Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin ...neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.
Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly ...explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (β = 61.58, p = 0.015) and 72 months (β = 97.78, p = 0.001); food responsiveness at 48 months (β = 83.79, p = 0.009) satiety at 48 months (β = -43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (β = 30.48, p = 0.006) food fussiness score (β = -24.07, p = 0.02) and satiety score at 60 months (β = -17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life.
•Adversity exposure in early life contributes to the development of eating disorder.•Neonatal stress increases anxiogenic-like behavior, but only in male rats.•Maternal deprivation induces decreased ...hypothalamic POMC levels in adult males.•Early life adversities affect serotonergic activity in the hypothalamus and amygdala.•Effects of neonatal stress are sexually dimorphic.
Early life experiences have strong influences on brain programming and can affect eating behavior control and body weight later in life. However, there is no consensus about the relationship between neonatal stress and feeding behavior. We evaluated whether maternal deprivation (MD) and maternal separation (MS) alter body weight and appetite using standard rat chow consumption and palatable food. Also, we evaluated anxiety and the expression of the leptin receptor, neuropeptides POMC, CART, NPY in the hypothalamus, as well as the serotoninergic system in the amygdala and hypothalamus as possible modulators of these behaviors. We found a decrease in standard rat chow consumption in MD. However, both neonatal stress protocols increased the consumption of palatable food and led to anxiogenic behavior in male animals. MD led to decreased hypothalamic POMC levels in adult males. Serotonin in the hypothalamus was decreased by both stress models in males and females. In the amygdala, MS decreased serotonin levels while MD increased its metabolite levels. We observed that males are more vulnerable and females are more resilient to the effects of neonatal stress on anxiety-like behavior, as well as on food consumption and on the central changes observed. These data together add support to the concept that the early environment contributes to the development of eating disorders later in life.
This study evaluated the effects of chronic stress and lithium treatments on oxidative stress parameters in hippocampus, hypothalamus, and frontal cortex. Adult male Wistar rats were divided into two ...groups: control and submitted to chronic variate stress, and subdivided into treated or not with LiCl. After 40 days, rats were killed, and lipoperoxidation, production free radicals, total antioxidant reactivity (TAR) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were evaluated. The results showed that stress increased lipoperoxidation and that lithium decreased free radicals production in hippocampus; both treatments increased TAR. In hypothalamus, lithium increased TAR and no effect was observed in the frontal cortex. Stress increased SOD activity in hippocampus; while lithium increased GPx in hippocampus and SOD in hypothalamus. We concluded that lithium presented antioxidant properties, but is not able to prevent oxidative damage induced by chronic variate stress.
This study was undertaken to verify the effects of chronic stress and lithium treatments on the hippocampal Na
+,K
+-ATPase activity of rats, as well as to investigate the effects of stress ...interruption and post-stress lithium treatment on this enzyme activity and on spatial memory. Two experiments were carried out; in the first experiment, adult male Wistar rats were divided into two groups: control and submitted to a chronic variate stress paradigm, and subdivided into treated or not with LiCl. After 40 days of treatment, rats were killed, and Na
+,K
+-ATPase activity was determined. In the second experiment, rats were stressed during 40 days, and their performance was evaluated in the Water Maze task. The stressed group was then subdivided into four groups, with continued or interrupted stress treatment and treated or not with lithium for 30 additional days. After a second evaluation of performance in the Water Maze, rats were killed and Na
+,K
+-ATPase activity was also measured. Results showed an impairment in Na
+,K
+-ATPase activity and in Water Maze performance of chronically stressed rats, which were prevented by lithium treatment and reversed by lithium treatment and by stress interruption. These results suggest that the modulation of Na
+,K
+-ATPase activity may be one of the mechanisms of action of lithium in the treatment of mood disorders.
Early life adversity has been linked with a higher probability of developing behavioral impairments and environmental manipulation is a strategy that may reduce the negative effects of exposure to ...adversity in early life. Here, we focused on exploring the influence of environmental enrichment (EE) as a protective factor in the context of early life adversity. We hypothesized that 24 hours of maternal deprivation (MD), in the second week of life, could induce anxiety-like behavior alterations and that exposure to EE could induce resilience to these behaviors due to alterations in the serotonergic system. Male Wistar rats were exposed to MD, on postnatal days 11 and 13, and to EE, after weaning. In adulthood, we performed a series of behavioral tests for fear, anxiety, and locomotor activity. We also measured the levels of serotonin in the amygdala and dorsal raphe nucleus. Our results revealed that MD does not impact fear behavior or the levels of serotonin, while EE decreases locomotor activity in a novel environment and enhances exploration in the predator odor test. EE also decreases serotonin in the amygdala and increases its turnover rate levels. Our findings provide insights into the critical timeframe during which stress exposure impacts the development and confirm that exposure to EE has an independent and protective effect for anxiety-like behaviors later in life.
•Maternal deprivation on postnatal days 11 and 13 showed no impact on fear extinction or anxiety.•Environmental enrichment (EE) reduces locomotion and increases exploration time.•EE influences the amygdala, but not dorsal raphe nucleus serotonergic levels.
O Museu de Ciências da Vida, primeiro museu de plastinação do Brasil, é um espaço de difusão e popularização científica de temas ligados ao corpo humano, origem e evolução do homem, e as ciências da ...vida. Desde sua idealização preza pela aces-sibilidade e inclusão de pessoas com deficiência ao acervo e ao espaço museal. Um grande passo a favor da inclusão foi o desenvolvimento da técnica de plastinação, que possibilita a transformação do acervo, de peças fixadas em formaldeído, para espécimes plastinados, manipuláveis e que não oferecem quaisquer riscos à saúde. Pretende-se aqui descrever a trajetória do museu no âmbito da inclusão e acessibili-dade de pessoas com deficiência. Para tanto, realizou-se levantamento de informa-ções de documentos do museu sobre o histórico de suas ações inclusivas, bem co-mo uma entrevista com o coordenador e curador do museu, dr. Athelson Stefanon Bittencourt, o qual relatou a iniciativa pessoal e da equipe em promover a acessibi-lidade e a transformação do acervo para atender as especificidades da deficiência, trazendo contribuições aos museus no âmbito da acessibilidade ao público. As mu-danças ocorridas no espaço museal, visando a acessibilidade em seu acervo e bus-cando a inclusão, foram iniciativas para atender os anseios da comunidade interna e externa à Universidade Federal do Espírito Santo (UFES). A maior parte do conte-údo do Museu é passível de manipulação e estudo por pessoas com deficiência vi-sual, sendo a técnica de plastinação importante para que a instituição seja acessível.
Abstract
Leptin is a hormone involved in the regulation of food intake, with receptors largely expressed centrally and peripherally, in structures like the hypothalamus and the liver. Beyond its ...well-known actions as an energy-balance regulator, leptin is linked to psychiatric disorders. Considering that the association between genetic and early environmental factors contributes to psychopathology, disruptions of leptin signaling could be a key mechanism in this interaction. To investigate this possibility, we created an expression-based polygenic risk score (ePRS) reflecting variations in the function of the LepR gene network in the liver and hypothalamus, and investigated its interaction with postnatal adversity on Child Behavior Checklist in 4 years old children (main cohort: MAVAN, N=137) and 17 years old teenagers (Replication Cohort: ALSPAC, N=2630). There is an interaction effect between adversity exposure and liver-based LepR-ePRS, increasing depressive and anxiety problems on the MAVAN cohort (β=78.16, p=0.02, β=83.77, p=0.01). In ALSPAC, the results were replicated, showing an interaction between adversity exposure and liver-based LepR-ePRS, increasing the depression score and somatic symptoms (β=24.65, p=0.005; β=33.51, p=0.009). No significant interactions were found using the hypothalamus-based LepR-ePRS (p>0.05), suggesting specificity for the liver LepR gene network to predict these behavioral outcomes. A parallel-independent component analysis showed relationships between the SNPs from the liver ePRS-LepR and gray matter density in cortical areas involved in emotion regulation (middle frontal gyrus, inferior parietal lobule and anterior cingulate). Finally, the relationship between gene and MRI components in this analysis is moderated by the history of early life adversity exposure. Enrichment analysis of the liver LepR co-expression network shows that these genes are related to biological processes including regulation of glucose transport, cholesterol metabolism and cellular glucose homeostasis, which indicates possible underlying mechanisms linking peripheral metabolism-related gene expression and the development of emotional symptoms. Our data supports the hypothesis that exposure to early adversity affects emotional behavior, and the liver LepR gene network is an important moderator of these effects. Further studies on development of emotional symptoms should consider metabolic markers to understand these complex phenotypes.
Pleasant and unpleasant flavors and odors can modulate pain perception, and the efficacy of sweet flavors in reducing pain seems to be related to its hedonic value. Chronic variate stress paradigm is ...a model of depression, and is suggested to induce anhedonia. We observed previously that lithium may prevent behavioral and neurochemical alterations induced by chronic stress; so we hypothesized that chronically stressed animals may present different nociceptive response to pleasant and unpleasant tastes that could be prevented by lithium treatment. Adult male Wistar rats were divided into four groups, control and stressed, treated or not with lithium. A Chronic Variate Stress paradigm was used, and lithium was added to the chow. After 40 days of treatment, the tail flick latency of the animals was evaluated, and rats were immediately placed in a box with access to a 5% acetic acid solution (acid flavor). After 5 min, tail flick latency was measured again. On the following day, animals were submitted to the same procedure, with the substitution of acetic acid by condensed sweet milk (sweet flavor). The stressed group was the only group who did not present analgesia after sweet taste exposition. All groups, except the control group, presented increased tail flick latency after exposition to the acid flavor. These results indicate that pleasant and unpleasant flavors present different relevance for the induction of antinociception in stressed animals, and the absence of sweet flavor-induced analgesia may represent an anhedonic effect of the chronic variate stress paradigm. On the other hand, perception of different flavors may be more prominent in animals treated with lithium.
Esta tese foi desenvolvida para investigar os mecanismos envolvidos nos efeitos protetores do tratamento com lítio sobre a memória espacial de ratos submetidos a um modelo de estresse crônico ...variado, bem como verificar os efeitos destes tratamentos em alguns parâmetros relacionados com depressão. Foram utilizados ratos Wistar (Rattus norvegicus), divididos em 4 grupos experimentais: controles, controles tratados com lítio, estressados e estressados tratados com lítio. Observamos que em 21 dias de tratamentos com estresse e lítio não há alteração na memória espacial, e que aos 30 dias o tratamento com lítio induz um efeito facilitador sobre a memória. A partir disso, os tratamentos tiveram duração de quarenta dias, após os quais as medidas comportamentais e bioquímicas foram desenvolvidas. Observamos que o estresse diminui a atividade da enzima Na+, K+-ATPase em membranas sinápticas hipocampais, e este efeito é prevenido pelo tratamento com lítio, bem como revertido tanto pela interrupção do estresse quanto pelo tratamento pós-estresse com lítio. A interrupção do estresse por um período de trinta dias também reverte os seus efeitos sobre a memória, assim como o faz o tratamento pós-estresse com lítio. Estes dados indicam que o déficit cognitivo induzido pelo estresse crônico é mediado por alterações plásticas, e a similaridade temporal com os efeitos sobre a atividade da enzima Na+, K+-ATPase sugere que ela esteja envolvida no prejuízo observado na memória espacial. Também avaliamos os efeitos destes tratamentos sobre a transmissão glutamatérgica hipocampal, e observamos que o estresse aumenta a liberação basal de glutamato e diminui a captação deste neurotransmissor por fatias hipocampais. Este efeito pode induzir excitotoxicidade glutamatérgica e colaborar no agravamento de outros insultos, como o aumento na morte celular observado após a privação de oxigênio e glicose. Por sua vez, o lítio aumentou a captação de glutamato por sinaptossomas, o que pode ser uma ferramenta adicional na neuroproteção após diversos tipos de insulto. Também houve um aumento na liberação de glutamato após estímulo, e este efeito pode, por um lado, estar facilitando os mecanismos de plasticidade sináptica, por outro, ter contribuído para o aumento na morte celular observado após privação de oxigênio e glicose. Foram realizadas medidas de estresse oxidativo, onde o tratamento com lítio induziu um relativo efeito antioxidante, demonstrado pela diminuição na formação de espécies oxidantes no hipocampo e pelo aumento da reatividade antioxidante total em hipocampo e hipotálamo, bem como pelo aumento na atividade da superóxido dismutase (SOD) e da glutationa peroxidase (GPX) em hipotálamo e hipocampo, respectivamente. Contudo, este efeito antioxidante não foi eficiente na prevenção da peroxidação lipídica hipocampal provocada pelo estresse, e o aumento desproporcional na atividade da SOD em animais estressados e estressados + lítio é um possível causador da peroxidação dos lipídeos de membrana em hipocampo. Os tratamentos com estresse e lítio induziram aumento no consumo de alimentos doces, sem, contudo, alterar o consumo de ração padrão pelos animais. No entanto, somente animais tratados com lítio apresentaram aumento também no consumo de alimentos salgados, e o aumento no consumo de doces por este grupo foi muito mais acentuado do que nos animais estressados. Estes efeitos não parecem ser devidos a uma maior ansiedade, visto que não houve efeito ansiogênico dos tratamentos no labirinto em cruz elevado. Animais estressados não apresentaram a analgesia característica após exposição a um sabor doce agradável (leite condensado) na medida de latência de retirada da cauda; contudo, mostraram analgesia induzida por um sabor ácido e desagradável, o que caracteriza alguns dos efeitos clássicos da depressão. Já animais tratados com lítio apresentaram analgesia tanto após o sabor agradável quanto o aversivo, sugerindo uma maior sensibilidade a estímulos gustativos nestes animais, e o lítio preveniu a ausência de analgesia induzida por doce em animais estressados, o que pode ser tomado como um efeito antidepressivo deste tratamento. Por fim, observamos uma diminuição na atividade dopaminérgica ventro-estriatal de animais estressados, que pode estar envolvida na ausência de comportamento apetitivo condicionado por um estímulo palatável. Por outro lado, animais tratados com lítio apresentaram um aumento no tônus dopaminérgico, demonstrado pela aquisição de comportamento apetitivo e pela sensibilização cruzada com dietilpropiona, sem, contudo, apresentarem alteração no conteúdo total de dopamina no núcleo accumbens. Pode-se sugerir que o tratamento com lítio induza um aumento na liberação fásica de dopamina ou alteração em seus receptores, e estes efeitos podem estar envolvidos no aumentado interesse de animais tratados com lítio por alimentos novos
These studies were undertaken to investigate the mechanisms involved in the protective effects of lithium treatment on spatial memory of rats submitted to chronic variate stress paradigm, and to verify the effects of these treatments in some depression related parameters. Adult male Wistar rats (Rattus norvegicus) were divided into 4 groups: control, control treated with lithium, stressed and stressed treated with lithium. We observed that 21 days of stress and lithium treatments did not alter spatial memory, and that 30 days of lithium treatment had a facilitative effect on memory. From these results on, all treatments lasted 40 days, and after that behavioral and biochemical measurements were performed. We observed that stress decreases Na+, K+-ATPase activity in hippocampal synaptic membranes and this effect is prevented by lithium treatment, as well as it is reversed by stress interruption and post-stress lithium treatment. Thirty days of stress interruption also reversed its effects on spatial memory, as well as does a post-stress lithium treatment. These data suggest that the cognitive deficit induced by chronic stress is mediated by plastic alterations, and the parallelism between the effects on spatial memory and on Na+, K+-ATPase activity suggests that this enzyme may be involved in the spatial memory damage observed in stressed animals. We also evaluated the effects of stress and lithium on hippocampal glutamatergic transmission, and we observed that stress increases basal synaptosomal release and decreases glutamate uptake in slices of hippocampus. These effects may favor glutamatergic excitotoxicity and contribute to neuronal loss after other kinds of insults, as it was observed after oxygen and glucose deprivation. Lithium increased synaptosomal glutamate uptake, what can represent an additional tool in neuroprotection against several kinds of insults. Lithium also increased stimulated glutamate release, what can be benefic for neuronal plasticity but can also contribute to neuroendangerment after oxygen and glucose deprivation. We performed some oxidative stress measurements, and lithium treatment induced an antioxidant effect, evidenced by a decreased formation of oxidative agents in hippocampus and an increased on total antioxidant reactivity in hippocampus and hypothalamus, as well as an increased activity of superoxide dismuthase (SOD) and gluthathione peroxidase (GPx) in hippocampus and hypothalamus, respectively. However, this antioxidant effect was not enough to prevent the hippocampal lipid peroxidation induced by stress, and the disproportional increase on SOD activity in stressed and stressed + lithium is a possible mediator for the lipid peroxidation observed in this structure. Stress and lithium treatments induced an increased consumption of sweet foods, not altering standard chow consumption. However, just lithium-treated animals presented an increase in intake of savory foods, and their intake of sweet foods was notably higher than in stressed animals. These effects do not seem to be related to higher anxiety levels, since there was no anxiogenic effects of stress and lithium in the Plus Maze test. Stressed animals did not present sweet-induced analgesia, as evaluated by the tail-flick measurement, but they presented analgesia induced by an unpleasant flavor, characterizing some effects observed in depression. Conversely, lithiumtreated animals presented analgesia after pleasant and unpleasant tastes, suggesting an increased sensibility to gustative stimuli in these animals, and lithium prevented the absence of sweet-induced analgesia observed in stressed animals, what can be taken as an antidepressive effect of this treatment. Finally, we observed a decreased ventral-striatal dopaminergic activity in stressed animals that can be involved in the absence of a palatableconditioned appetitive behavior. On the other hand, lithium-treated animals presented an increased dopaminergic tonus, as showed by the acquired appetitive behavior and by the cross-sensitization with diethylpropione, without presenting any alteration in the total amount of dopamine in the nucleus accumbens. We can suggest that lithium treatment induces an increase on phasic dopamine release or an alteration in its receptors, and these effects can be involved in the increased interest of lithium-treated animals by new palatable foods.
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