Alterações na epigenética do sistema ocitocinérgico em resposta ao cuidado materno negligente

O cuidado materno negligente, a falta de afeto e a dificuldade de interagir socialmente estão relacionadas com o desequilíbrio neurofisiológico da ocitocina, neurormônio com papel importante de modulação dos comportamentos sociais. Em seres humanos existem ligações conhecidas entre o estresse pré-natal e perinatal e transtornos psiquiátricos e de desenvolvimento. O objetivo deste estudo foi revisar o conceito de epigenética com foco no efeito a longo prazo do cuidado materno negligente e sua relação com alterações do sistema ocitocinérgico baseado em estudos com animais e humanos. Uma revisão narrativa da literatura foi realizada entre junho/2017 e janeiro/2019 através da busca de estudos na base PUBMED, com foco nos resultados qualitativos das relações epigenéticas com a negligência infantil, doenças psiquiátricas e sitema ocitocinérgico. Os estudos referidos demonstram que o cuidado materno negligente é um fator de risco para o desenvolvimento de transtornos mentais, principalmente os que incluem sintomas de desordem social. A ocitocina, por ser um neurormônio que age como um potente mediador das interações sociais, confiança e controle da ansiedade, parece ter papel fundamental neste contexto. A notória transgeracionalidade dos transtornos encontrados em proles de mães negligentes parece estar envolvida com mecanismos epigenéticos que inativam genes específicos do sistema ocitocinérgico no sistema nervoso central. Palavras chaves: Comportamentos sociais; ocitocina; metilação; transtornos mentai

Técnicas de substituição de DNA mitocondrial para reduzir a transmissão da síndrome de leigh

A Síndrome de Leigh (SL) é uma doença neuro-metabólica congênita, que faz parte do grupo das encefalopatias fatais, com progressão e morte dentro de 2 anos, em média. A SL é causada por mutações no DNA que causam alterações na geração de ATP celular pelas mitocôndrias. As mitocôndrias contêm seu próprio DNA (mtDNA) e, ao contrário do DNA nuclear, o mtDNA é herdado somente da mãe. Mulheres portadores de mutações causadoras da SL podem vivenciar experiências muito tristes ao tentarem realizar o sonho da maternidade. As técnicas de substituição de mtDNA mutado com mtDNA saudável de doadora, oferecem a essas mulheres a possibilidade de terem uma criança geneticamente relacionada sem a SL. O desenvolvimento e a aplicação clínica de terapias de substituição de mtDNA já são uma realidade, tendo o primeiro bebê gerado a partir da técnica nascido em 2016. Mas será que essas técnicas são seguras? Neste trabalho, revisamos a SL e algumas técnicas de substituição de mtDNA já aplicadas em humanos, que envolvem a transferência de pronúcleos de zigotos ou de fuso acromático de oócitos. Concluímos que, apesar dos resultados promissores, ainda é cedo para assegurar a aplicabilidade clínica de técnicas de substituição de mtDNA em seres humanos

Progesterone and maternal aggressive behavior in rats

Females usually display low levels of aggressiveness; however, during lactation, the aggressive behavior against intruders to the nest area is an important component of the maternal behavioral repertoire. The present study aimed to analyze the influence of progesterone (P4) on the maternal aggressive behavior in rats. Lactating rat were ovariectomized on the first day after delivery and, on the 6th postpartum day, aggressive behaviors against a male intruder were recorded. Also in the 6th PPD, the effects of a P4 receptor antagonist (RU 486) as well as of finasteride – which inhibits the conversion of P4 to its metabolite allopregnanolone – on the aggressive behavior of non-ovariectomized lactating rats were analyzed. Finally, plasma concentration of prolactin was measured on the 8th PPD. This study shows, for the first time, that ovariectomy just after parturition reduces some aspects of the maternal behavior (frequency of licking) and the aggressive behavior and increased plasma prolactin. On the other hand, the administration of RU486 induced a marked increase in the aggressiveness of lactating females. No changes were detected after finasteride injection. Gonadal hormones after parturition seem necessary for the development of maternal aggressive behavior. Furthermore, our results suggest that the increase in P4 levels throughout the postpartum period could be one of the causes for the natural reduction of the aggressive behavior in lactating rats

Oxytocin modulates social interaction but is not essential for sexual behavior in male mice

Recently, several studies have shown different conclusions regarding the effect of oxytocin (OT) on the social behaviors of male mice. Most of these studies used exogenous OT, but currently, investigations of the neural bases of social behavior are increasingly employing gene inactivation. This study aimed to analyze the role of OT in the modulation of social behaviors (i.e., sexual and social interaction behaviors) in male mice with selective deletions of the OT gene (OTKO) and the influence of this deletion in basal vasopressin (AVP) plasma concentrations. Our results showed that in the social interaction test, OTKO mice exhibited lower levels of social behaviors and higher levels of non-social behaviors compared to the wild type (WT) group. Additionally, the OTKO group showed a decrease in the number of agonistic behaviors delivered, and consequently, their dominance score was lower than that of the WT group. In the ethological analysis, the OTKO group had a lower aggressive performance and increased social investigation than the WT group. No significant differences were observed in the sexual behavior between groups. Finally, we found lower AVP plasma concentrations in the OTKO compared with the WT group. In conclusion, our data suggest that OT modulates social investigation behavior and the aggressiveness of male mice. The decrease in AVP concentrations in the OTKO group allows us to infer that AVP is physiologically relevant to these behavioral modulations. However, sexual behaviors do not seem to be affected by the lack of OT or by a decrease in the AVP concentration

Sexual behavior and dendritic spine density of posterodorsal medial amygdala neurons in oxytocin knockout female mice

Central oxytocin (OT) and arginine-vasopressin (AVP) have been shown to play an important role in sexual behavior and neuroendocrine secretion in rodents. The results of exogenous OT administration on sexual behaviors in male and female mice are controversial. This study aimed to analyze the role of OT in sexual behavior, the number of oocytes and the density of dendritic spines in the posterodorsal medial amygdala (MePD) of female mice with selective deletion of the OT gene (OTKO). Female C57BL/6 mice were genotyped and divided into control (WT) and OTKO groups (n = 11 each). All experiments were performed in the proestrus phase. Compared to WT data, our results showed that the OTKO group had a significant increase in the latency for the display of lordosis behavior (490.8 ± 113.8 and 841.9 ± 53.9, respectively) and a decrease in both the frequency (6.3 ± 2.4 and 0.5 ± 0.4) and duration (49.3 ± 19.9 and 7.2 ± 7.1) of lordosis and a reduction in the number of oocytes (12.2 ± 0.8 and 9.9 ± 0.6). However, the OTKO group showed a higher density of proximal dendritic spines in the MePD compared to the WT group (2.4 ± 0.1 and 1.9 ± 0.1 spines/dendritic μm, respectively). No significant difference was observed in the plasma levels of AVP between the groups (OTKO: 617.1 ± 96.0 and WT: 583.3 ± 112.0 pg/mL). Our data suggest that OT plays a crucial role in the sexual behavior display, number of released oocytes and density of dendritic spines in the MePD of female mice. The AVP plasma concentration was not affected in the OTKO animals

Analysis of transcriptional levels of the oxytocin receptor in different areas of the central nervous system and behaviors in high and low licking rats

The natural variation in maternal care is an interesting model to analyze the physiological mechanisms that lead to differences in the mother–infant interaction. Several studies have shown differences in the expression of brain receptors such as the dopamine, estrogen and oxytocin receptors in areas classically involved in the onset and/or maintenance of maternal behavior: the medial preoptic area, the nucleus accumbens, the amygdala, the lateral septum, and the bed nucleus of the stria terminalis. The present study examined the responses of HL and LL rats in several behavioral tests and analyzes the transcription of the oxytocin receptor (OXTR) in the olfactory bulb (OB), the prefrontal cortex (FPC), the hippocampus (HP) and the striatum (ST) in different patterns of licking behavior. Our results showed that, in the second week postpartum, HL and LL mothers did not show behavioral differences in the elevated plus maze (EPM), the forced swimming test (FST) or the open field test. In the maternal aggressive behavior test, HL females showed a higher frequency of biting compared to LL females, but no significant differences in other aggressive behaviors were detected. LL mothers had higher levels of transcriptional OXTR in the OB and in the HP when compared to HL mothers. No differences in other areas were detected when compared LL and HL. These findings suggest that variations in maternal behavior may be associated with biting behavior of mothers and that OXTR participates in modulation of maternal behavior in rats, while other emotional behaviors are less related to such behavior