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Maternal deprivation, as a result of the artificial rearing (AR) paradigm, disturbs electrophysiological and histological characteristics of the peripheral sensory sural (SU) nerve of infant and adult male rats. Such changes are prevented by providing tactile or social stimulation during isolation. AR also affects the female rat's brain and behavior; however, it is unknown whether this early adverse experience also alters their SU nerve development or if tactile stimulation might prevent these possible developmental effects. To assess these possibilities, the electrophysiological and histological characteristics of the SU nerve from adult diestrus AR female rats that: (i) received no tactile stimulation (AR group), (ii) received tactile stimulation in the anogenital and body area (AR-Tactile group), or (iii) were mother reared (MR group) were determined. We found that the amplitude, but not the area, of the evoked compound action potential response in SU nerves of AR rats was lower than those of SU nerves of MR female rats. Tactile stimulation prevented these effects. Additionally, we found a reduction in the outer diameter and myelin thickness of axons, as well as a large proportion of axons with low myelin thickness in nerves of AR rats compared to the nerves of the MR and AR-Tactile groups of rats; however, tactile stimulation only partially prevented these effects. Our data indicate that maternal deprivation disturbs the development of sensory SU nerves in female rats, whereas tactile stimulation partially prevents the changes generated by AR. Considering that our previous studies have shown more severe effects of AR on male SU nerve development, we suggest that sex-associated factors may be involved in these processes.
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Privação Materna , Nervo Sural , Tato , Animais , Feminino , Ratos , Nervo Sural/fisiologia , Tato/fisiologia , Estimulação Física , Ratos Wistar , Axônios/fisiologia , Potenciais de Ação/fisiologia , Bainha de Mielina/fisiologiaRESUMO
Major depressive disorder (MDD) is a severe disorder that causes enormous loss of quality of life, and among the factors underlying MDD is stress in maternal deprivation (MD). In addition, classic pharmacotherapy has presented severe adverse effects. Centella asiatica (C. asiatica) demonstrates a potential neuroprotective effect but has not yet been evaluated in MD models. This study aimed to evaluate the effect of C. asiatica extract and the active compound madecassic acid on possible depressive-like behavior, inflammation, and oxidative stress in the hippocampus and serum of young rats submitted to MD in the first days of life. Rats (after the first day of birth) were separated from the mother for 3 h a day for 10 days. When adults, these animals were divided into groups and submitted to treatment for 14 days. After subjecting the animals to protocols of locomotor activity in the open field and behavioral despair in the forced swimming test, researchers then euthanized the animals. The hippocampus and serum were collected and analyzed for the inflammatory cytokines and oxidative markers. The C. asiatica extract and active compound reversed or reduced depressive-like behaviors, inflammation in the hippocampus, and oxidative stress in serum and hippocampus. These results suggest that C. asiatica and madecassic acid have potential antidepressant action, at least partially, through anti-inflammatory and antioxidant profiles.
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BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.
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Antidepressivos , Encéfalo , Ácido Butírico , Epigênese Genética , Privação Materna , Ratos Wistar , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/tratamento farmacológico , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ratos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Histona Desacetilases/metabolismo , Depressão/tratamento farmacológico , Histona Acetiltransferases/metabolismo , Natação/psicologiaRESUMO
Many aspects of the impact of childhood trauma remain unknown, such as the age at which individuals are most vulnerable to trauma, whether traumatic experiences have more severe and lasting effects when experienced early in life, and whether early life trauma causes psychiatric conditions such as anxiety and major depressive disorder (MDD) that persist over time or evolve into other disorders. Thus, this study aimed to investigate the impact of traumatic experiences in childhood on susceptibility to mood disorders in adulthood, particularly MDD. Animal models were used to address these questions, and different stressor protocols at various stages of the offspring's life were used. Three-hit starting with injections of Poly: IC was performed on the 9th day of gestation and then considered the first stressor. After birth, the animals were exposed to the maternal deprivation (MD) protocol, which separated the pups from the mother 3 h a day during the first ten days of life. From the 60th day of life, the animals were divided to receive the chronic mild stress (CMS) protocol over 21 days. The stressors can induce anxiety-like behaviors, such as increased locomotor activity through a maternal immune activation protocol using Poly: IC and demonstrating depressive-like behaviors through the MD and CMS protocols. It also showed changes in brain structures for pro-inflammatory parameters, IL-1ß and TNF-α, and alterations in anti-inflammatory parameters, IL-4 and IL-10, at different ages of life. The study also found that regulating pro- and anti-inflammatory cytokines is necessary for appropriate neuronal behavior, and stress responses can be both friendly and enemy, with costs and benefits balanced to provide the best-fit result. In conclusion, phenotypic characteristics of animals' life history are shaped by signals transmitted directly or indirectly to developing animals, known as "predictive adaptive responses."
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Transtorno Depressivo Maior , Transtornos Mentais , Humanos , Ratos , Animais , Encéfalo , Depressão/etiologia , Estresse Psicológico/complicações , Anti-InflamatóriosRESUMO
This chapter presents a brief overview of attachment theory and discusses the importance of the neonatal period in shaping an individual's physiological and behavioural responses to stress later in life, with a focus on the role of the parent-infant relationship, particularly in rodents. In rodents, the role of maternal behaviours goes far beyond nutrition, thermoregulation and excretion, acting as hidden regulators of the pup's physiology and development. In this review, we will discuss the inhibitory role of specific maternal behaviours on the ACTH and corticosterone (CORT) stress response. The interest of our group to explore the long-term consequences of maternal deprivation for 24 h (DEP) at different ages (3 days and 11 days) in rats was sparked by its opposite effects on ACTH and CORT levels. In early adulthood, DEP3 animals (males and females alike) show greater negative impact on affective behaviours and stress related parameters than DEP11, indicating that the latter is more resilient in tests of anxiety-like behaviour. These findings create an opportunity to explore the neurobiological underpinnings of vulnerability and resilience to stress-related disorders. The chapter also provides a brief historical overview and highlights the relevance of attachment theory, and how DEP helps to understand the effects of childhood parental loss as a risk factor for depression, schizophrenia, and PTSD in both childhood and adulthood. Furthermore, we present the concept of environmental enrichment (EE), its effects on stress responses and related behavioural changes and its benefits for rats previously subjected to DEP, along with the clinical implications of DEP and EE.
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Encéfalo , Comportamento Materno , Masculino , Humanos , Feminino , Ratos , Animais , Ansiedade , Corticosterona , Privação Materna , Hormônio Adrenocorticotrópico , Estresse Psicológico/psicologiaRESUMO
Parental care is essential for proper development of stress response and emotion-related behaviours. Epidemiological studies show that parental loss in childhood represents a major risk factor for the development of mental disorders throughout the lifespan, including schizophrenia, depression, and anxiety. In most mammalian species, the mother is the main source of care and maternal behaviours regulate several physiological systems. Maternal deprivation (DEP) for 24 h is a paradigm widely used to disinhibit the hypothalamic-pituitary-adrenal axis response to stress during the stress hyporesponsive period. In this mini-review we will highlight the main DEP-induced neurobiological and behavioural outcomes, including alterations on stress-related hormones, neurogenesis, neurotransmitter/neuromodulatory systems and neuroinflammation. These neurobiological changes may be reflected by aberrant behaviours, which are relevant to the study of mental disorders. The evidence indicates that DEP consequences depend on the sex, the age when the DEP takes place and the age when the animals are evaluated, reflecting dynamic plasticity and individual variability. Individual variability and sex differences have a great relevance for the study of biological factors of stress resilience and vulnerability and the DEP paradigm is a suitable model for evaluation of phenotypes of stress- and emotion-related psychopathologies.
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Maternal deprivation (MD) leads to long-lasting memory deficits. Conversely, maternal exercise could potently modify the offspring's cellular machinery. Here, we tested whether starting to run or reducing the intensity of running during pregnancy can protect prepubertal female offspring against MD-induced memory deficits. Female rats were divided into different groups submitted or not to MD: one started to run before pregnancy and reduced the intensity during the pregnancy (PGE); another started to run at the beginning of pregnancy (GE); and, finally, a control group (CT) was not submitted to exercise. All the rats but those of the CT ran on a treadmill until the delivery day (PND 0). Subsequently, MD was performed from PND 1 to 10. We assessed object recognition (OR) and spatial memory (SM) of female offspring after weaning (PND22, pre-pubertal stage). MD caused OR memory deficit; GE female offspring did not present this deficit, but PGE did. Both PGE and GE alone enhanced offspring spatial learning, but their combination with MD impaired it. MD promoted hippocampal lipid peroxidation increase, which both PGE and GE prevented. Total antioxidant capacity in the hippocampus was higher in both MD-exercised groups compared to all others. Although the antioxidant effects of exercise were similar in both MD exercise groups, we observed better results in the memory tests in the GE group than in the PGE group. These results suggest that starting to exercise during pregnancy is better than reducing the exercise intensity during pregnancy to prevent MD-induced memory deficits in female offspring.
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Privação Materna , Corrida , Gravidez , Ratos , Animais , Feminino , Transtornos da Memória/etiologia , Transtornos da Memória/prevenção & controle , Aprendizagem Espacial , Percepção Visual , HipocampoRESUMO
Stress is related to major depressive disorder (MDD). This study investigated the action that early stress, represented by maternal deprivation (MD), has on the behavior and oxidative stress of Wistar female and male rats. Also, it was evaluated whether changes induced by MD could be reversed by environmental enrichment (EE). Male and female rats were divided into a non-MD and MD group. The MD group was subdivided into 3 groups: (1) assessed on the 31st day after exposure to EE for 10 days, (2) assessed on the 41st day after exposure to EE for 20 days, and (3) assessed on the 61st day after exposure to EE for 40 days. Behavioral tests were performed (memory habituation and elevated plus maze). Oxidative stress parameters were evaluated peripherally. MD was able to promote anxiety-like behavior at postnatal day (PND) 41 and impair memory at PND 31 and PND 61 in male and PND 41 and PND 61 in female rats. MD was associated with increased oxidative stress parameters (reactive species to thiobarbituric acid levels (TBARS), carbonylated proteins, nitrite/nitrate concentration), and altered antioxidant defenses (superoxide dismutase (SOD) and catalase (CAT), and sulfhydryl content) in different stages of development. The EE was able to reverse almost all behavioral and biochemical changes induced by MD; however, EE effects were sex and developmental period dependent. These findings reinforce the understanding of the gender variable as a biological factor in MDD related to MD and EE could be considered a treatment option for MDD treatment and its comorbidities.
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Transtorno Depressivo Maior , Feminino , Masculino , Animais , Ratos , Ratos Wistar , Privação Materna , Estresse Oxidativo , AntioxidantesRESUMO
A wealth of evidence associates disruptions of the parent-infant relationship (e.g. childhood parental loss or parental neglect) with the later appearance of panic disorder. In rodents, neonatal maternal separation and maternal deprivation (MD) are reported to increase the expression of anxiety-related defensive responses in adult animals. However, little is known about the long-term consequences of these early-life stressors in animal models of panic. We here investigated the effects of a single 24 h-episode of MD on post-natal day 11 (PND 11) in adult male Wistar rats submitted to two animal models that associate escape expression with panic attacks: the elevated T-maze and exposure to severe hypoxia (7% O2). We also investigated the involvement of serotonin (5-HT) in the observed changes. Although neonatal MD did not affect the behavioral responses measured in the elevated T-maze, it facilitated the expression of escape during hypoxia exposure, indicating a panicogenic-like effect. Pre-test administration of the 5-HT synthesis inhibitor, para-chlorophenylalanine (PCPA; 4 daily injections of 100 mg/kg) facilitated escape attempts in non-deprived animals during the hypoxia challenge, but did not interfere with the expression of this behavior in maternally-deprived rats. The levels of 5-HT1A receptors in key panic- and anxiety-associated areas, the dorsal periaqueductal gray and amygdala, respectively, were not different between previously deprived and non-deprived animals. Plasma corticosterone levels were significantly increased by hypoxia exposure, independently of the animals' previous stress condition or PCPA administration. Therefore, MD on PND 11 predisposes the adult animal to the panic-evoking effects of severe hypoxia, a stimulus also reported to induce panic attacks in humans. The lack of PCPA effect on the pro-escape consequence of MD may be indicative that 5-HT signaling is impaired in the stressed animal.
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Privação Materna , Serotonina , Animais , Animais Recém-Nascidos , Reação de Fuga , Fenclonina , Hipóxia , Masculino , Pânico , Substância Cinzenta Periaquedutal , Ratos , Ratos WistarRESUMO
This study aimed at evaluating the treatment effects with ketamine, electroconvulsive stimulation (ECS), escitalopram, alone or in combination in adult rats of both sexes, subjected to the animal model of maternal deprivation (MD). All groups were subjected to the forced swimming test (FST), splash and open field tests. The prefrontal cortex (PFC), hippocampus and serum were collected to analyze oxidative stress and inflammatory parameters. MD induced depressive-like behavior in the FST test in males and reduced grooming time in male and female rats. The treatments alone or combined reversed depressive and anhedonic behavior in females. In males, all treatments increased grooming time, except for ECS + escitalopram + ketamine. MD increased lipid peroxidation and protein carbonylation, nitrite/nitrate concentration and myeloperoxidase activity in the PFC and hippocampus of males and females. However, the treatment's response was sex dependent. Catalase activity decreased in the PFC of males and the PFC and hippocampus of females, and most treatments were not able to reverse it. MD increased the inflammation biomarkers levels in the PFC and hippocampus of males and females, and most treatments were able to reverse this increase. In all groups, a reduction in the interleukin-10 levels in the PFC and hippocampus of female and male rats was observed. Our study shows different responses between the sexes in the patterns evaluated and reinforces the use of the gender variable as a biological factor in MDD related to early stress and in the response of the therapeutic strategies used.
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Ketamina , Privação Materna , Animais , Comportamento Animal , Encéfalo/metabolismo , Escitalopram , Feminino , Hipocampo/metabolismo , Inflamação/metabolismo , Ketamina/farmacologia , Masculino , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
Microglia are immune cells found in the central nervous system (CNS) involved in infection combat and cellular debris clean. These glial cells are involved in synaptogenesis during brain development by their interactions with neurons and other glial cells. These relations are associated with the secretion of signaling molecules, such as chemokines and neurotrophic factors. Microglia cells influence synapsis and neuron morphology during different phases of development. Also, other systems, for example, gut microbiota, indirectly affect microglial functions and morphology. Several factors that can occur in different development periods, including intrauterine through adult life, could impact microglia. Impairment in these cells could be associated with the development of some psychiatric conditions, such as schizophrenia, autistic spectrum disorder (ASD), and depression. This review focuses on describing microglia functions in the maintenance of CNS and how they are associated with other systems, as the gutmicrobiota brain axis and environmental stressors, such as stress, maternal deprivation, sleep deprivation, immune activation, and ethanol exposure, that can influence the function of the microglia during neurodevelopment.
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Encéfalo , Microglia , Etanol , Ativação de Macrófagos , Microglia/fisiologia , NeurogêneseRESUMO
Neonatal adversity can impact neurodevelopmental trajectories. This study examined the long-term effects of maternal deprivation on day 9 (DEP9), associated or not to a stressor (saline injection [SAL]), on contextual fear conditioning (Experiment 1) and emotional behaviors (Experiment 2) in Wistar rats. Whole litters were either assigned to DEP9 or control groups, and on day 10, half of the litters in each group received an SAL or not (NSAL). DEP9-SAL male adolescents showed the longest freezing time and DEP9 adult males froze more than females. Females exhibited less anxiety-like behavior than males; DEP9-SAL females spent more time in the open arms and DEP9 males visited less the extremity of the open arm in the elevated plus maze. Early life stress increased conditioned and innate fear in males, but not in females, indicating a clear sexual dimorphism in the response to potentially threatening stimuli.
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Emoções , Estresse Psicológico , Animais , Feminino , Masculino , Ratos , Ansiedade/psicologia , Comportamento Animal/fisiologia , Privação Materna , Aprendizagem em Labirinto , Ratos Wistar , Estresse Psicológico/psicologiaRESUMO
This study aimed to evaluate the effects of ketamine, on behavioral parameters, oxidative stress, and inflammation in the brain of male and female rats submitted to the animal model of maternal deprivation (MD). Wistar rats were deprived of maternal care in the first 10 days of life (three hours daily). As adults, male and female rats were divided: control + saline deprived + saline and deprived + ketamine (15 mg/kg). The behavior was evaluated through the open field and forced swimming tests. Then brain was removed for analysis of oxidative damage, the activity of superoxide dismutase (SOD), catalase (CAT), and myeloperoxidase (MPO) activity, and levels of interleukin-6 (IL-6). MD induced depressive behavior in males and ketamine reversed these changes. MD induced an increase in lipid peroxidation in males and females; ketamine reversed these effects in males. Protein carbonylation was increased in males and females, with ketamine decreasing such effects. The concentration of nitrite/nitrate increased in males and females, whereas ketamine decreased this in the PFC of males. SOD and CAT activities were decreased in male and female deprived groups and deprived groups treated with ketamine. MPO activity and IL-6 levels increased in males subjected to MD and ketamine reversed this effect. The results suggest that stressful events in early life can induce behavioral, neuroimmune changes, and oxidative stress, however, such effects depend on sex and brain area. Ketamine presents anti-inflammatory and antioxidant properties and could be considered an alternative for individuals who are resistant to classical treatments.
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Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Privação Materna , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Estresse Psicológico/metabolismo , Animais , Catalase/metabolismo , Feminino , Hipocampo/metabolismo , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , Atividade Motora/efeitos dos fármacos , Peroxidase/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Superóxido Dismutase/metabolismoRESUMO
This study aimed to evaluate the effects of environmental enrichment (EE) in Wistar rats subjected to maternal deprivation (MD). MD was performed in the first post-natal days (PND) ten for 3 h/day. The groups were: control; deprived without EE; and deprived with EE. The EE was applied for 3 h/day. Forced swimming test (FST) and open field test were performed, and histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities in the prefrontal cortex (PFC) and hippocampus were evaluated on 31, 41, and 61 PND. MD altered spontaneous locomotor activity and immobility time in FST, but the effects were sex- and developmental period dependent. In deprived females at PND 31, 41, and 61, HDAC and DNMT increased in the PFC and hippocampus. In females exposed to EE for 20 days, there was a decrease of HDAC in the hippocampus and DNMT in the PFC and hippocampus. Exposure of females to EE for 40 days can reverse HDAC and DNMT increase in all brain areas. In deprived males at PND 31, 41, and 61, HDAC and DNMT increased in the hippocampus, and in the group exposed to EE for 40 days, there was a decrease in hippocampal activity. In PFC of male deprived rats at PND 61 and EE for 40 days, there was a reduction of HDAC and DNMT. MD induced lifelong persistent behavioral and epigenetic changes, and such effects were more evident in female than male rats. EE can be considered an essential non-pharmacological strategy to treat long-term trauma-induced early life changes.
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Meio Ambiente , Epigênese Genética , Estresse Psicológico , Animais , Feminino , Masculino , Ratos , Hipocampo , Privação Materna , Ratos Wistar , Fatores Sexuais , Comportamento AnimalRESUMO
Maternal deprivation (MD) is known to be related to long-term changes that could influence the onset of psychiatric disorders. Studies have demonstrated that early life stress makes the cells in the brain more susceptible to subsequent stressors. To test it, we used an animal model of MD conducted from postnatal day (PND) 1 to 10. Deprived and non-deprived rats (control) were randomized to receive or not lipopolysaccharide (LPS) at 5 mg/kg on PND 50. The behavior and glial cells activation were evaluated in all groups from 51 to 53 PND. There was an increase in the immobility time in the MD and MD+LPS groups. The spontaneous locomotor activity was not changed between groups. We found elevated ionized calcium-binding adapter molecule 1 (Iba-1)-positive cells levels in the control+LPS and MD+LPS groups. In the MD+LPS group, it was found an increase in Iba-positive cells compared to the MD+sal group. The glial fibrillary acidic protein (GFAP)-positive cells were also increased in the MD+LPS, compared to control+sal, control+LPS, and MD+sal groups. Immune challenge by LPS in late adolescence, which was subjected to MD, did not influence the depressive-like behavior but exerted a pronounced effect in the microglial activation and astrocyte atrophy.
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Comportamento Animal , Imunidade , Privação Materna , Neuroglia , Estresse Psicológico , Animais , Feminino , Ratos , Astrócitos/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Depressão , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/biossíntese , Imunidade/fisiologia , Lipopolissacarídeos , Ativação de Macrófagos , Proteínas dos Microfilamentos/metabolismo , Atividade Motora , Neuroglia/imunologia , Ratos Wistar , Estresse Psicológico/imunologia , Natação/psicologiaRESUMO
Early life stress is considered a risk factor for the development of long-term psychiatric disorders. Maternal deprivation (MD) is a useful paradigm to understand the neurobiological underpinnings of early stress-induced changes in neurodevelopment trajectory. The goal of the present study was to examine the effects of a chronic treatment with escitalopram (ESC) on the hippocampal levels of BDNF and neuropeptide Y (NPY), expression of serotonin type 1A receptor (5-HT1A), plasma corticosterone levels and emotional behaviours in male and female adolescent rats submitted to MD at 9 days of life (group DEP9) and challenged with a brief and mild stress (saline injection (SAL)) at the end of MD. Whole litters were kept with mothers (CTL) or submitted to MD (DEP9). Within each group, pups were stress-challenged (CTL-SAL and DEP9-SAL) or not (CTL-NSAL and DEP9-NSAL). ESC or vehicle treatments began at weaning and lasted 24 days, when animals were sacrificed for determination of neurobiological variables or submitted to a battery of tests for evaluation of emotional behaviours. The results showed that BDNF levels were higher in SAL-challenged males and in DEP9-SAL females, whereas 5-HT1A receptor expression was reduced in DEP9 males and in SAL-challenged females. There were no changes in NPY or corticosterone levels. In the forced swim test, SAL-challenged males and DEP9 females displayed less immobility and ESC only increased social motivation in males. The results indicated that neonatal stress led to sex-dependent changes in neurobiology and behaviour and that chronic ESC treatment had minor effects on these parameters.
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Envelhecimento/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citalopram/farmacologia , Emoções , Hipocampo/metabolismo , Serotonina/metabolismo , Estresse Psicológico/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Teste de Labirinto em Cruz Elevado , Emoções/efeitos dos fármacos , Feminino , Masculino , Neuropeptídeo Y/metabolismo , Ratos Wistar , Receptores de Serotonina/metabolismo , Comportamento Social , NataçãoRESUMO
Early life stress such as physical abuse, trauma or neglect during a critical period of development can elicit negative long-lasting effects on health. Neonatal maternal deprivation (MD) is a stressful event capable of triggering structural and neurobiological changes in Central Nervous System (CNS) development during proliferative and migratory cell differentiation. In this study, we investigated the maternal behavior of lactating rats submitted to protocol of chronic neonatal maternal deprivation (MD) during postnatal day (PND) 1 until 10. We analyzed the effects of the MD in the olfactory memory and cellular proliferation and differentiation in the hippocampus and olfactory bulb in Wistar rat pups on 7, 11 and 21â¯days postpartum. Analysis in active neurons, cellular differentiation and proliferation, were marked and evaluated by flow cytometry in tissue samples of hippocampi and olfactory bulb. Our results demonstrated an increase in maternal behavior immediately after dam's return to the home-cage in MD group compared to the non-deprived group. In addition, MD pups spent more time (higher latency) to identify the nest odor in comparison to the non-deprived rat pups in the olfactory learning task and showed a significant delay in the neural differentiation and proliferation in the hippocampus and olfactory bulb. These results reveal that disruptions in the mother-infant bonding by the MD induce changes in maternal behavior and interaction with the offspring that could be leading to delayed CNS development and significant impairment in offspring's olfactory learning.
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Aprendizagem/fisiologia , Comportamento Materno , Privação Materna , Neurônios/fisiologia , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/fisiologia , Feminino , Citometria de Fluxo , Hipocampo/crescimento & desenvolvimento , Hipocampo/fisiologia , Masculino , Memória/fisiologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/fisiologia , Gravidez , Ratos , Ratos Wistar , Olfato/fisiologiaRESUMO
Schizophrenia (SCZ) is a severe and chronic neurodevelopmental disorder with onset occurring during adolescence or early adulthood; notwithstanding, the brain dysfunction occurs before the disease and is not clinically evident. Recently, memantine (MEM) had been postulated as an effective preventive treatment in rats. In this study, was performed the Early Maternal Deprivation (EMD) protocol in Sprague-Dawley rats, establishing four groups (control, EMD, EMD treated with MEM, and MEM treatment). Behavioral parameters such as active linking (AL) and T maze were evaluated as well as quantitative brain histological changes at 3, 7, and 10 weeks of age, to understand the longitudinal demeanor of the disease. Prefrontal evoked potentials (PFEPs) were recorded to study functional synaptic connectivity and neuronal synchronicity changes. The results showed that EMD induces a decrease of AL and poor performance of T maze, in addition to volumetric changes of cortical and subcortical brain structures and abnormalities in PFEPs. The majority of this changes were absent by neonatal MEM administration. Taking into account that all these abnormalities are associated to SCZ, we propose to MEM as a potential preventive treatment.
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Córtex Auditivo , Comportamento Animal , Disfunção Cognitiva/prevenção & controle , Corpo Estriado , Potenciais Evocados/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo , Privação Materna , Memantina/farmacologia , Córtex Pré-Frontal , Esquizofrenia/prevenção & controle , Animais , Animais Recém-Nascidos , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/patologia , Córtex Auditivo/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Disfunção Cognitiva/etiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memantina/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Gravidez , Ratos , Ratos Sprague-Dawley , Esquizofrenia/patologia , Esquizofrenia/fisiopatologiaRESUMO
Maternal deprivation (MD) induces behavioral changes and impacts brain circuits that could be associated with the pathophysiology of depression. This study investigated the markers of microglia and astrocyte activation as well as indoleamine 2,3-dioxygenase (IDO) expression in developmental programming after early life MD (on postnatal days (PNDs) 20, 30, 40, and 60). On PND 60, the rats that were subjected to MD displayed depressive-like behavior. On PND 10, it was found that there was a decrease in the level of glial fibrillary acidic protein (GFAP) immunopositive cells, a decrease in the level of IDO expression, and an increase in the level of Iba-1 (microglial marker) in the hippocampus of rats that were subjected to MD. On PND 20, levels of GFAP were also found to have decreased in the hippocampus, and there was an increase in the level of Iba-1 in the hippocampus. AIF-1 (microglial marker) expression was observed in the PFC following MD. On PND 30, the levels of Iba-1 remained elevated. On PND 40, the levels of GFAP were found to have increased in the hippocampus of rats that were subjected to MD. On PND 60, the levels of GFAP and AIF-1 remained elevated following MD. These results suggest that early life stress induces negative developmental programming in rats, as demonstrated by depressive-like behavior in adult life. Moreover, MD increases microglial activation in both early and late developmental phases. The levels of GFAP and IDO decreased in the early stages but were found to be higher in later developmental periods. These findings suggest that MD could differentially affect the expression of the IDO enzyme, astrocytes, and microglial activation depending on the neurodevelopmental period. The onset of an inflammatory state from resident brain cells could be associated with the activation of the kynurenine pathway and the development of depressive behavior in adulthood.
Assuntos
Comportamento Animal/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Microglia/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Depressão/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Privação Materna , Proteínas dos Microfilamentos/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/metabolismoRESUMO
Maternal deprivation for 24 h produces an immediate increase in basal and stress-induced corticosterone (CORT) secretion. Given the impact of elevated CORT levels on brain development, the goal of the present study was to characterize the effects of maternal deprivation at postnatal days 3 (DEP3) or 11 (DEP11) on emotional behavior and neuropeptide Y immunoreactivity (NPY-ir) in the basolateral amygdala (BLA) and dorsal hippocampus (dHPC) of male and female rats. Litters were distributed in control non-deprived (CTL), DEP3, or DEP11 groups. In Experiment 1, within each litter, one male and one female were submitted to one of the following tests: novelty suppressed feeding (NSF), sucrose negative contrast test (SNCT), and forced swimming test (FST), between postnatal days 52 and 60. In Experiment 2, two males and two females per litter were exposed to the elevated plus maze and 1 h later, perfused for investigation of NPY-ir, on PND 52. The results showed that DEP3 rats displayed greater anxiety-like behavior in the NSF and EPM, compared to CTL and DEP11 counterparts. In the SNCT, DEP3 and DEP11 males showed less suppression of the lower sucrose concentration intake, whereas all females suppressed less than males. Both manipulated groups displayed more immobility in the FST, although this effect was greater in DEP3 than in DEP11 rats. NPY-ir was reduced in DEP3 and DEP11 males and females in the BLA, whereas in the dHPC, DEP3 males showed less NPY-ir than DEP11, which, in turn, presented less NPY-ir than CTL rats. Females showed less NPY-ir than males in both structures. Because the deprivation effects were more intense in DEP3 than in DEP11, in Experiment 3, the frequency of nursing posture, licking-grooming, and interaction with pups was assessed upon litter reunion with mothers. Mothers of DEP11 litters engaged more in anogenital licking than mothers of DEP3 litters. The present results indicate that maternal deprivation changed affective behavior with greater impact in the earlier age and reduced the expression of NPY in emotion-related brain areas. The age-dependent differential effects of deprivation on maternal behavior could, at least in part, explain the outcomes in young adult rats.