Genetic Variations in Elements of the Oxytocinergic Pathway are Associated with Attention/Hyperactivity Problems and Anxiety Problems in Childhood.

Genetic alterations related to oxytocin system seem to influence the neurobiology of attention-deficit hyperactivity disorder and anxiety problems leading to greater functional, social and emotional impairment. Here, we analyzed the association of OXTR rs2254298 and CD38 rs6449182 variants with attention/hyperactivity problems and anxiety problems in children. The study enrolled 292 children and adjusted regression model revealed OXTR rs2254298 AA genotype as a risk factor for attention deficit/hyperactivity problems (PR: 2.37; PadjFDR = 0.006), attention problems (PR: 2.71; PadjFDR = 0.003) and anxiety problems (PR: 1.92; PadjFDR = 0.018). CD38 rs6449182 G allele showed as a risk factor for attention deficit/hyperactivity problems (PR: 1.56; PadjFDR = 0.028). Moreover, in silico approach for regulatory roles found markers that influence chromatin accessibility and transcription capacity. Together, these data provide genetic information of oxytocin in developmental and behavioral disorders opening a range of opportunities for future studies that clarify their neurobiology in childhood.

Leptin polymorphism rs3828942: risk for anxiety disorders?

Leptin is an anorexigenic hormone well recognized by its role in mediating energy homeostasis. Recently, leptin has been associated with psychiatric disorders and interestingly, leptin treatment has shown antidepressant and anxiolytic effects. We examined the association of leptin levels and leptin (LEP) gene rs3828942 polymorphism with anxiety disorders considering sex differences. A cross-sectional population-based study, including 1067 young adults, of whom 291 presented anxiety disorders diagnosed by the Mini International Neuropsychiatric Interview (MINI 5.0). The rs3828942 polymorphism was genotyped by real-time PCR and ELISA measured leptin levels. Leptin levels were not associated with anxiety disorders after adjusting for sex and body mass index (BMI) [ß = - 0.009 (- 0.090-0.072); p = 0.832]. The distribution of rs3828942 genotypes was not associated with anxiety disorders. However, in a sex-stratified sample, the A-allele of rs3828942 polymorphism was associated with risk for GAD in women even when adjusting for confounding variables [OR = 1.87 (1.17-2.98); p = 0.008]. In a subsample of 202 individuals with GAD and control matched by sex and BMI, results suggest an interaction between genotypes and GAD diagnosis based on leptin levels only in the male group [F (1, 54) = 6.464; p = 0.0139]. Leptin is suggested to be related with the neurobiology of anxiety disorders in a sex-dependent manner since women carrying the A-allele of LEP rs3828942 present a higher risk for GAD, while leptin levels seem to be lower in men with GAD carrying A-allele. Studies on the relationship between leptin polymorphisms and levels are scarce and, therefore, further research is necessary.

Generalized Anxiety Disorder, Depressive Symptoms and the Occurrence of Stressors Events in a Probabilistic Sample of Pregnant Women.

The aim of the study is to verify the association between GAD, the severity of depressive symptoms and stressors in pregnant women between the first and second trimester. Cross-sectional study, part of a cohort that followed 980 women during the gestational period of a city in southern Brazil. We performed bivariate analysis using the t-test and chi-square. The variables that presented p ≤ 0.20 were taken for multivariate analysis, through logistic regression, in order to control possible confounding factors. The Mini International Neuropsychiatric Interview Plus was used to evaluate GAD, the severity of depressive symptoms was investigated through the Beck Inventory of Depression II, and stress events according to the Social Readjustment Assessment Scale of Holmes e Rahe. The sample consisted of 980 women. Women with mild depression symptoms had 9.8 (IC95% 4.6;21.0) times more GAD, those with moderate symptoms had 27.5 (IC95% 12.5;60.0) times more GAD, and those with severe symptoms had 52.9 (IC95% 19.1;146.5) times more GAD when compared to pregnant women with no symptoms or minimal symptoms. Regarding the stressful events, the pregnant women who presented GAD had an increase of 1.0 (IC95% 1.0;1.1) point in the mean of occurrence of stressor events when compared to those without GAD. These findings highlight the need for prevention strategies and interventions to promote maternal mental health, which benefit the development of infants in the long term.

Impact of genetic variations in ADORA2A gene on depression and symptoms: a cross-sectional population-based study.

Genetic variants involved in adenosine metabolism and its receptors were associated with increased risk for psychiatric disorders, including anxiety, depression, and schizophrenia. Here, we examined an association between a single nucleotide polymorphism in A2A receptor gene (ADORA2A, rs2298383 SNP) with current depressive episode and symptom profile. A total of 1253 individuals from a cross-sectional population-based study were analyzed by the Mini International Neuropsychiatric Interview 5.0. Our data showed that the TT genotype of ADORA2A rs2298383 SNP was associated with reduced risk for depression when compared to the CC/CT genotypes (p = 0.020). This association remained significant after adjusting for confounding variables such as smoking, gender, socioeconomic class, and ethnicity (OR = 0.631 (95% CI 0.425-0.937); p = 0.022). Regarding the symptoms associated with depression, we evaluated the impact of the ADORA2A SNP in the occurrence of sad/discouraged mood, anhedonia, appetite changes, sleep disturbances, motion changes, energy loss, feelings of worthless or guilty, difficulty in concentrating, and presence of bad thoughts. Notably, the TT genotype was independently associated with reduced sleep disturbances (OR = 0.438 (95% CI 0.258-0.743); p = 0.002) and less difficulty in concentrating (OR = 0.534 (95% CI 0.316-0.901; p = 0.019). The cross-sectional design cannot evaluate the cause-effect relationship and did not evaluate the functional consequences of this polymorphism. Our data support an important role for ADORA2A rs2298383 SNP in clinical heterogeneity associated with depression. The presence of the TT genotype was associated with decrease risk for current depression and disturbances in sleep and attention, two of the most common symptoms associated with this disorder.

Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.

Can glutathione be a biomarker for suicide risk in women 18 months postpartum?

Background: Suicide risk is prominent among the problems affecting populations, mainly due to the broad family, psychosocial and economic impact. Most individuals at suicidal risk have some mental disorder. There is considerable evidence that psychiatric disorders are accompanied by the activation of neuro-immune and neuro-oxidative pathways. The aim of the study is to evaluate the serum levels of oxidative stress biomarkers in women at risk of suicide after 18 months of postpartum. Methods: This is a case-control study, nested within a cohort study. From this cohort, 45 women [15 without mood disorders and 30 with mood disorders (Major depression and Bipolar disorder)] were selected at 18 months postpartum, the depression and suicide risk were assessed using the Mini-International Neuropsychiatric Interview Plus (MINI-Plus) instrument, module A and C, respectively. Blood was collected and stored for later analysis of the reactive species (DCFH), superoxide dismutase (SOD), and glutathione reduced (GSH). For data analysis, the SPSS program was used. To compare the nominal covariates with the outcome GSH levels, the Student's t-test or analysis of variance (ANOVA) was used. Spearman's correlation was performed for analysis between the quantitative covariates and the outcome. To analyze the interaction between the factors, multiple linear regression was performed. Bonferroni analysis was used as an additional/secondary result to visualize differences in glutathione levels according to risk severity. After the adjusted analysis, p-values < 0.05 were considered statistically significant. Results: The percentage of suicide risk observed in our sample of women at 18 months postpartum was 24.4% (n = 11). After adjusting for the independent variables, only the presence of suicide risk remained associated with the outcome (ß = 0.173; p = 0.007), low levels of GSH at 18 months after postpartum. Likewise, we verified the difference in GSH levels according to the degree of suicide risk, observing a significant association between the differences in glutathione means in the group of women with moderate to high risk compared to the reference group (no suicide risk) (p = 0.009). Conclusion: Our findings suggest that GSH may be a potential biomarker or etiologic factor in women at moderate to high risk of suicide.

Maternal expression of miR-let-7d-3p and miR-451a during gestation influences the neuropsychomotor development of 90 days old babies: "Pregnancy care, healthy baby" study.

INTRODUCTION: Studies on maternal microRNA expression have emerged to better understand regulatory mechanisms during the gestational period, since microRNA expression has been associated with pregnancy disorders. OBJECTIVES: This study aims to investigate the association between the expression of the maternal microRNAs miR-let-7d-3p and miR-451a during the second gestational trimester and neuropsychomotor development at 90 days of life of infants. METHODS: This is a case-control study nested within a cohort, with the groups being divided into dyads in which pregnant women presented Major Depressive Episode (MDE) (n = 64), these being the cases, and their respective controls (no MDE; n = 64). The Bayley Scale III was used to assess the outcome of child development, and MDE was assessed through the Mini International Neuropsychiatric Interview Plus. The analysis of miR-let-7d-3p and miR-451a was done via serum from the pregnant women, utilizing the qRT-PCR (n = 128). RESULTS: The results indicated a negative association between expression levels of miR-451a (ß -3.3 CI95% -6.4;-0.3) and a positive associated of the miR-let-7d-3p with the cognitive development domain (ß 1.7 CI95% 0.1; 3.0), and a positive association between expression of miR-let-7d-3p with motor development of the infants (ß 1.6 CI95% 0.3; 2.9). CONCLUSION: This is a pioneering study on the topic that indicates a biological interrelationship between the miRNAs miR-let-7d-3p and miR-451a evaluated during the pregnancy and the motor and cognitive domains of infant development at 90 days postpartum.

Cd modifies hepatic Zn deposition and modulates δ-ALA-D activity and MT levels by distinct mechanisms.

Cadmium (Cd) is a pollutant that is harmful to human and animals. The liver is a target for Cd accumulation and it can disrupt Zn homeostasis. Here we examined the interaction of Zn and Cd to determine how these two metals could affect δ-aminolevulinate-dehydratase (δ-ALA-D) and metallothionein (MT), two potential molecular endpoints for Cd hepatotoxicity. Cd exposure (0.25 and 1 mg kg1 body weight, i.p., for 10 days) caused a marked increase in hepatic Zn deposition, which was not modified by treatment with Zn (2 mg kg1 , i.p.). Cd caused a dose-dependent increase in hepatic Cd content that was not modified by Zn. Zn and/or Cd treatment increased hepatic δ-ALA-D activity, although the increase caused by Cd was less marked. Reactivation index of δ-ALA-D by DTT was decreased by Zn and Cd exposure, which indicates that Zn protects enzyme from oxidation. Hepatic MT was increased only after exposure to 1 mg kg(-1) Cd and Zn reduced the stimulation of MT synthesis. The results presented here indicate that Cd can redistribute Zn from non-hepatic tissues to liver and the increase in hepatic Zn deposition can account for the increase in hepatic δ-ALA-D activity after Cd exposure. However, Zn blocked the increase in hepatic MT levels caused by Cd. Thus, the modulation of the two molecular endpoints of Cd toxicity used here was distinct, which indicates that the mechanism(s) involved in Zn and Cd distribution, δ-ALA-D and MT regulation are not coincident.

Brief cognitive behavioral therapy in pregnant women at risk of postpartum depression: Pre-post therapy study in a city in southern Brazil.

BACKGROUND: Postpartum depression (PPD) affects a high number of women, often the first manifestation of a mood disorder that will occur later in life, bringing serious consequences for the patient and her offspring. Depression today is the leading cause of disability worldwide. The aim of this study was to evaluate the effectiveness of a preventive cognitive behavioral therapy (CBT) for PPD. METHODS: Pre-post therapy study, as part of a population-based cohort study. Pregnant women without a diagnosis of depression participated, who were divided into two groups: risk of depression (CBT) and a control group (without therapy). The preventive therapy consisted of six sessions of CBT, administered weekly. The Outcome Questionnaire (OQ-45) was used in all sessions. The Mini International Neuropsychiatric Interview and Beck Depression Inventory-II were used on three occasions. The final statistical analyses were performed by Poisson regression. RESULTS: The prevalence of PPD in the risk group was 5.5% and in the control group 2.2%, with no difference between the groups (PR 1.66 95% CI 0.44-6.18). The OQ-45 averages gradually reduced during the therapy sessions, indicating therapeutic progress. Schooling was an associated factor, both with the manifestation of PPD and with the greater effectiveness of the therapy. LIMITATIONS: Rate of 40.5% refusal to preventive treatment and absence of a group with similar characteristics in another therapy model. CONCLUSIONS: Brief cognitive behavioral therapy applied by mental health professionals with basic training was effective in preventing the manifestation of PPD.

Diphenyl diselenide and diphenyl ditelluride: neurotoxic effect in brain of young rats, in vitro.

This study examined whether maturity of rat brain may be relevant for the sensitivity to diphenyl diselenide (PhSe)(2) and diphenyl ditelluride (PhTe)(2) on [(3)H]glutamate uptake and release, in vitro. Brain synaptosomes were isolated from young (14- and 30-day-old) and adult rats and incubated at different concentrations of (PhSe)(2) or (PhTe)(2). The results demonstrated that the highest concentration (100 microM) of (PhSe)(2) and (PhTe)(2) inhibited the [(3)H]glutamate uptake by synaptosomes of brain at all ages. In the adult brain, (PhSe)(2) did not inhibit the [(3)H]glutamate uptake at the lowest concentration (10 microM). The highest concentration of (PhTe)(2) inhibited the [(3)H]glutamate uptake more in the 14-day-old than in the 30-day-old rats or adult rats. In the 30-day-old animals, the highest concentration of (PhSe)(2), and the lowest concentration of (PhTe)(2), increased the basal [(3)H]glutamate release. At the highest concentration, (PhTe)(2) increased the basal and K(+)-stimulated glutamate release on all ages evaluated. The results suggest that (PhSe)(2) and (PhTe)(2) caused alterations on the homeostasis of the glutamatergic system at the pre-synaptic level. These alterations were age-, concentration-, and compound-dependent. The maturity of rat brain is relevant for the glutamatergic system sensitivity to (PhSe)(2) and (PhTe)(2) .

The role of CACNA1C gene and childhood trauma interaction on bipolar disorder.

Studies on gene x environment interaction (GxE) have provided vital information for uncovering the origins of complex diseases. When considering the etiology of bipolar disorder (BD), the role of such interactions is unknown. Here, we tested whether trauma during childhood could modify the effect of two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) in terms of susceptibility to BD. The study enrolled 878 Caucasian young adults in a cross-sectional population-based survey. BD diagnosis was performed using a clinical interview MINI 5.0, and trauma was assessed with the childhood trauma questionnaire (CTQ). Binary logistic regression models were employed to test the main effects of polymorphisms, haplotypes, and GxE interactions using sex as a confounder. We did not observe an association between the polymorphisms and diagnosis of BD. However, we noted that childhood trauma modified the effect of the rs4765913 polymorphism (p = .018) and the AA haplotype (rs1006737 - rs4765913) (p = .018) on BD susceptibility. A allele carriers of the rs4765913 polymorphism or the AA haplotype exposed to childhood trauma are more likely to develop BD compared to the individuals without a genetic risk. Thus, this study showed that the risk of developing BD in individuals exposed to childhood trauma was influenced by the individual's genetic background, varying according to the CACNA1C genotypes.

Temperament traits moderate the relationship between Childhood Trauma and Interleukin 1ß profile in young adults.

Early life stressors, such as childhood trauma, have been associated to alterations in immune response that can last until adulthood. In this context, interleukin 1ß (IL-1ß) emerges as a pro-inflammatory cytokine with a pivotal role. Also, considering the temperament differences in stress susceptibility, and even immune dysfunction, studies investigating the complex interaction between these factors are scarce. Thus, the aim of the present study was to evaluate the moderating role of temperament traits in the relationship between childhood trauma and serum IL-1ß levels. This cross-sectional study consisted of 325 individuals, men and women, aged 18-35, enrolled from a population-based study in the city of Pelotas, Southern Brazil. Our main results indicate that higher serum levels of IL-1ß were associated with trauma severity (p < 0.01), and the variance of anger could explain 29% of IL-1ß increase in individuals who suffered severe trauma (p < 0.05). The effect of anger was considerably stronger in men than in women (46% and 25%, respectively). Moreover, the variance of sensitivity also explained 15% of IL-1ß increase (p < 0.05) as well as the variance of volition explained 11% of IL-1ß decrease (p < 0.05) in individuals who suffered severe trauma in the general population. Our results indicate that emotional individual differences can moderate the impact of childhood trauma on low-grade inflammation in young adults.

Inosine prevents hyperlocomotion in a ketamine-induced model of mania in rats.

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.

Exposure to diphenyl ditelluride, via maternal milk, causes oxidative stress in cerebral cortex, hippocampus and striatum of young rats.

The present study evaluated the effect of diphenyl ditelluride [(PhTe)(2)] exposure to mothers on the cerebral oxidative status of their offspring. The dams received (PhTe)(2) or canola oil via subcutaneous injection once daily during the first 14 days of lactational period. At post natal day 28, biochemical parameters of oxidative stress were evaluated in cerebral structures-cortex, hippocampus and striatum-of young rats. Exposure to (PhTe)(2) increased lipid peroxidation levels and inhibited delta-ALA-D, catalase and SOD activities in hippocampus and striatum of young rats. (PhTe)(2) induced changes in the levels of non-enzymatic antioxidant defenses in cortex and striatum of young rats. The exposure to (PhTe)(2), via maternal milk, caused oxidative stress in cerebral structures of young rats. Thus, the possible role of disrupted prooxidant/antioxidant balance in (PhTe)(2) toxicity was demonstrated. These results highlighted a possible molecular mechanism involved in toxicity caused by (PhTe)(2).

Passive smoke exposure induces oxidative damage in brains of rat pups: Protective role of diphenyl diselenide.

The protective effect of diphenyl diselenide, (PhSe)(2), on oxidative stress induced by cigarette smoke exposure in brains of rat pups was evaluated. Animals were exposed to passive cigarette smoke (15 min/day) in two different experimental protocols: P1 (1, 2, and 3 cigarettes) and P2 (4, 5, and 6 cigarettes) for 3 weeks. Before each period of smoke exposure, animals received an oral administration of (PhSe)(2) (0.5 mg/kg). A number of toxicological parameters in the brain were examined, such as lipid peroxidation, delta-aminolevulinate dehydratase (delta-ALA-D) activity, and components of enzymatic (superoxide dismutase and catalase activities) and non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol levels). In P1, smoke exposure induced an inhibition of catalase activity and an increase of ascorbic acid levels. (PhSe)(2) treatment was able to protect catalase activity but not ascorbic acid levels. In P2, an augmentation of lipid peroxidation, a reduction of enzymatic and non-enzymatic antioxidant status, and an inhibition of delta-ALA-D activity caused by smoke exposure were found. (PhSe)(2) protected the brains of rat pups against oxidative damage induced by smoke exposure. The results are consistent with the antioxidant effect of (PhSe)(2) demonstrated by the reduction of oxidative changes caused by smoke exposure in the brains of pups.

Caffeine improves adult mice performance in the object recognition task and increases BDNF and TrkB independent on phospho-CREB immunocontent in the hippocampus.

Caffeine is one of the most psychostimulants consumed all over the world that usually presents positive effects on cognition. In this study, effects of caffeine on mice performance in the object recognition task were tested in different intertrial intervals. In addition, it was analyzed the effects of caffeine on brain derived neurotrophic factor (BDNF) and its receptor, TrkB, immunocontent to try to establish a connection between the behavioral finding and BDNF, one of the neurotrophins strictly involved in memory and learning process. CF1 mice were treated during 4 consecutive days with saline (0.9g%, i.p.) or caffeine (10mg/kg, i.p., equivalent dose corresponding to 2-3 cups of coffee). Caffeine treatment was interrupted 24h before the object recognition task analysis. In the test session performed 15min after training session, caffeine-treated mice recognized more efficiently both the familiar and the novel object. In the test session performed 90min and 24h after training session, caffeine did not change the time spent in the familiar object but increased the object recognition index, when compared to control group. Western blotting analysis of hippocampus from caffeine-treated mice revealed an increase in BDNF and TrkB immunocontent, compared to their saline-matched controls. Phospho-CREB immunocontent did not change with caffeine treatment. Our results suggest that acute treatment with caffeine improves recognition memory, and this effect may be related to an increase of the BDNF and TrkB immunocontent in the hippocampus.

Sex differences in the effects of pre- and postnatal caffeine exposure on behavior and synaptic proteins in pubescent rats.

Few studies have addressed the effects of caffeine in the puberty and/or adolescence in a sex dependent manner. Considering that caffeine intake has increased in this population, we investigated the behavioral and synaptic proteins changes in pubescent male and female rats after maternal consumption of caffeine. Adult female Wistar rats started to receive water or caffeine (0.1 and 0.3g/L in drinking water; low and moderate dose, respectively) during the active cycle at weekdays, two weeks before mating. The treatment lasted up to weaning and the offspring received caffeine until the onset of puberty (30-34days old). Behavioral tasks were performed to evaluate locomotor activity (open field task), anxious-like behavior (elevated plus maze task) and recognition memory (object recognition task) and synaptic proteins levels (proBDNF, BDNF, GFAP and SNAP-25) were verified in the hippocampus and cerebral cortex. While hyperlocomotion was observed in both sexes after caffeine treatment, anxiety-related behavior was attenuated by caffeine (0.3g/L) only in females. While moderate caffeine worsened recognition memory in females, an improvement in the long-term memory was observed in male rats for both doses. Coincident with memory improvement in males, caffeine increased pro- and BDNF in the hippocampus and cortex. Females presented increased proBDNF levels in both brain regions, with no effects of caffeine. While GFAP was not altered, moderate caffeine intake increased SNAP-25 in the cortex of female rats. Our findings revealed that caffeine promoted cognitive benefits in males associated with increased BDNF levels, while females showed less anxiety. Our findings revealed that caffeine promotes distinct behavioral outcomes and alterations in synaptic proteins during brain development in a sex dependent manner.

Different effects of caffeine on behavioral neurophenotypes of two zebrafish populations.

Caffeine is a substance present in several foods and drinks of common western diet. Although high caffeine concentrations induce anxiogenic properties in various species, the influence of the different baselines of anxiety levels on caffeine-mediated responses is poorly understood. The short-fin wild-type (WT) and leopard (leo) zebrafish populations present significant behavioral differences, in which leo shows exacerbated anxiety-like responses. Since behavioral neurophenotyping may be easily assessed in adult zebrafish by associating temporal and spatial three-dimensional reconstructions of locomotion, we investigated the effects of caffeine on exploration and anxiety-like behavior of WT and leo zebrafish. Moreover, the whole-body cortisol content was assessed in the absence and presence of caffeine. For this purpose, animals were acutely exposed to caffeine (25, 50, 100 and 200mg/L) for 15min and further tested in the novel tank. Endpoint data and 3D reconstruction plots revealed that caffeine was anxiogenic in both WT and leo populations by altering vertical swimming, freezing, and erratic movements depending on the concentration. Prominent anxiogenic effects during habituation to novelty were observed in WT, suggesting a fundamental role of the phenotype in caffeine-mediated neurobehavioral responses. Although untreated leo showed higher baseline cortisol levels than control WT, caffeine increased whole-body cortisol in both populations. Moreover, caffeine induced aberrant swimming profiles in WT and leo following 200mg/L exposure, which could reflect nonspecific toxicity and/or seizure-like behaviors. Collectively, our novel findings show that caffeine effects in zebrafish differ in a population-dependent manner.

Caffeine Reverts Memory But Not Mood Impairment in a Depression-Prone Mouse Strain with Up-Regulated Adenosine A2A Receptor in Hippocampal Glutamate Synapses.

Caffeine prophylactically prevents mood and memory impairments through adenosine A2A receptor (A2AR) antagonism. A2AR antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 ± 7 %) and GABAergic (vGAT; -23 ± 8 %) markers in the hippocampus. HM displayed higher A2AR density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A2AR agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the A2AR antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A2AR controlling synaptic glutamatergic function.

Caffeine exposure during rat brain development causes memory impairment in a sex selective manner that is offset by caffeine consumption throughout life.

Caffeine is the psychostimulant most consumed worldwide. In moderate doses, it affords a beneficial effect in adults and upon aging, but has a deleterious effect during brain development. We now tested if caffeine consumption by rats (0.1, 0.3, 1.0 g/L in the drinking water, only during active cycle and weekdays) during adulthood could revert the potentially negative effects of caffeine during early life. Thus, we compared caffeine intake starting 15 days before mating and lasting either up to weaning (development) or up to adulthood, on behavior and synaptic proteins in male and female rats. Recognition memory was impaired only in female rats receiving caffeine (0.3 and 1.0 g/L) during development, coincident with increased proBDNF and unchanged BDNF levels in the hippocampus. Caffeine in both treatment regimens caused hyperlocomotion only in male rats, whereas anxiety-related behavior was attenuated in both sexes by caffeine (1.0 g/L) throughout life. Both caffeine treatment regimens decreased GFAP (as an astrocyte marker) and SNAP-25 (as a nerve terminals marker) in the hippocampus from male rats. TrkB receptor was decreased in the hippocampus from both sexes and treatment regimens. These findings revealed that caffeine intake during a specific time window of brain development promotes sex-dependent behavioral outcomes related to modification in BDNF signaling. Furthermore, caffeine throughout life can overcome the deleterious effects of caffeine on recognition memory during brain development in female rats.