paradigm presupposes that emotions and behavior are a response to risk prediction. Individuals make choices and engage in actions to manage potential risks/rewards in order to seek or maintain homeostasis in their internal and external environments - a mechanism that the authors call predostatic (predictive mechanism with homeostatic purpose). The model considers three main modes of the predostatic mind: (1) Alarm Mode, activated by high and/or imminent risk prediction; (2) Seek Mode, activated by long-term risk or reward prediction; and (3) Balance Mode, a self-regulating state of mind related to low risk prediction, a soothing system and a calm state. Addiction is seen as a chronic dysregulation of organism systems leading to internalizing or externalizing phenomena mainly related to the Seek and Alarm Modes, which are persistently activated by reward and risk prediction, respectively, thus hindering Balance. Addiction neuroscience research has shown that chronic drug use or engagement in addictive behaviors can lead to neuroadaptations in the brain reward circuitry, disrupting normal balance and the regulation of reward processes. This dysregulation can contribute to persistent drug-seeking/addictive behaviors despite negative consequences. This newly proposed dynamic and integrative model, named dysregulation based on externalizing and internalizing phenomena of the three main modes of the predostatic mind (DREXI3), proposes six dysregulation dimensions with basic emotional and behavioral symptoms, such as neurophysiological alterations, impulsivity, compulsion, cognitive impairment/psychosis, mood, and anxiety/anger. In this paper, the authors explain the rationale behind DREXI3 and present some hypothetical clinical examples to better illustrate the use of the model in clinical practice. The development of this innovative model could possibly guide tailored treatment interventions in the addiction field.

A cross-sectional study of the association between exposure to violence, intelligence, and executive function in Brazilian youths

Abstract We carried out an exploratory study of the association between exposure to violence, intelligence, and executive functions in Brazilian preadolescents. The study included 56 participants (31 males) aged 8 to 14 years old (mean = 11.3, SD = 1.0). We administered neuropsychological tests to evaluate executive functions and the Juvenile Victimization Questionnaire (JVQ) to evaluate exposure to violence. We used the following neuropsychological instruments: Wechsler Abbreviated Scale of Intelligence (WASI), Stroop Color-Word Interference task, digits subtest of the Wechsler Intelligence Scale for Children, and an N-back task. We generated a composite score from neuropsychological test scores and investigated the association of that score, and individual test scores, with exposure to violence and socioeconomic status (SES). Results suggest, first, that exposure to violence is associated with a 0.5-point lower intelligence quotient score for every reported victimization event in the Juvenile Victimization Questionnaire. Results also show that the digits backward subtest scores showed a significant negative correlation with exposure to violence (JVQ; rho = -0.29, p < 0.05); both analyses were adjusted for the level of schooling of parents or guardians, which was also found to be significantly associated with lower intelligence quotient scores. We discuss results in the light of the existing literature on the effects of exposure to violence on adolescent development, and the amounting evidence that suggests an association of exposure to violence, and of victimization, with tests that evaluate constructs of executive functions. The study struggled with low compliance from participants, and we underscore the challenges of carrying out empirical studies aimed at better understanding the development of underrepresented youths, such as those from Central and Latin America.

Validation of the Brazilian Portuguese version of the Quick Inventory of Depressive Symptomatology and Self-Report (QIDS-SR16) for the Brazilian population

Abstract Objectives To evaluate the psychometric properties of the Quick Inventory of Depressive Symptomatology (QID-SR16), a self-report instrument based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria that assesses the severity of depression symptoms, in the Brazilian population. Methods Participants were 4,400 Brazilians over the age of 15 years recruited for an online survey assessing depressive symptoms during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Brazil. The internal consistency, construct validity, and convergent and discriminant validity of the QIDS-SR16 were evaluated. Results The model tested was considered an adequate fit to the data (comparative fit index [CFI] = 0.947, Tucker-Lewis index [TLI] = 0.927, and root-mean-square error of approximation [RMSEA] = 0.051) and its internal consistency was good, with a Cronbach's alpha of 0.71 and an average item correlation of 0.23. The correlations between the total QIDS-SR16 score and the total scores of the Patient Health Questionnaire (PHQ-9) instruments (r = 0.67, p < 0.001), the Posttraumatic Symptoms Checklist (PCL-5) (r = 0.61, p < 0.001), and the Patient-Reported Outcomes Measurement Information System (PROMIS) (r = 0.60, p < 0.001) indicate good concurrent and convergent validity. Conclusion The QIDS-SR16 has robust psychometric properties in terms of its internal consistency, construct validity, and convergent and discriminant validity. The Portuguese version of the QIDS-SR16 is an adequate instrument for assessment of depressive symptoms in the context of an online survey.

Gender differences in progression to crack-cocaine use and the role of sexual and physical violence.

OBJECTIVE: This study aimed to evaluate whether progression from first drug use to crack-cocaine use differs according to gender, and whether the report of sexual or physical violence impacts the time of progression. METHODS: We interviewed 896 crack-cocaine users (548 men; 348 women) from addiction treatment units. Cox regression models evaluated the time of progression from first drug use to crack use. We analyzed gender differences according to the absence or presence of sexual or physical violence, also considering whether violence, when present, had occurred before or after the onset of crack use. RESULTS: Women presented a faster progression to crack use regardless of exposure to sexual or physical violence (p < 0.05). Compared to unexposed men, there was a similar progression for men exposed to sexual or physical violence before the first use of crack (p = 0.167 and p = 0.393, respectively). In both genders, we observed a faster progression among individuals exposed to these types of violence after the onset of crack use (p < 0.01). CONCLUSIONS: We found a faster progression to crack use among women and among individuals exposed to sexual and physical violence after the onset of crack use. These results encourage differentiated treatment strategies, focused on gender and individual characteristics.

Cingulate cortical thickness in cocaine use disorder: mediation effect between early life stress and cocaine consumption.

OBJECTIVE: The cingulate gyrus is implicated in the neurobiology of addiction, such as chronic cocaine consumption. Early life stress (ELS) is an important moderator of cocaine use disorder (CUD). Therefore, we investigated the effect of CUD on cingulate cortical thickness and tested whether a history of ELS could influence the effects of CUD. METHODS: Participants aged 18-50 years (78 with CUD due to crack cocaine consumption and 53 healthy controls) underwent magnetic resonance imaging and the cingulate thickness (rostral anterior, caudal anterior, posterior, and isthmus regions) was analysed. The clinical assessment comprised the Childhood Trauma Questionnaire (CTQ) and the Addiction Severity Index. Group comparisons adjusting by sex, age, and education were performed. Mediation models were generated where lifetime cocaine use, CTQ score, and cortical thickness corresponded to the independent variable, intermediary variable, and outcome, respectively. RESULTS: Group comparisons revealed significant differences in six out of eight cingulate cortices, showing lower thickness in the CUD group. Furthermore, years of regular cocaine use was the variable most associated with cingulate thickness. Negative correlations were found between CTQ scores and the isthmus cingulate (right hemisphere), as well as with the rostral anterior cingulate (left hemisphere). In the mediation analysis, we observed a significant negative direct effect of lifetime cocaine use on the isthmus cingulate and an indirect effect of cocaine use mediated by CTQ score. CONCLUSION: Our findings suggest that a history of ELS could aggravate the negative effects of chronic cocaine use on the cingulate gyrus, particularly in the right isthmus cingulate cortex.

Gender differences in progression to crack-cocaine use and the role of sexual and physical violence

Objective: This study aimed to evaluate whether progression from first drug use to crack-cocaine use differs according to gender, and whether the report of sexual or physical violence impacts the time of progression. Methods: We interviewed 896 crack-cocaine users (548 men; 348 women) from addiction treatment units. Cox regression models evaluated the time of progression from first drug use to crack use. We analyzed gender differences according to the absence or presence of sexual or physical violence, also considering whether violence, when present, had occurred before or after the onset of crack use. Results: Women presented a faster progression to crack use regardless of exposure to sexual or physical violence (p < 0.05). Compared to unexposed men, there was a similar progression for men exposed to sexual or physical violence before the first use of crack (p = 0.167 and p = 0.393, respectively). In both genders, we observed a faster progression among individuals exposed to these types of violence after the onset of crack use (p < 0.01). Conclusions: We found a faster progression to crack use among women and among individuals exposed to sexual and physical violence after the onset of crack use. These results encourage differentiated treatment strategies, focused on gender and individual characteristics.

A systematic review and meta-analysis of epigenetic clocks in schizophrenia.

INTRODUCTION: Evidence suggests that schizophrenia (SZ) is associated with accelerated biological aging. DNA methylation can be used as an indicator of biological aging by means of epigenetic clock estimates. OBJECTIVE: The aim of this systematic review and meta-analysis was to investigate the association between SZ and different epigenetic clocks. METHODS: Search terms were applied in different databases: Embase, MEDLINE (EBSCO), Cochrane Central Register of Controlled Trials, PubMed, PsychINFO and Web of Science. To assess for risk of bias we utilized an adapted version of the Newcastle-Ottawa Scale. Meta-analyses were conducted using the random effects model and meta-regressions were used to assess factors associated with heterogeneity. RESULTS: Eight studies were included (Controls, n = 3394; SZ subjects, n = 3096), which analyzed five different epigenetic clocks. Overall meta-analysis revealed no significant differences between SZ and controls on epigenetic aging (Standardized Mean Difference - SMD = -0.21; p = 0.13). However, epigenetic clock method was a significant moderator of heterogeneity (p = 0.004). Using Horvath's clock as reference, higher SMD's were found for PhenoAge and Intrinsic epigenetic age acceleration (IEAA) clocks. In a stratified meta-analysis restricted to the two clocks mentioned above, a significant accelerating effect was found in patients with SZ when compared to controls (SMD = 0.29; p = 0.003). CONCLUSION: Our findings suggest that the method of epigenetic clocks is a critical factor associated with estimates of aging acceleration in SZ. However, more studies are needed to confirm these findings and in order to evaluate a possible minor effect in overall analysis.

The Perceptions of Women About Their High Experience of Using Crack Cocaine.

Introduction: The aim of this study was to explore the perceptions of women about their experience in using crack cocaine, discussing their motivations for using it and the repercussions in their lives. Objective: To investigate these experiences, a qualitative exploratory study was conducted, using the inductive thematic analyses of the content. Methods: Eight female crack cocaine users took part in this study. They were assessed by a semi-structured interview, addressing the crack cocaine use experience. Four main themes emerged in the interviews: (1) crack cocaine "high" experience; (2) symptoms related to crack cocaine use; (3) circumstances of crack cocaine use; and (4) crack cocaine use consequences. Results: The main perceptions reported by the users were related to a feeling of being disconnected to the world preceded by a pleasant experience, especially during the first moments of use. They revealed that the drug fulfills a key role of coping strategy to handle with negative thoughts, emotions or life experiences. An important influence of social issues was reported in relation to the onset of crack cocaine use. Negative consequences and significant impact on their lives appeared in their reports, regarding the loss of family ties, involvement with prostitution, traumatic experiences and violence. Conclusion: Taking together all women's perceptions suggests that beyond the positive immediate rewarding effect, the maintenance of use might be related to the dissociative experience and self-medication role, acting as negative reward by relieving of negative life experiences that, in turn, are both cause and consequence of the drug use.

Sex differences in brain regional homogeneity during acute abstinence in cocaine use disorder.

There are significant sex differences in the clinical characteristics of cocaine use disorder (CUD). As this is a brain disorder that involves changes in functional connectivity, we investigated the existence of sex differences among people with CUD and controls. We used a data-driven method comparing males (n = 20, CK-M) and females with CUD (n = 20, CK-F) and healthy controls (20 males, HC-M and 20 females, HC-F). The participants undertook a resting-state functional magnetic resonance imaging exam. Regional homogeneity (ReHo) was performed to identify group and sex differences. Persons with CUD of both sexes presented lower ReHo parameters than controls, especially within the parietal lobule. Males with CUD showed higher ReHo than females in three right-side brain areas: postcentral gyrus, putamen and fusiform gyrus. It was found that abstinence symptoms severity was associated with lower ReHo values in the right postcentral gyrus and the right fusiform gyrus. Participants with CUD exhibited altered ReHo parameters compared to controls, similar to what is found in ageing-related disorders. Our data also indicate that cocaine has sex-specific effects on brain functioning when analysing ReHo.

Sex differences in risk behavior parameters in adolescent mice: Relationship with brain-derived neurotrophic factor in the medial prefrontal cortex.

Adolescence is as a period of development characterized by impulsive and risk-seeking behaviors. Risk behaviors (RB) involves exposure to dangerous or negative consequences to achieve goal-directed behaviors, such as reward-seeking. On the other hand, risk aversion/assessment behaviors allow the individual to gather information or avoid potentially threatening situations. Evidence has suggested that both behavioral processes, RB and risk assessment (RA), may have sex-differences. However, sex-specific behavioral patterns implicated in RB and RA are not fully understood. To address that, we investigated sex differences in risk-behavioral parameters in a decision-making task developed for rodents. In addition, we investigated the potential role of sex-dependent differences in gene expression of brain-derived neurotrophic factor (BDNF) exon IV in the medial prefrontal cortex (mPFC), which has been implicated to mediate PFC-related behavioral dysfunctions. Male and female C57BL/6J adolescent mice were evaluated in the elevated plus-maze (EPM) to assess anxiety-like behaviors and in the predator-odor risk taking (PORT) task. The PORT task is a decision-making paradigm in which a conflict between the motivation towards reward pursuit and the threat elicited by predatory olfactory cues (coyote urine) is explored. After behavioral testing, animals were euthanized and BDNF exon IV gene expression was measured by RT-qPCR. Comparative and correlational analyses for behavioral and molecular parameters were performed for both sexes. We observed that female mice spent more time exploring the middle chamber of the PORT apparatus in the aversive condition, which is an indicative of avoidance behavior. Female mice also had a higher latency to collect the reward than male mice and presented less time exploring the open arms of the EPM. BDNF exon IV gene expression was higher among females, and there was a positive correlation between the BDNF and PORT behavioral parameters. Our findings suggest sex-dependent effects in the PORT task. Females presented higher RA and avoidance behavior profile and expressed higher levels of BDNF exon IV in the mPFC. Moreover, higher BDNF expression was correlated with RA behaviors, which suggests that adolescent females tend to evaluate the risks more than adolescent males and that BDNF gene expression may be mediating decision-making processes.

Gestational stress alters maternal behavior and inflammatory markers in the olfactory bulb of lactating mice.

Inflammatory markers represent important candidates responsible for the altered behavior and physiology observed after stressful experiences. In the maternal brain, the olfactory bulb (OB) is a key constituent of the neural circuit that mediates the reciprocal interaction between mother and infant. This study aimed to investigate the effects of stress during pregnancy on maternal behavior and inflammatory changes in the olfactory bulb of lactating mice. Female Balb/c mice were divided into two groups: control (CT) and restraint stress (RS). Maternal behavior was performed during the first 8 days of life of the offspring. On the 10th day after parturition, corticosterone, gene, and protein expression were assessed. Stress during pregnancy decreased the maternal index at postnatal day 4 and the nuclear factor-κB 1 (NFκB1) gene expression in the OB. Moreover, females from the RS group showed increased interleukin (IL-1ß) protein expression. In contrast, stressed females exhibited a decreased tumor necrosis factor (TNF-α) protein expression in the OB. In conclusion, exposure to stress during pregnancy was able to induce specific postnatal effects on maternal behavior and balance of inflammatory mediators in the OB.