DIAGNÓSTICO PRECOCE DE NEFROTOXICIDADE INDUZIDA PELA CISPLATINA EM PACIENTES EM TRATAMENTO QUIMIOTERÁPICO: QUANTIFICAÇÃO DE ÁCIDO QUINOLÍNICO COMO MARCADOR

A cisplatina é um fármaco utilizado para tratamento de vários tipos de tumores, dentre os principais: mama e ovários. Sua indicação é limitada por sua alta neurotoxicidade e nefrotoxicidade. Pacientes tratados com esse quimioterápico exigem um acompanhamento dos efeitos adversos, que atualmente é feito pela dosagem de creatinina sérica. Porém, a avaliação de lesão renal pela dosagem da creatinina sérica não é indicada devido às várias interferências do método, destacando-se a detecção tardia de possíveis agressões aos rins. A dosagem do metabólito endógeno ácido quinolínico tem se mostrado uma forma alternativa mais precoce para acompanhamento de pacientes submetidos ao tratamento com cisplatina. Palavras-chave: Ácido quinolínico (AQ). Cisplatina. Nefrotoxicidade

Sex-dependent effect on mitochondrial and oxidative stress parameters in the hypothalamus induced by prepubertal stress and access to high fat diet

Objective: Some factors related to lifestyle, including stress and high-fat diet (HFD) consumption, are associated with higher prevalence of obesity. These factors can lead to an imbalance between ROS production and antioxidant defenses and to mitochondrial dysfunctions, which, in turn, could cause metabolic impairments, favoring the development of obesity. However, little is known about the interplay between these factors, particularly at early ages, and whether long-term sex-specific changes may occur. Here, we evaluated whether social isolation during the prepubertal period only, associated or not with chronic HFD, can exert long-term effects on oxidative status parameters and on mitochondrial function in the whole hypothalamus, in a sex-specific manner. Methods: Wistar male and female rats were divided into two groups (receiving standard chow or standard chow + HFD), that were subdivided into exposed or not to social isolation during the prepubertal period. Oxidative status parameters, and mitochondrial function were evaluated in the hypothalamus in the adult age. Results: Regarding antioxidant enzymes activities, HFD decreased GPx activity in the hypothalamus, while increasing SOD activity in females. Females also presented increased total thiols; however, non-protein thiols were lower. Main effects of stress and HFD were observed in TBARS levels in males, with both factors decreasing this parameter. Additionally, HFD increased complex IV activity, and decreased mitochondrial mass in females. Complex I-III activity was higher in males compared to females. Conclusion: Stress during the prepubertal period and chronic consumption of HFD had persistent sex-specific effects on oxidative status, as well as on its consequences for the cell and for mitochondrial function. HFD had more detrimental effects on females, inducing oxidative imbalance, which resulted in damage to the mitochondria. This HFD-induced imbalance may be related to the development of obesity

Efeitos bioquímicos sexo-específicos da exposição ao isolamento social durante o período pré-púbere associado à dieta rica em gordura sobre a programação do metabolismo energético em ratos adultos

A obesidade é uma condição multifatorial cujo aumento da prevalência está relacionado a mudanças no estilo de vida, no qual o estresse e o consumo de dietas ricas em gordura estão amplamente envolvidos. A exposição a fatores ambientais em períodos precoces do desenvolvimento pode causar alterações persistentes no sistema nervoso central e no sistema endócrino-metabólico que, por consequência, podem resultar no desenvolvimento do fenótipo da obesidade. O período pré-púbere é uma fase sensível do desenvolvimento, caracterizada pela maturação de sistemas envolvidos na homeostase energética e nas respostas ao estresse. Intervenções durante esse período podem influenciar a susceptibilidade a doenças ou a resiliência na idade adulta. O isolamento social é considerado um potente estressor para roedores e humanos e a exposição a esse fator durante o período pré-púbere pode ter efeitos emocionais, comportamentais e metabólicos em longo prazo. A exposição ao estresse durante fases precoces do desenvolvimento pode causar alterações no comportamento alimentar e induzir a maior preferência por alimentos confortantes (“comfort foods”), ricos em açúcares e gorduras. O estresse e a ingestão de dietas ricas em gordura podem programar o metabolismo de forma distinta entre os sexos por modular a sinalização de hormônios envolvidos na regulação da homeostase energética. Além disso, esses fatores ambientais podem levar a um desequilíbrio entre a produção de espécies reativas e as defesas antioxidantes, favorecendo o estresse oxidativo, o qual pode induzir a oxidação de biomoléculas e levar a disfunções mitocondriais. Com base no exposto acima, o objetivo dessa tese foi investigar os efeitos em longo prazo do isolamento social durante o período pré-púbere (21-28 dias pós-natal), associado ou não à dieta rica em gordura crônica, sobre parâmetros metabólicos, oxidativos, sobre a função mitocondrial e sobre parâmetros de dano à célula no hipotálamo total, comparando machos e fêmeas. Para alcançar esse objetivo foram avaliados aspectos murinométricos e metabólicos relacionados à sinalização da leptina no hipotálamo total dos ratos na idade adulta, verificando possíveis diferenças sexo-específicas. Para verificar se os fatores estresse e o consumo crônico de dieta rica em gordura teriam efeitos sobre o metabolismo celular, também foram analisados parâmetros oxidativos e de função mitocondrial no hipotálamo total desses animais na idade adulta. Os resultados mostraram que os machos e as fêmeas responderam de forma diferente ao estresse no período pré-púbere e à dieta rica em gordura. Os machos apresentaram características murinométricas que pareceram refletir uma resistência à leptina. Entretanto, o prejuízo na sinalização desse hormônio aconteceu apenas parcialmente no hipotálamo e foi principalmente influenciado pela dieta rica em gordura nesses animais. Por outro lado, as fêmeas foram mais susceptíveis ao isolamento social no período pré-púbere, o qual levou a prejuízos na sinalização da leptina na idade adulta. De modo interessante, a via alternativa de sinalização da leptina, através do eixo hipotálamo-hipófise-tireoide, permaneceu ativada nos machos. Porém, a maior liberação de hormônios da tireoide nesses animais não teve os efeitos metabólicos esperados devido à menor conversão do T4 em T3. Embora ambos fatores, estresse e a dieta rica em gordura assim como a interação entre eles tenham apresentado efeitos distintos em machos e fêmeas, o consumo crônico da dieta rica em gordura teve efeitos mais proeminentes nas fêmeas quando considerados parâmetros oxidativos e de função mitocondrial. A dieta induziu um desequilíbrio oxidativo que resultou em danos celulares e mitocondriais nas fêmeas. De forma ampla, essa tese mostrou que intervenções em fases precoces da vida do indivíduo podem ter desfechos diferentes em machos e fêmeas. O isolamento social no período pré-púbere e o consumo crônico da dieta rica em gordura podem programar o metabolismo ao longo da vida. O consumo crônico da dieta rica em gordura levou a uma perturbação na comunicação do metabolismo periférico com o central nos machos que repercutiu em um fenótipo semelhante ao da obesidade nesses animais. As fêmeas foram mais susceptíveis à dieta rica em gordura, porém os prejuízos maiores foram observados no metabolismo energético central, marcado pelo desequilíbrio oxidativo e pelas disfunções mitocondriais. Assim, nosso trabalho destaca a importância de intervenções ambientais, no início da vida, para a programação metabólica em longo prazo. Adicionalmente, esses resultados podem revelar alvos importantes para a elucidação dos mecanismos relacionados ao desenvolvimento da obesidade e contribuir para que novos trabalhos sejam desenvolvidos além de auxiliar para que futuras medidas terapêuticas e preventivas sejam desenvolvidas respeitando as particularidades de cada gênero.Obesity is a multifactorial disorder in which increased prevalence is related to changes in lifestyle, and both stress and consumption of high-fat diets are largely involved. Exposure to environmental factors at early stages of development may cause persistent changes in the central nervous system and endocrine-metabolic system, which may result in the development of the obesity phenotype. The pre-pubertal period is a sensitive phase of development, characterized by the maturation of systems involved in energy homeostasis and stress responses. Interventions during this period may influence the susceptibility to disease or resilience in adulthood. Social isolation is considered a potent stressor for rodents and humans and exposure to this factor during the pre-pubertal period may have long-term emotional, behavioral, and metabolic effects. The stress exposure during early stages of development can cause changes in eating behavior and induce the preference for “comfort foods”, rich in sugars and fats. Both, stress and high-fat diets intake can program the metabolism in a sex-different manner through modulation of hormones signaling involved in regulation of energy homeostasis. In addition, these environmental factors may lead to an imbalance between the production of reactive oxygen species and antioxidant defenses favoring oxidative stress, which can induce the oxidation of biomolecules and lead to mitochondrial dysfunctions. Based on the above ideas, the aim of this thesis was to investigate the long-term effects of social isolation during the pre-pubertal period (postnatal day 21-28), associated with chronic high-fat diet on metabolic, oxidative and mitochondrial parameters in the total hypothalamus, comparing males and females. To achieve this goal, we evaluated murine and metabolic aspects related to the leptin signaling in the total hypothalamus of rats in adulthood, verifying possible sex-specific differences. To verify if the stress factor and the chronic consumption of high-fat diet would have effects on cellular metabolism, oxidative and mitochondrial function parameters were also analyzed in the total hypothalamus of these animals in adulthood. The results showed that males and females respond differently to pre-pubertal stress and high-fat diet. Males presented murinometric characteristics that reflect leptin resistance, however the damage in this hormone signaling occurred only partially in hypothalamus, and was mainly influenced by high-fat diet in these animals. On the other hand, females were more susceptible to social isolation in the pre-pubertal period, which led to impaired leptin signaling in adulthood. Interestingly, the alternative pathway of leptin signaling through the hypothalamic-pituitary-thyroid axis remained activated in males. However, the greater release of thyroid hormones in these animals did not have the expected metabolic effects due to the lower conversion of T4 into T3. Although both factors, stress and high-fat diet had different effects in males and females, chronic consumption of high-fat diet had more prominent effects in females when considered mitochondrial function and oxidative parameters. The diet induced an oxidative imbalance that resulted in cellular and mitochondrial damage in females. Generally, this thesis showed that interventions in early stages of individual life may have different outcomes in males and females. Social isolation in the prepubertal period and the chronic consumption of high-fat diet can program the metabolism throughout life. The high-fat diet chronic consumption led to a disturbance in the communication of peripheral and central energetic metabolism in males that led to a phenotype similar to that of obesity in these animals. Females were also more susceptible to high-fat diet, but the impairments were observed in central energy metabolism, which was marked by oxidative imbalance and mitochondrial dysfunctions. Thus, our work highlights the importance of early interventions for long-term metabolic programming. Additionally, these results may reveal important targets for the elucidation of the mechanisms related to the development of obesity and contribute to the development of new original works that stimulate the development of future therapeutic and preventive measures respecting the particularities of each sex

Efeitos bioquímicos sexo-específicos da exposição ao isolamento social durante o período pré-púbere associado à dieta rica em gordura sobre a programação do metabolismo energético em ratos adultos

A obesidade é uma condição multifatorial cujo aumento da prevalência está relacionado a mudanças no estilo de vida, no qual o estresse e o consumo de dietas ricas em gordura estão amplamente envolvidos. A exposição a fatores ambientais em períodos precoces do desenvolvimento pode causar alterações persistentes no sistema nervoso central e no sistema endócrino-metabólico que, por consequência, podem resultar no desenvolvimento do fenótipo da obesidade. O período pré-púbere é uma fase sensível do desenvolvimento, caracterizada pela maturação de sistemas envolvidos na homeostase energética e nas respostas ao estresse. Intervenções durante esse período podem influenciar a susceptibilidade a doenças ou a resiliência na idade adulta. O isolamento social é considerado um potente estressor para roedores e humanos e a exposição a esse fator durante o período pré-púbere pode ter efeitos emocionais, comportamentais e metabólicos em longo prazo. A exposição ao estresse durante fases precoces do desenvolvimento pode causar alterações no comportamento alimentar e induzir a maior preferência por alimentos confortantes (“comfort foods”), ricos em açúcares e gorduras. O estresse e a ingestão de dietas ricas em gordura podem programar o metabolismo de forma distinta entre os sexos por modular a sinalização de hormônios envolvidos na regulação da homeostase energética. Além disso, esses fatores ambientais podem levar a um desequilíbrio entre a produção de espécies reativas e as defesas antioxidantes, favorecendo o estresse oxidativo, o qual pode induzir a oxidação de biomoléculas e levar a disfunções mitocondriais. Com base no exposto acima, o objetivo dessa tese foi investigar os efeitos em longo prazo do isolamento social durante o período pré-púbere (21-28 dias pós-natal), associado ou não à dieta rica em gordura crônica, sobre parâmetros metabólicos, oxidativos, sobre a função mitocondrial e sobre parâmetros de dano à célula no hipotálamo total, comparando machos e fêmeas. Para alcançar esse objetivo foram avaliados aspectos murinométricos e metabólicos relacionados à sinalização da leptina no hipotálamo total dos ratos na idade adulta, verificando possíveis diferenças sexo-específicas. Para verificar se os fatores estresse e o consumo crônico de dieta rica em gordura teriam efeitos sobre o metabolismo celular, também foram analisados parâmetros oxidativos e de função mitocondrial no hipotálamo total desses animais na idade adulta. Os resultados mostraram que os machos e as fêmeas responderam de forma diferente ao estresse no período pré-púbere e à dieta rica em gordura. Os machos apresentaram características murinométricas que pareceram refletir uma resistência à leptina. Entretanto, o prejuízo na sinalização desse hormônio aconteceu apenas parcialmente no hipotálamo e foi principalmente influenciado pela dieta rica em gordura nesses animais. Por outro lado, as fêmeas foram mais susceptíveis ao isolamento social no período pré-púbere, o qual levou a prejuízos na sinalização da leptina na idade adulta. De modo interessante, a via alternativa de sinalização da leptina, através do eixo hipotálamo-hipófise-tireoide, permaneceu ativada nos machos. Porém, a maior liberação de hormônios da tireoide nesses animais não teve os efeitos metabólicos esperados devido à menor conversão do T4 em T3. Embora ambos fatores, estresse e a dieta rica em gordura assim como a interação entre eles tenham apresentado efeitos distintos em machos e fêmeas, o consumo crônico da dieta rica em gordura teve efeitos mais proeminentes nas fêmeas quando considerados parâmetros oxidativos e de função mitocondrial. A dieta induziu um desequilíbrio oxidativo que resultou em danos celulares e mitocondriais nas fêmeas. De forma ampla, essa tese mostrou que intervenções em fases precoces da vida do indivíduo podem ter desfechos diferentes em machos e fêmeas. O isolamento social no período pré-púbere e o consumo crônico da dieta rica em gordura podem programar o metabolismo ao longo da vida. O consumo crônico da dieta rica em gordura levou a uma perturbação na comunicação do metabolismo periférico com o central nos machos que repercutiu em um fenótipo semelhante ao da obesidade nesses animais. As fêmeas foram mais susceptíveis à dieta rica em gordura, porém os prejuízos maiores foram observados no metabolismo energético central, marcado pelo desequilíbrio oxidativo e pelas disfunções mitocondriais. Assim, nosso trabalho destaca a importância de intervenções ambientais, no início da vida, para a programação metabólica em longo prazo. Adicionalmente, esses resultados podem revelar alvos importantes para a elucidação dos mecanismos relacionados ao desenvolvimento da obesidade e contribuir para que novos trabalhos sejam desenvolvidos além de auxiliar para que futuras medidas terapêuticas e preventivas sejam desenvolvidas respeitando as particularidades de cada gênero.Obesity is a multifactorial disorder in which increased prevalence is related to changes in lifestyle, and both stress and consumption of high-fat diets are largely involved. Exposure to environmental factors at early stages of development may cause persistent changes in the central nervous system and endocrine-metabolic system, which may result in the development of the obesity phenotype. The pre-pubertal period is a sensitive phase of development, characterized by the maturation of systems involved in energy homeostasis and stress responses. Interventions during this period may influence the susceptibility to disease or resilience in adulthood. Social isolation is considered a potent stressor for rodents and humans and exposure to this factor during the pre-pubertal period may have long-term emotional, behavioral, and metabolic effects. The stress exposure during early stages of development can cause changes in eating behavior and induce the preference for “comfort foods”, rich in sugars and fats. Both, stress and high-fat diets intake can program the metabolism in a sex-different manner through modulation of hormones signaling involved in regulation of energy homeostasis. In addition, these environmental factors may lead to an imbalance between the production of reactive oxygen species and antioxidant defenses favoring oxidative stress, which can induce the oxidation of biomolecules and lead to mitochondrial dysfunctions. Based on the above ideas, the aim of this thesis was to investigate the long-term effects of social isolation during the pre-pubertal period (postnatal day 21-28), associated with chronic high-fat diet on metabolic, oxidative and mitochondrial parameters in the total hypothalamus, comparing males and females. To achieve this goal, we evaluated murine and metabolic aspects related to the leptin signaling in the total hypothalamus of rats in adulthood, verifying possible sex-specific differences. To verify if the stress factor and the chronic consumption of high-fat diet would have effects on cellular metabolism, oxidative and mitochondrial function parameters were also analyzed in the total hypothalamus of these animals in adulthood. The results showed that males and females respond differently to pre-pubertal stress and high-fat diet. Males presented murinometric characteristics that reflect leptin resistance, however the damage in this hormone signaling occurred only partially in hypothalamus, and was mainly influenced by high-fat diet in these animals. On the other hand, females were more susceptible to social isolation in the pre-pubertal period, which led to impaired leptin signaling in adulthood. Interestingly, the alternative pathway of leptin signaling through the hypothalamic-pituitary-thyroid axis remained activated in males. However, the greater release of thyroid hormones in these animals did not have the expected metabolic effects due to the lower conversion of T4 into T3. Although both factors, stress and high-fat diet had different effects in males and females, chronic consumption of high-fat diet had more prominent effects in females when considered mitochondrial function and oxidative parameters. The diet induced an oxidative imbalance that resulted in cellular and mitochondrial damage in females. Generally, this thesis showed that interventions in early stages of individual life may have different outcomes in males and females. Social isolation in the prepubertal period and the chronic consumption of high-fat diet can program the metabolism throughout life. The high-fat diet chronic consumption led to a disturbance in the communication of peripheral and central energetic metabolism in males that led to a phenotype similar to that of obesity in these animals. Females were also more susceptible to high-fat diet, but the impairments were observed in central energy metabolism, which was marked by oxidative imbalance and mitochondrial dysfunctions. Thus, our work highlights the importance of early interventions for long-term metabolic programming. Additionally, these results may reveal important targets for the elucidation of the mechanisms related to the development of obesity and contribute to the development of new original works that stimulate the development of future therapeutic and preventive measures respecting the particularities of each sex

Región : diario de la mañana: Año III Número 710 - 1925 Noviembre 22

A pré-puberdade é um período crítico para maturação dos circuitos neuronais que controlam a homeostase energética e as respostas ao estresse, além de ser um período de grande desenvolvimento emocional. A exposição a fatores ambientais como o estresse e dietas ricas em gordura durante esse período, podem modificar os processos de maturação neural causando alterações comportamentais e neuroquímicas que podem repercutir em disfunções e patologias na idade adulta. Dessa forma, o objetivo desse estudo foi investigar os efeitos da exposição ao estresse por isolamento social durante o período da pré-puberdade em ratos machos e fêmeas com ou sem o acesso crônico a uma dieta rica em gordura e seus efeitos a longo prazo sobre parâmetros de consumo, deposição de gordura e hormônios como leptina e adiponectina. Além disso, nosso estudo investigou se a exposição ao estresse durante o período pré-púbere com ou sem acesso a dieta rica em gordura pode levar a um comportamento do tipo depressivo e se esse comportamento estaria relacionado com parâmetros inflamatórios. Os ratos machos isolados recebendo apenas ração padrão apresentaram menor ganho de peso que seus controles, efeito revertido pelo acesso à dieta rica em gordura que aumentou o peso dos animais na semana em que foram submetidos ao estresse. Na semana do isolamento, a dieta rica em gordura diminuiu a eficiência calórica nos animais. Diferentemente do que ocorreu na idade adulta, quando o consumo da dieta rica em gordura aumentou a eficiência calórica nos animais, sendo mais pronunciada nos machos do que nas fêmeas. Além disso, foi observado que a dieta rica em gordura aumentou os níveis de leptina e os níveis de adiponectina na idade adulta. Tanto os animais estressados quanto aqueles que receberam a dieta rica em gordura exibiram comportamento do tipo depressivo, que não parece estar associado aos parâmetros inflamatórios avaliados. Esses resultados sugerem que intervenções como o estresse por isolamento durante o período pré-púbere associado ao acesso crônico a uma dieta rica em gordura podem causar modificações no metabolismo de forma sexo-específica e levar ao comportamento do tipo depressivo a longo prazo.The pre-puberty period is critical for the maturation of neural circuits that control energy homeostasis and stress responses, besides being a period of emotional development. Exposure to environmental factors, such as stress and high-fat diet, during this period can modify the neural maturation process causing behavioral and neurochemical changes that may impact in disorders in adult age. Thus, the aim of this study was to investigate the effects of exposure to isolation stress during the prepubertal period in male and female rats with or without chronic access to high-fat diet and its long-term effects on consumption parameters, fat deposition and on hormones such as leptin and adiponectin. Furthermore, our study investigated whether exposure to stress during prepubertal period with or without access to high-fat diet would lead to depressive-like behavior and whether this behavior would be related to inflammatory parameters. Stressed male rats receiving standard chow had less body weight gain than their controls, effect reversed by access to high-fat diet that increased the body weight gain of animals during first week, when they were submitted to stress. During the isolation week, the access to high-fat diet decreased caloric efficiency in all animals. Differently, in adulthood high-fat diet consumption increased caloric efficiency in animals, being more pronounced in males than females. Moreover, it was observed that high-fat diet increased leptin levels and adiponectin levels in adulthood. Both stressed animals and those receiving high-fat diet exhibited depressive-like behavior that seems to be not associated with evaluated inflammatory parameters. These results suggest that interventions such as isolation stress during prepubertal period and chronic access to a high-fat diet can cause changes in a sex-specific manner and lead to depressive-like behavior in the long-term

Neonatal handling affects learning, reversal learning and antioxidant enzymes activities in a sex-specific manner in rats

Early life experiences have profound influences on behavior and neurochemical parameters in adult life. The aim of this study is to verify neonatal handling-induced sex specific differences on learning and reversal learning as well as oxidative stress parameters in the prefrontal cortex and striatum of adult rats. Litters of rats were non-handled or handled (10 min/day, days 1–10 after birth). In adulthood, learning and reversal learning were evaluated using a Y maze associated with palatable food in male and female rats. Morris water maze reversal learning was verified in males. Oxidative stress parameters were evaluated in both genders. Male neonatal handled animals had a worse performance in the Y maze reversal learning compared to non-handled ones and no difference was observed in the water maze reversal learning task. Regarding females, neonatal handled rats had a better performance during the Y maze learning phase compared to non-handled ones. In addition, neonatal handled female animals showed a decreased SOD/CAT ratio in the PFC compared to non-handled females. We conclude that neonatal handling effects on learning and memory in adult rats are sex and task specific. The sex specific differences are also observed in the evaluation of antioxidant enzymes activities with neonatal handling affecting only females

Experimental Design Applied to the Optimization and Partial Characterization of Pectin Liase from a Newly Isolated Penicillium brasilianum

Penicillium brasilianum was previously isolated from tea and identified by molecular biology technique. A Plackett-Burman design, followed by a complete second order design was used for the screening of most important factors and to maximize the pectin liase (PMGL) activity, respectively. The maximum PMGL activity by P. brasilianum achieved was 9.0 U/mL after 48 h of cultivation in a medium containing pectin (33.0 g/L), yeast extract (30.0 g/L) and potassium phosphate (2.0 g/L) at 30ºC, with a stirring rate of 180 rpm, initial pH 5.5 and 5x106spores/mL inoculum size. The kinetic evaluation in terms of substrate consumption demonstrated that the maximum production of PMGL was at 72 h, and 40% of the total organic carbon, 25% of the nitrogen, 88% of the magnesium, 13% of the potassium and 66% of the iron were consumed. The pH remained almost stable during the whole period of production (5.33 to 4.9). The partial characterization of the crude PMGL enzyme extract showed optimal pH and temperature of 5.5 and 37°C, respectively

Early life adversities or high fat diet intake reduce cognitive function and alter BDNF signaling in adult rats : interplay of these factors changes these effects

Environmental factors, like early exposure to stressors or high caloric diets, can alter the early programming of central nervous system, leading to long-term effects on cognitive function, increased vulnerability to cognitive decline and development of psychopathologies later in life. The interaction between these factors and their combined effects on brain structure and function are still not completely understood. In this study, we evaluated long-term effects of social isolation in the prepubertal period, with or without chronic high fat diet access, on memory and on neurochemical markers in the prefrontal cortex of rats. We observed that early social isolation led to impairment in short-term and working memory in adulthood, and to reductions of Na+,K+-ATPase activity and the immunocontent of phospho-AKT, in prefrontal cortex. Chronic exposure to a high fat diet impaired short-term memory (object recognition), and decreased BDNF levels in that same brain area. Remarkably, the association of social isolation with chronic high fat diet rescued the memory impairment on the object recognition test, as well as the changes in BDNF levels, Na+,K+-ATPase activity, MAPK, AKT and phospho-AKT to levels similar to the control-chow group. In summary, these findings showed that a brief social isolation period and access to a high fat diet during a sensitive developmental period might cause memory deficits in adulthood. On the other hand, the interplay between isolation and high fat diet access caused a different brain programming, preventing some of the effects observed when these factors are separately applied

Short post-weaning social isolation induces long-term changes in the dopaminergic system and increases susceptibility to psychostimulants in female rats

Childhood and adolescence are sensitive periods of development, marked by high brain maturation and plasticity. Exposure to early life stress, such as social isolation, is able to prompt changes in sensitive brain circuitries, essentially in the mesolimbic dopaminergic system and increase the risk for addictive behaviors later in life. Post-weaning social isolation can stimulate the consumption of rewarding substances, like drugs of abuse and palatable foods. However, most studies analyze long periods of social isolation and very little is known about the effects of a brief social isolation in a sensitive period of development and its association with palatable food on the reward system sensitization. Furthermore, females are more susceptible to the reinforcing effect of drugs than males. Therefore, the aim of this study was to analyze the effects of a short post-weaning social isolation combined with a free access to a chronic high sugar diet (HSD) on the dopaminergic system, oxidative status and behavioral response to an amphetamine-like drug in adulthood. We used female Wistar rats that were socially isolated from post-natal days (PD) 21 to 35 and received free access to a HSD until PD 60. On PD 65, animals were submitted to a challenge with diethylpropion (DEP), an amphetamine-like drug and different responses were analyzed: locomotor activity, immmunocontent of dopamine related proteins, and the oxidative status in the striatum, before and after the DEP challenge. We showed that a short post-weaning social isolation (SI) increased the locomotor response to DEP, when compared with previous saline administration. Social isolation also increased dopamine transporter, tyrosine hydroxylase, and decreased dopamine D2 receptor immunocontent. Additionally, SI increased the overall oxidative status parameters after the challenge with DEP. Interestingly, the exposure to a HSD prevented the SI effects on locomotor response, but did not interfere in the dopaminergic parameters evaluated, despite having modified some oxidative parameters. This study showed for the first time that a short post-weaning social isolation was able to induce long-term changes in the striatal dopaminergic system and increased the response to psychostimulants. These results emphasize the importance of stressful experiences during a short period of development on programming susceptibility to psychostimulants later in life

Impact of high-fat diet and early stress on depressive-like behavior and hippocampal plasticity in adult male rats

During development, the brain goes through fundamental processes, including organization of neural networks and plasticity. Environmental interventions may change initial brain programming, leading to long-lasting effects and altering the susceptibility to psychopathologies, including depression disorder. It is known that depression is a psychiatric disorder with a high prevalence worldwide, including high rates among adolescents. In this study, we evaluated whether social isolation in the prepubertal period and chronic use of high-fat diet (HFD) may induce depressive-like behavior in male adult rats. We also investigated hippocampal plasticity markers and neurotransmitter systems. We found both social isolation and HFD induced a depressive-like behavior in the forced swimming task. Moreover, chronic HFD reduced synaptic markers in hippocampus, demonstrated by reductions in βIII-tubulin (neuronal marker), PSD-95, SNAP-25, and neurotrophin-3. The HFD group also presented decreased glutamatergic and GABAergic receptors subunits. On the other hand, stress affected hippocampal brain-derived neurotrophic factor (BDNF) signaling pathways, and increased expression of subunit of the NMDA receptor (NR2A). Both factors (stress and diet) decreased GR in the hippocampus without affecting plasma corticosterone at basal levels. Interactions between early stress and HFD access were observed only in the BNDF receptor (tropomyosin receptor kinase B; TrkB) and synaptophysin. In summary, these findings showed that a brief social isolation and chronic HFD, during a sensitive developmental period, cause depressive-like behavior in adulthood. The mechanisms underlying these behavioral effects may involve changes in the levels of synaptic proteins in hippocampus: HFD consumption appears to affect synaptic markers, while social isolation affected BDNF signaling more significantly