Maternal separation induces long-term oxidative stress alterations and increases anxiety-like behavior of male Balb/cJ mice.

Early life stress (ELS) exposure is a well-known risk factor for the development of psychiatric conditions, including anxiety disorder. Preclinical studies show that maternal separation (MS), a classical model of ELS, causes hypothalamic-pituitary-adrenal (HPA) axis alterations, a key contributor to the stress response modulation. Given that HPA axis activation has been shown to induce oxidative stress, it is possible to hypothesize that oxidative stress mediates the relationship between chronic ELS exposure and the development of several disorders. Here, we investigate the effects of MS in the oxidative status [plasma and brain reduced glutathione, catalase and thiobarbituric acid reactive substances (TBARS)], metabolism (glucose, triglycerides and cholesterol) and anxiety-like behaviors in adult Balb/cJ mice. In short, we found that MS increased anxiety-like behaviors in the open field, light/dark test but not in the elevated-plus maze. Animals also presented increased circulating cholesterol, increased TBARS in the plasma and decreased catalase in the hippocampus. Our findings suggest that MS induces long-term alterations in oxidative stress and increased anxiety-like behaviors.

Maternal behavior of the mouse dam toward pups: implications for maternal separation model of early life stress.

Maternal care is essential for an adequate pup development, as well as for the health of the dam. Exposure to stress in early stages of life can disrupt this dam-pup relationship promoting altered neurobiological and behavioral phenotypes. However, there is a lack of consensus regarding the effects of daily maternal separation (MS) on the pattern of maternal behavior. The aim of this study is to compare the patterns of maternal behavior between mice exposed to MS and controls. BALB/c mice were subjected to MS for a period of 180 min/day from postnatal day 2-7 (n = 17) or designated to be standard animal facility reared (AFR) controls (n = 19). Maternal behaviors were computed as frequency of nursing, licking pups and contact with pups, and nonmaternal behaviors were computed as frequency of actions without interaction with pups and eating/drinking. A total of 18 daily observations of maternal behavior were conducted during these six days, and considering the proportion of maternal and nonmaternal behaviors, an index was calculated. There was no difference when comparing the global index of maternal behavior between the AFR and MS animals by the end of the observed period. However, the pattern of maternal behavior between groups was significantly different. While MS dams presented low frequency of maternal behavior within the first couple days of the stress protocol, but increasing over time, AFR dams showed higher maternal behavior at the beginning, reducing over time. Together, our results indicate that MS alters the maternal behavior of the dams toward pups throughout the first week of the stress protocol and provoked some anxiety-related traits in the dams. The inversion of maternal behavior pattern could possibly be an attempt to compensate the low levels of maternal care observed in the first days of MS.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice.

In rodents, disruption of mother-infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long-term neurobiological consequences. Particularly stress-induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex-dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related ß -catenin (ß -Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH-2 and CDH-8 mRNA levels, as well as an upregulation of CDH-1 in the prefrontal cortex in both males and females. MS-reared female mice presented lower CDH-1 mRNA levels in the hippocampus. In addition, hippocampal CDH-1 mRNA levels were positively correlated with recognition memory performance in females. MS-reared male mice exhibited higher ß -Cat mRNA levels in the hippocampus. Considering sex-specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH-1, ß -Cat, and CDH-6 in the hippocampus, as well as CDH-1, CDH-8 and CDH-11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.

Running during adolescence rescues a maternal separation-induced memory impairment in female mice: Potential role of differential exon-specific BDNF expression.

Exposure to early life stress has been associated with memory impairments related to changes in brain-derived neurotrophic factor (BDNF) signaling. However, the potential impact of physical exercise to reverse these effects of maternal separation has been under investigated. Mice were subjected to maternal separation during the first 2 weeks of life and then exposed to a 3-week running protocol during adolescence. The spontaneous object recognition task was performed during adolescence followed by analysis of hippocampal expression of exons I, IV, and IX of the BDNF gene. As expected, maternal separation impaired recognition memory and this effect was reversed by exercise. In addition, running increased BDNF exon I expression, but decreased expression of BDNF exon IV in all groups, while exon IX expression increased only in MS animals exposed to exercise. Our data suggest that memory deficits can be attenuated by exercise and specific transcripts of the BDNF gene are dynamically regulated following both MS and exercise.

Brain-Derived Neurotrophic Factor and Delayed Verbal Recall in Crack/Cocaine Dependents.

BACKGROUND/AIMS: Considering the role of brain-derived neurotrophic factor (BDNF) in memory processes and its peripheral response during the detoxification of cocaine, the aim of this study was to investigate whether plasma BDNF levels could be related to memory performance in women with crack/cocaine dependence. METHODS: Twenty-five abstinent female crack/cocaine users (CCD) and 25 unmedicated healthy women (HW), carefully matched for age and years of formal education, were assessed regarding memory performance. Logical Memory was used to assess the immediate verbal recall (IVR), delayed verbal recall (DVR) and memory retention. Plasma BDNF levels were measured by Elisa immunoassay. Beck Depression Inventory was used to assess the severity of depressive symptoms, and the Cocaine Selective Severity Assessment the severity of cocaine abstinence symptoms. RESULTS: The CCD group had lower DVR scores and higher plasma BDNF levels when compared to HW group. In addition, a linear regression model showed that BDNF levels predicted DVR scores within CCD group independently of depressive symptoms (R = 0.51; R(2) = 0.26; t(22) = 4.025, p = 0.03). CONCLUSION: Despite higher plasma BDNF levels, crack users exhibited memory impairments when compared to healthy women. Specifically, peripheral BDNF levels predicted better cognitive performance only within individuals who already had cognitive impairment.

Dual-memory processes in crack cocaine dependents: The effects of childhood neglect on recall.

Exposure to adversities during sensitive periods of neurodevelopment is associated with the subsequent development of substance dependence and exerts harmful, long-lasting effects upon memory functioning. In this study, we investigated the relationship between childhood neglect (CN) and memory using a dual-process model that quantifies recollective and non-recollective retrieval processes in crack cocaine dependents. Eighty-four female crack cocaine-dependent inpatients who did (N = 32) or did not (N = 52) report a history of CN received multiple opportunities to study and recall a short list composed of familiar and concrete words and then received a delayed-recall test. Crack cocaine dependents with a history of CN showed worse performance on free-recall tests than did dependents without a history of CN; this finding was associated with declines in recollective retrieval (direct access) rather than non-recollective retrieval. In addition, we found no evidence of group differences in forgetting rates between immediate- and delayed-recall tests. The results support developmental models of traumatology and suggest that neglect of crack cocaine dependents in early life disrupts the adult memory processes that support the retrieval of detailed representations of events from the past.

The Relationship between Lifestyle, Mental Health, and Loneliness in the Elderly during the COVID-19 Pandemic.

The study focused on examining the relationship between well-being and various psychological factors such as loneliness, anxiety, depression, and stress, whilst also considering changes in lifestyle. A total of 108 elderly participants, with an average age of 70.38 years, were enrolled in this quantitative cross-sectional study. The research employed a battery of assessment tools including a Sociodemographic Data Questionnaire, Mini-Mental State Examination, Positive Mental Health Scale, Stress Perception Scale, Geriatric Anxiety Inventory, Geriatric Depression Scale (reduced version), Loneliness Scale, and International Physical Activity Questionnaire. Descriptive analysis was conducted in order to understand the distribution of scores across these variables, followed by the categorization of participants based on the reported alterations in eating and physical activity behaviors. Correlations between variables were assessed using Spearman correlation and an EBIC-LASSO network analysis. The findings indicated a potential detriment to the well-being of elderly individuals practicing social distancing, evidenced by heightened symptoms of loneliness, depression, anxiety, and stress, alongside the reported changes in dietary patterns and physical activity. The study underscores the importance of understanding the pandemic's impact on the well-being of older adults and advocates for longitudinal investigations to delineate the evolving effects of social distancing measures across different phases of the pandemic.

Consequences of post-weaning sleep deprivation on behaviour and oxidative stress parameters in rat plasma and brain.

Sleep is essential for health: Adequate sleep is essential for healthy development and sleep deprivation results in several consequences. Indeed, sleep deprivation early in life is associated with poor behaviour and cognition, as well as impaired mental and physical health. Preclinical studies have shown that sleep deprivation alters several physiological functions later in life such as the cardiovascular, immune and endocrine systems, resulting in altered oxidative states. Most of the preclinical literature is focused on adult animals, and little is known about oxidative alterations during development, especially in the context of sleep deprivation. Hence, we adapted a classic and well-documented model of sleep deprivation, paradoxical sleep deprivation using multiple platforms, for juvenile rats and explored central and peripheral oxidative parameters, as well as the behavioural consequences of sleep deprivation post-weaning. We showed that 96 h of paradoxical sleep deprivation induced a significant reduction in body weight, decreased sucrose preference-a behaviour suggestive of anhedonia-and increased glucose and decreased cholesterol in the plasma. In the brain, we observed a decrease in reduced glutathione levels in the medial prefrontal cortex and an increase in thiobarbituric acid reactive substance levels in the hypothalamus, indicating oxidative damage in these regions. Taken together, our findings suggest that paradoxical sleep deprivation during development induces anhedonic behaviour and promotes central and peripheral alterations in oxidative parameters.

Can anxiety-like behavior and spatial memory predict the extremes of skilled walking performance in mice? An exploratory, preliminary study.

Introduction: Skilled walking is influenced by memory, stress, and anxiety. While this is evident in cases of neurological disorders, memory, and anxiety traits may predict skilled walking performance even in normal functioning. Here, we address whether spatial memory and anxiety-like behavior can predict skilled walking performance in mice. Methods: A cohort of 60 adult mice underwent a behavioral assessment including general exploration (open field), anxiety-like behavior (elevated plus maze), working and spatial memory (Y-maze and Barnes maze), and skilled walking performance (ladder walking test). Three groups were established based on their skilled walking performance: superior (SP, percentiles ≥75), regular (RP, percentiles 74-26), and inferior (IP, percentiles ≤25) performers. Results: Animals from the SP and IP groups spent more time in the elevated plus maze closed arms compared to the RP group. With every second spent in the elevated plus maze closed arms, the probability of the animal exhibiting extreme percentiles in the ladder walking test increased by 1.4%. Moreover, animals that spent 219 s (73% of the total time of the test) or more in those arms were 4.67 times more likely to exhibit either higher or lower percentiles of skilled walking performance. Discussion: We discuss and conclude anxiety traits may influence skilled walking performance in facility-reared mice.

Vulnerability and resilience to prenatal stress exposure: behavioral and molecular characterization in adolescent rats.

Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention.

Changes in lung function in adolescents with substance use disorders: an exploratory study.

OBJECTIVE: To compare lung function between adolescents with and without substance use disorder (SUD). METHODS: This was an observational, cross-sectional exploratory study. The sample consisted of 16 adolescents with SUD and 24 age-matched healthy controls. The adolescents in the clinical group were recruited from a psychiatric inpatient unit for detoxification and rehabilitation; their primary diagnosis was SUD related to marijuana, cocaine, or polysubstance use. Questionnaires and pulmonary function tests were applied for clinical evaluation. RESULTS: We found that FVC, FEV1, and their percentages of the predicted values were significantly lower in the adolescents with SUD than in those without. Those differences remained significant after adjustment for BMI and the effects of high levels of physical activity. The largest effect size (Cohen's d = 1.82) was found for FVC as a percentage of the predicted value (FVC%), which was, on average, 17.95% lower in the SUD group. In addition, the years of regular use of smoked substances (tobacco, marijuana, and crack cocaine) correlated negatively with the FVC%. CONCLUSIONS: This exploratory study is innovative in that it demonstrates the early consequences of smoked substance use for the lung health of adolescents with SUD.

Sleep quality among parents and their children during COVID-19 pandemic.

OBJECTIVE: To evaluate sleep characteristics of parents and their children during the COVID-19 pandemic and predictors for sleep disturbances. METHODS: Cross-sectional web-based study using an online survey made available for dyads of parents and their children during the 7th week of quarantine in southern Brazil. Parents' and adolescents' sleep were characterized using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. For children aged 0-3 years parents completed the Brief Infant Sleep Questionnaire, for those aged 4-12 years the Sleep Disturbance Scale for Children. Parents also informed, subjectively, their perception about sleep habits during social distancing. Multiple regression was run to predict sleep disturbances in adults using independent variables: sex, income, education, children age, and children with sleep disturbances. RESULTS: Data from 577 dyads showed sleep alterations in 69,8% of adults, in 58,6% of children aged 0-3 years, 33,9% in the 4-12 years range (with a predominance of disorders of initiating or maintaining sleep), and 56,6% in adolescents. Sex (female) and children with sleep disturbances were significant predictors of a sleep problem in parents (p < 0.005). Subjective perception revealed complaints related to emotional concerns such as anxiety and fear in adults and due to alterations in routine in children and adolescents. CONCLUSION: The present study's data showed an increased rate of sleep problems among families during quarantine both measured by validated instruments and also based on personal perception.

Gestational stress alters maternal behavior and inflammatory markers in the olfactory bulb of lactating mice.

Inflammatory markers represent important candidates responsible for the altered behavior and physiology observed after stressful experiences. In the maternal brain, the olfactory bulb (OB) is a key constituent of the neural circuit that mediates the reciprocal interaction between mother and infant. This study aimed to investigate the effects of stress during pregnancy on maternal behavior and inflammatory changes in the olfactory bulb of lactating mice. Female Balb/c mice were divided into two groups: control (CT) and restraint stress (RS). Maternal behavior was performed during the first 8 days of life of the offspring. On the 10th day after parturition, corticosterone, gene, and protein expression were assessed. Stress during pregnancy decreased the maternal index at postnatal day 4 and the nuclear factor-κB 1 (NFκB1) gene expression in the OB. Moreover, females from the RS group showed increased interleukin (IL-1ß) protein expression. In contrast, stressed females exhibited a decreased tumor necrosis factor (TNF-α) protein expression in the OB. In conclusion, exposure to stress during pregnancy was able to induce specific postnatal effects on maternal behavior and balance of inflammatory mediators in the OB.

Long-term Effects of Maternal Separation on Anxiety-Like Behavior and Neuroendocrine Parameters in Adult Balb/c Mice.

Introduction: Disruption of maternal care using maternal separation (MS) models has provided significant evidence of the deleterious long-term effects of early life stress. Several preclinical studies investigating MS showed multiple behavioral and biomolecular alterations. However, there is still conflicting results from MS studies, which represents a challenge for reliability and replicability of those findings. Objective: To address that, this study was conducted to investigate whether MS would affect anxiety-like behaviors using a battery of classical tasks, as well as central and peripheral stress-related biomarkers. Methods: Male Balb/c mice were exposed to MS from postnatal day (PND) 2 to 14 for 180-min per day. Two independent cohorts were performed to evaluate both baseline and anxiety-like behavior responses to MS at PND60. We performed composite scores to evaluate MS effects on anxiety and risk assessment phenotypes. Also, we assessed mRNA gene expression in the medial pre-frontal cortex (mPFC) of glucocorticoid and mineralocorticoid receptors (GR and MR) using real-time PCR and peripheral corticosterone levels (CORT) to investigate possible neurobiological correlates to anxiety behaviors. Results: We found increased anxiety-like behavior and decreased risk assessment and exploratory behaviors in MS mice. The animals exposed to MS also presented a decrease in MR mRNA expression and higher levels of CORT compared to controls. Conclusions: Our findings reinforce the body of evidence suggesting that long-term MS induces effects on anxiety and risk assessment phenotypes following the exposure to a standardized MS protocol. Moreover, MS affected the expression of MR mRNA and induced significant changes on CORT response. This data highlights that the reprograming MS effects on HPA axis could be mediate by MR gene expression in mPFC and chronic overactivity of peripheral CORT levels.

Prenatal stress and KCl-induced depolarization modulate cell death, hypothalamic-pituitary-adrenal axis genes, oxidative and inflammatory response in primary cortical neurons.

Maternal stress has been described as an important component in the offspring's cerebral development, altering the susceptibility to diseases in later life. Moreover, the postnatal period is essential for the development and integration of several peripheral and central systems related to the control of homeostasis. Thus, this study aimed to evaluate the effects of prenatal stress on the activation of cortical neurons, by performing experiments both under basal conditions and after KCl-induced depolarization. Female mice were divided in two groups: control and prenatal restraint stress. Cortical neurons from the offspring were obtained at gestational day 18. The effects of prenatal stress and KCl stimulations on cellular mortality, autophagy, gene expression, oxidative stress, and inflammation were evaluated. We found that neurons from PNS mice have decreased necrosis and autophagy after depolarization. Moreover, prenatal stress modulated the HPA axis, as observed by the increased GR and decreased 5HTr1 mRNA expression. The BDNF is an important factor for neuronal function and results demonstrated that KCl-induced depolarization increased the gene expression of BDNF I, BDNF IV, and TRκB. Furthermore, prenatal stress and KCl treatment induced significant alterations in oxidative and inflammatory markers. In conclusion, prenatal stress and stimulation with KCl may influence several markers related to neurodevelopment in cortical neurons from neonate mice, supporting the well-known long-term effects of maternal stress.

Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation.

Epidemiological studies have shown that environmental insults and maternal stress during pregnancy increase the risk of several psychiatric disorders in the offspring. Converging lines of evidence from humans, as well as from rodent models, suggest that prenatal stress (PNS) interferes with fetal development, ultimately determining changes in brain maturation and function that may lead to the onset of neuropsychiatric disorders. From a molecular standpoint, transcriptional alterations are thought to play a major role in this context and may contribute to the behavioral phenotype by shifting the expression of genes related to excitatory and inhibitory (E/I) transmission balance. Nevertheless, the exact neurophysiological mechanisms underlying the enhanced vulnerability to psychopathology following PNS exposure are not well understood. In the present study, we used a model of maternal stress in rats to investigate the distal effects of PNS on the expression of genes related to glutamatergic and GABAergic neurotransmissions. We inspected two critical brain regions involved in emotion regulation, namely, the prefrontal cortex (PFC) and the amygdala (AMY), which we show to relate with the mild behavioral effects detected in adult rat offspring. We observed that PNS exposure promotes E/I imbalance in the PFC of adult males only, by dysregulating the expression of glutamatergic-related genes. Moreover, such an effect is accompanied by increased expression of the activity-dependent synaptic modulator gene Npas4 specifically in the PFC parvalbumin (PV)-positive interneurons, suggesting an altered regulation of synapse formation promoting higher PV-dependent inhibitory transmission and increased overall circuit inhibition in the PFC of males. In the AMY, PNS more evidently affects the transcription of GABAergic-related genes, shifting the balance toward inhibition. Collectively, our findings suggest that the E/I dysregulation of the PFC-to-AMY transmission may be a long-term signature of PNS and may contribute to increase the risk for mood disorder upon further stress.

Early environmental enrichment rescues memory impairments provoked by mild neonatal hypoxia-ischemia in adolescent mice.

Hypoxia-ischemia (HI) is a consequence of a lack of oxygen and glucose support to the developing brain, which causes several neurodevelopmental impairments. Environmental enrichment (EE) is considered an option to recover the alterations observed in rodents exposed to HI. The aim of this study was to investigate the impact of early EE on memory, hippocampal volume and brain-derived neurotrophic factor (Bbnf) and glucocorticoid receptor (Nr3c1) gene expression of mice exposed to HI. At P10, pups underwent right carotid artery permanent occlusion followed by 35 min of 8% O2 hypoxic environment. Starting at P11, animals were reared in EE or in standard cage (HI-SC or SHAM-SC) conditions until behavioral testing (P45). SHAM pups did not undergo carotid ligation and hypoxic exposure. Memory performance was assessed in the Y-maze, Novel object recognition, and Barnes maze. Animals were then sacrificed for analysis of hippocampal volume and Bdnf and Nr3c1 gene expression. We observed that animals exposed to HI performed worse in all three tests compared to SHAM animals. Furthermore, HI animals exposed to EE did not differ from SHAM animals in all tasks. Moreover, HI decreased hippocampal volume, while animals reared in early EE were not different compared to SHAM animals. Animals exposed to HI also showed upregulated hippocampal Bdnf expression compared to SHAM animals. We conclude that early EE from P11 to P45 proved to be effective in recovering memory impairments and hippocampal volume loss elicited by HI. Nevertheless, Bdnf expression was not associated with the improvements in memory performance observed in animals exposed to EE after a hypoxic-ischemic event.

Maternal Separation Combined With Limited Bedding Increases Anxiety-Like Behavior and Alters Hypothalamic-Pituitary-Adrenal Axis Function of Male BALB/cJ Mice.

Early life stress (ELS) is considered a risk factor for the development of psychiatric conditions, including depression and anxiety disorder. Individuals that live in adverse environments are usually exposed to multiple stressors simultaneously, such as maternal neglect, maltreatment, and limited resources. Nevertheless, most pre-clinical ELS models are designed to explore the impact of these events separately. For this reason, this study aims to investigate the effects of a combined model of ELS on anxiety-like behavior and hypothalamic-pituitary-adrenal (HPA) axis related targets. From PND 2 to PND 15 BALB/cJ mice were exposed simultaneously to maternal separation (MS; 3 h per day) and limited bedding (LB; ELS group) or left undisturbed (CT group). Maternal behavior was recorded in intercalated days, from PND 1 to PND 9. Male offspring were tested for anxiety-like behavior from PND 53 to PND 55 in the open field test (OF), elevated plus-maze (EPM), and light/dark test (LD). After behavioral testing, animals were euthanized, and glucocorticoid receptor (Nr3c1), corticotrophin-releasing hormone (Crh), and its receptor type 1 (Crhr1) gene expression in the hypothalamus were measured. Moreover, plasma corticosterone levels were analyzed. We observed that ELS dams presented altered quality of maternal care, characterized by a decrease in arched-back nursing, and an increase in passive nursing. Stressed dams also showed an increase in the number of exits from the nest when compared to CT dams. Furthermore, ELS animals showed increased anxiety-like behavior in the OF, EPM, and LD. Regarding gene expression, we identified an increase in hypothalamus Crh levels of ELS group when compared to CT animals, while no differences in Nr3c1 and Crhr1 expression were observed. Finally, stressed animals showed decreased levels of plasma corticosterone when compared to the CT group. In conclusion, we observed an alteration in maternal behavior in ELS dams. Later in life, animals exposed to the combined model of ELS showed increased levels of anxiety-like behavior. Moreover, the central and peripheral HPA measures observed could indicate a dysregulation in HPA function provoked by ELS exposure.

Corticotropin-releasing factor infusion in the bed nucleus of the stria terminalis of lactating mice alters maternal care and induces behavioural phenotypes in offspring.

The peripartum period is accompanied by numerous physiological and behavioural adaptations organised by the maternal brain. These changes are essential for adequate expression of maternal behaviour, thereby ensuring proper development of the offspring. The corticotropin-releasing factor (CRF) plays a key role in a variety of behaviours accompanying stress, anxiety, and depression. There is also evidence that CRF contributes to maladaptations during the peripartum period. We investigated the effects of CRF in the bed nucleus of the stria terminalis (BNST) of lactating mice during maternal care and analysed locomotor activity and anxiety-like behaviour in the offspring. The BNST has been implicated in anxiety behaviour and regulation of the stress response. The effects of intra-BNST CRF administration were compared with those induced by the limited bedding (LB) procedure, a model that produces altered maternal behaviour. BALB/cJ dams were exposed to five infusions of CRF or saline into the BNST in the first weeks after birth while the LB dams were exposed to limited nesting material from postnatal days (P) 2-9. Maternal behaviour was recorded in intercalated days, from P1-9. Offspring anxiety-like behaviour was assessed during adulthood using the open-field, elevated plus-maze, and light/dark tests. Both intra-BNST CRF and LB exposure produced altered maternal care, represented by decreased arched-back nursing and increased frequency of exits from the nest. These changes in maternal care resulted in robust sex-based differences in the offspring's behavioural responses during adulthood. Females raised by CRF-infused dams exhibited increased anxiety-like behaviour, whereas males presented a significant decrease in anxiety. On the other hand, both males and females raised by dams exposed to LB showed higher locomotor activity. Our study demonstrates that maternal care is impaired by intra-BNST CRF administrations, and these maladaptations are similar to exposure to adverse early environments. These procedures, however, produce distinct phenotypes in mice during young adulthood and suggest sex-based differences in the susceptibility to poor maternal care.

Vulnerable and resilient cognitive performance related to early life stress: The potential mediating role of dopaminergic receptors in the medial prefrontal cortex of adult mice.

RATIONALE: Exposure to early life stress (ELS) is known to have pronounced effects on the prefrontal cortex (PFC). However, not all individuals exposed to ELS manifest the same neurobiological and cognitive phenotypes when adults. Dopamine signaling could be a key factor in understanding the effects of stress on PFC-related cognitive function. OBJECTIVES: We aimed to investigate the differential effects of ELS on cognitive performance of adult mice and the dopaminergic receptors expression in the PFC. METHODS: BALB/c males were exposed to the maternal separation (MS) procedure and their cognitive performance on the eight-arm radial maze (8-RAM) were assessed during adulthood. For molecular-level assessments, we performed mRNA expression analyses for dopamine receptors-DRD1, DRD2, DRD3-and Hers1 expression in the medial PFC. RESULTS: While MS produced an overall impairment on 8-RAM, the stressed animals could be divided in two groups based on their performance: those with impaired cognitive performance (vulnerable to maternal separation, V-MS) and those without any impairment (resilient to maternal separation, R-MS). V-MS animals showed increased DRD1 and DRD2 expression in comparison with other groups. Errors on 8-RAM were also positively correlated with DRD1 and DRD2 mRNA expression. CONCLUSIONS: Our findings suggest a potential role of the dopaminergic system in the programming mechanisms of cognitive vulnerability and resilience related to ELS.