The impact of stress and stress hormones on endogenous clocks and circadian rhythms.

In mammals, daily rhythms in physiology and behavior are under control of a circadian pacemaker situated in the suprachiasmatic nucleus (SCN). This master clock receives photic input from the retina and coordinates peripheral oscillators present in other tissues, maintaining all rhythms in the body synchronized to the environmental light-dark cycle. In line with its function as a master clock, the SCN appears to be well protected against unpredictable stressful stimuli. However, available data indicate that stress and stress hormones at certain times of day are capable of shifting peripheral oscillators in, e.g., liver, kidney and heart, which are normally under control of the SCN. Such shifts of peripheral oscillators may represent a temporary change in circadian organization that facilitates adaptation to repeated stress. Alternatively, these shifts of internal rhythms may represent an imbalance between precisely orchestrated physiological and behavioral processes that may have severe consequences for health and well-being.

Maternal deprivation during early infancy in rats increases oxytocin immunoreactivity in females and corticosterone reactivity to a social test in both sexes without changing emotional behaviour.

Impairment of social behaviour is a hallmark of emotional disorders, with increased avoidance of social contact. In rats, the 24 h maternal deprivation (DEP) paradigm is used to understand the impact of extreme neglect on neurodevelopment. Due to the distinct immediate effects of DEP on postnatal days (PND) 3 (DEP3) or 11 (DEP11), in the present study we investigated the long-term effects of DEP at these ages on anxiety-like behaviour, by recording the visits and time spent in the centre part of the open-field, social investigation of a confined, same-sex, unfamiliar animal, basal and post-social test corticosterone plasma levels and the immunoreactivity to oxytocin in the paraventricular (PVN) and supraoptic nuclei of the hypothalamus (SON). Whole litters were distributed into control (CTL), DEP3 or DEP11 groups and behavioural tests and biological samples were collected between PNDs 40 and 45 in males and females. There were no differences in the exploration of the central part of the open field or on the time investigating the unfamiliar rat. However, the percent increase in post-test corticosterone secretion from baseline was greater for both DEP3 male and female subgroups than their CTL and DEP11 counterparts. DEP3 females showed more oxytocin staining than DEP11 counterparts in magnocellular neurons of the SON and PVN. These results suggest that DEP at the ages chosen does not alter social investigation, although it results in distinct neurobiological outcomes, depending on the developmental phase when it is imposed.

Early life stress alters emotional learning in a sex- and age-dependent manner with no impact on emotional behaviors.

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.

Assessment of Executive Functions after Treatment of Childhood Acute Lymphoid Leukemia: a Systematic Review.

Individuals treated for childhood acute lymphoblastic leukemia (ALL) have a high survival rate. This fact, however, may lead to neurocognitive impairments in survivors, as shown in some studies. The prefrontal cortex and executive functions seem to be particularly vulnerable due to the late maturation in the development process. Executive impairments have been associated with poorer quality of life in childhood cancer survivors. A systematic review was carried out with studies that assessed executive functions in childhood ALL survivors.\ Studies were collected from five electronic databases: MEDLINE (PubMed); PsycInfo; WebOfScience; LILACS and IBECS. Eighty-four studies were retrieved from the database search, of which 50 were read in full and 26 met the inclusion criteria. The studies were heterogeneous as to the instruments used to assess executive function, the skills assessed and the comparison methods. Despite some discrepancies, ALL survivors seem to exhibit poorer executive functioning than typical controls, but this result did not hold true when subjects were compared to normative mean. Changes in brain structure and dynamics resulting from the disease itself, the toxicity of the treatment and difficulties in coping with the stress during treatment may be related to executive impairments in ALL survivors. Discussion proposed standardized methods and measures for assessing executive functioning in children during and after ALL treatment.

Chronic REM sleep restriction in young rats increases energy expenditure with no change in food intake.

NEW FINDINGS: What is the central question of this study? What are the effects of different periods of REM sleep restriction (7, 14 and 21 days) on metabolic parameters in young rats? What is the main finding and its importance? Animals submitted to each period of REM sleep deprivation showed a negative energy balance, with reduced body weight gain, body energy gain and gross food efficiency, less body fat content, and increased energy expenditure. There was no increase in food intake after any of the REM sleep restriction periods. In young rats, negative energy balance is not compensated by increased dietary intake as observed in adult rats. ABSTRACT: Reduced sleep is associated with metabolic alterations, not only in adults, but also in children and adolescents. Several studies have shown that sleep restricted (SR) adult rats exhibit metabolic changes, followed by increased food intake, but few have evaluated these functions in young animals. The aim of the present study was to establish the metabolic parameters of young rats subjected to different periods of REM sleep restriction and to propose a correction factor for the correct measurement of food intake. Young male Wistar rats were distributed in control and SR groups for 7, 14 or 21 days. Sleep restriction was performed by the single platform method for 18 h. Regardless of the length of sleep restriction, all SR rats had a negative energy balance, evidenced by reduction in body weight gain, body energy gain and gross food efficiency, accompanied by increased energy expenditure. In addition, sleep restriction reduced body fat content throughout the entire period. Discounting food spillage, there was no increase in food intake by SR rats. In conclusion, the present study revealed metabolic changes in SR young rats after different lengths of REM sleep restriction and that weight loss and increased energy expenditure were not compensated by increased dietary intake as occurs in adult rats, indicating that young rats use other mechanisms to cope with the negative energy balance caused by sleep restriction. In addition, we propose a correction factor for food intake, to prevent overestimation of this parameter, due to food spillage in the water containers.

Chronic unpredictable restraint stress increases hippocampal pro-inflammatory cytokines and decreases motivated behavior in rats.

Most chronic stress protocols are too laborious or do not abide by the two main characteristics of the stress concept: uncontrollability and unpredictability. The goal of this study was to establish a simple and reliable model of chronic stress, while maintaining the main features of the concept. Animals were exposed to chronic movement restraint with variable duration (2, 4 or 6 h, in an unpredictable schedule) for 3 weeks and assessed in several physiological and behavioral readouts known to reflect chronic stress states. Body weight, levels of plasma corticosterone, hippocampal pro-and anti-inflammatory cytokines, anxiety-like (novelty suppressed feeding and elevated plus maze) and motivated behaviors (sucrose negative contrast test and forced swim test) were evaluated three days after the end of the chronic protocol. Stressed animals had a lower body weight gain, higher levels of cytokines in the hippocampus, reduced suppression of a low concentration sucrose solution and increased immobility in the forced swim test. Based on these data, we suggest that chronic movement restraint with variable duration may be a suitable and simple protocol for the study of changes induced by chronic stress and for the testing of possible treatments relevant to psychiatry.

Memory impairment induced by different types of prolonged stress is dependent on the phase of the estrous cycle in female rats.

A growing body of evidence demonstrates that estrogen and corticosterone (CORT) impact on cognition and emotion. On the one hand, ovarian hormones may have beneficial effects on several neurophysiological processes, including memory. On the other hand, chronic exposure to stressful conditions has negative effects on brain structures related to learning and memory. In the present study, we used the plus-maze discriminative avoidance task (PMDAT) to evaluate the influence of endogenous variations of sex hormones and exposure to different types of prolonged stressors on learning, memory, anxiety-like behavior and locomotion. Female Wistar rats were submitted to seven consecutive days of restraint stress (4 h/day), overcrowding (18 h/day) or social isolation (18 h/day) and tested in different phases of the estrous cycle. The main results showed that: (1) neither stress conditions nor estrous cycle modified PMDAT acquisition; (2) restraint stress and social isolation induced memory impairments; (3) this impairment was observed particularly in females in metestrus/diestrus; (4) stressed females in estrus displayed less risk assessment behavior, suggesting reduced anxiety-like behavior; (5) restraint stress and social isolation, but not overcrowding, elevated corticosterone levels. Taken together, our findings suggest that the phase of the estrous cycle is an important modulatory factor of the cognitive processing disrupted by stress in female rats. Negative effects were observed in metestrus/diestrus, indicating that the peak of sex hormones may protect females against stress-induced memory impairment.

Association of 24 h maternal deprivation with a saline injection in the neonatal period alters adult stress response and brain monoamines in a sex-dependent fashion.

Maternal deprivation (MD) disinhibits the adrenal glands, rendering them responsive to various stressors, including saline injection, and this increased corticosterone (CORT) response can last for as long as 2 h. In the present study, we tested the hypothesis that association of MD on day 11 with a saline injection would alter emotional behavior, CORT response, and brain monoamine levels, in male and female adult rats. Rats were submitted to the novelty suppressed feeding (NSF), the sucrose negative contrast test (SNCT), social investigation test (SIT), and the elevated plus maze (EPM). One quarter of each group was not tested (providing basal values of CORT and brain monoamines) and the remainder was decapitated 15, 45, or 75 min after the EPM, to assess CORT reactivity. Monoamine levels were determined in the hypothalamus (HPT), frontal cortex (FC), amygdala (AMY), ventral, and dorsal hippocampus (vHPC, dHPC, respectively). MD reduced food intake, in the home-cage, and latency to eat in the NSF in both sexes; females explored less the target animal in the SIT and explored more the open arms of the EPM than males; the CORT response to the EPM was greater in maternally-deprived males and females than in their control counterparts, and this response was further elevated in maternally-deprived females injected with saline. Regarding monoamine levels, females were less affected, showing isolated effects of the stressors, while in males, MD increased 5-HT levels in the HPT and decreased this monoamine in the FC, MD associated with saline reduced dopamine levels in all brain regions, except the HPT. MD at 11 days did not alter emotional behaviors in adult rats, but had an impact in neurobiological parameters associated with this class of behaviors. The impact of MD associated with saline on dopamine levels suggests that males may be vulnerable to motivation-related disorders.

Consequences of continuous social defeat stress on anxiety- and depressive-like behaviors and ethanol reward in mice.

This study employed the intruder-resident paradigm to evaluate the effects of continuous social defeat on depressive- and anxiety-like behaviors and the reinforcing and motivational actions of ethanol in male Swiss mice. Male Swiss mice were exposed to a 10-day social defeat protocol, while control mice cohabitated with a non-aggressive animal. Continuous defeat stress consisted of episodes of defeat, followed by 24h or 48h cohabitation with the aggressor until the following defeat. Mice were assessed for sucrose drinking (anhedonia), social investigation test, elevated plus-maze, conditioned place preference to ethanol, and locomotor response to ethanol. Plasma corticosterone was measured prior to, after the first and the final defeat, and 10days after the end of defeat. Defeated mice exhibited a depressive-like phenotype as indicated by social inhibition and reduced sucrose preference, relative to non-defeated controls. Defeated mice also displayed anxiety-like behavior when tested in the elevated plus-maze. Stressed animals failed to present ethanol-induced locomotor stimulation, but showed increased sensitivity for ethanol-induced conditioned place preference. Corticosterone response to defeat was the highest after the first defeat, but was still elevated after the last defeat (day 10) when compared to non-stressed controls. Baseline corticosterone levels were unchanged 10days after the final defeat. These data suggest that social defeat stress increased depressive- and anxiety-like behavior as well increased vulnerability to ethanol reward in mice.

Brain prolactin is involved in stress-induced REM sleep rebound.

REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound.

Lead exposure is related to hypercortisolemic profiles and allostatic load in Brazilian older adults.

Lead levels (Pb) have been linked to both hyper- and hypo-reactivity of hypothalamic-pituitary-adrenal axis (HPA) axis to acute stress in animals and humans. Similarly, allostatic load (AL), the 'wear and tear' of chronic stress, is associated with inadequate HPA axis activity. We examined whether Pb levels would be associated with altered diurnal cortisol profile, as a primary mediator of AL, during aging. Pb levels were measured from blood samples (BPb) of 126 Brazilian individuals (105 women), between 50 and 82 years old. Six neuroendocrine, metabolic, and anthropometric biomarkers were analyzed and values were transformed into an AL index using clinical reference cut-offs. Salivary samples were collected at home over 2 days at awakening, 30-min after waking, afternoon, and evening periods to determine cortisol levels. A multiple linear regression model showed a positive association between BPb as the independent continuous variable and cortisol awakening response (R2=0.128; B=0.791; p=0.005) and overall cortisol concentration (R2=0.266; B=0.889; p<0.001) as the outcomes. Repeated measures ANOVA showed that individuals with high BPb levels showed higher cortisol at 30min after awakening (p=0.003), and in the afternoon (p=0.002) than those with low BPb values. Regarding AL, regression model showed that BPb was positively associated with AL index (R2=0.100; B=0.204; p=0.032). Correlation analyzes with individual biomarkers showed that BPb was positively correlated with HDL cholesterol (p=0.02) and negatively correlated with DHEA-S (p=0.049). These findings suggest that Pb exposure, even at levels below the reference blood lead level for adults recommended by the National Institute for Occupational Safety and Health and by the Center for Disease Control and Prevention, may contribute to AL and dysregulated cortisol functioning in older adults. Considering these findings were based on cross-sectional data future research is needed to confirm our exploratory results.

Restriction of rapid eye movement sleep during adolescence increases energy gain and metabolic efficiency in young adult rats.

NEW FINDINGS: What is the central question of this study? Sleep curtailment in infancy and adolescence may lead to long-term risk for obesity, but the mechanisms involved have not yet been determined. This study examined the immediate and long-term metabolic effects produced by sleep restriction in young rats. What is the main finding and its importance? Prolonged sleep restriction reduced weight gain (body fat stores) in young animals. After prolonged recovery, sleep-restricted rats tended to save more energy and to store more fat, possibly owing to increased gross food efficiency. This could be the first step to understand this association. Sleep curtailment is associated with obesity and metabolic changes in adults and children. The aim of the present study was to evaluate the immediate and long-term metabolic alterations produced by sleep restriction in pubertal male rats. Male Wistar rats (28 days old) were allocated to a control (CTL) group or a sleep-restricted (SR) group. This was accomplished by the single platform technique for 18 h per day for 21 days. These groups were subdivided into the following four time points for assessment: sleep restriction and 1, 2 and 4 months of recovery. Body weight and food intake were monitored throughout the experiment. At the end of each time period, blood was collected for metabolic profiling, and the carcasses were processed for measurement of body composition and energy balance. During the period of sleep restriction, SR animals consumed less food in the home cages. This group also displayed lower body weight, body fat, triglycerides and glucose levels than CTL rats. At the end of the first month of recovery, despite eating as much as CTL rats, SR animals showed greater energy and body weight gain, increased gross food efficiency and decreased energy expenditure. At the end of the second and fourth months of recovery, the groups were no longer different, except for energy gain and gross food efficiency, which remained higher in SR animals. In conclusion, sleep restriction affected weight gain of young animals, owing to reduction of fat stores. Two months were sufficient to recover this deficit and to reveal that SR rats tended to save more energy and to store more fat.

Maternal deprivation alters growth, food intake, and neuropeptide Y in the hypothalamus of adolescent male and female rats.

Maternal deprivation (MD) for 24 hr during the neonatal period impairs body weight gain in adolescent and adult rats. It has been previously shown that maternally deprived rats consume less standard and carbohydrate-rich diets. Because neuropeptide Y (NPY) is implicated in feeding behavior, we assessed, prospectively, the effects of maternal deprivation, imposed on postnatal days (PND) 3 (DEP3) or 11 (DEP11), on physical development (snout-anal length and body weight gain, measured once a week) and food intake (assessed daily, during the rest and active phases, from PND 23 to PND 51); NPY-immunoreactivity (NPY-ir) in the arcuate nucleus of the hypothalamus was evaluated in male (at PND 52) and female rats in estrous (at PND 53-60). DEP3 and DEP11 male and female adolescents were smaller, lighter, and ate less during the active phase, than their CTL counterparts. This change in food intake was accompanied by reduced NPY-ir in the arcuate nucleus of the hypothalamus. The present results indicate that maternal deprivation had a negative impact on the physical development and feeding behavior of adolescent rats that may be explained by reduced hypothalamic NPY production.

Prolonged REM sleep restriction induces metabolic syndrome-related changes: Mediation by pro-inflammatory cytokines.

Chronic sleep restriction in human beings results in metabolic abnormalities, including changes in the control of glucose homeostasis, increased body mass and risk of cardiovascular disease. In rats, 96h of REM sleep deprivation increases caloric intake, but retards body weight gain. Moreover, this procedure increases the expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which may be involved with the molecular mechanism proposed to mediate insulin resistance. The goal of the present study was to assess the effects of a chronic protocol of sleep restriction on parameters of energy balance (food intake and body weight), leptin plasma levels and its hypothalamic receptors and mediators of the immune system in the retroperitoneal adipose tissue (RPAT). Thirty-four Wistar rats were distributed in control (CTL) and sleep restriction groups; the latter was kept onto individual narrow platforms immersed in water for 18h/day (from 16:00h to 10:00h), for 21days (SR21). Food intake was assessed daily, after each sleep restriction period and body weight was measured daily, after the animals were taken from the sleep deprivation chambers. At the end of the 21day of sleep restriction, rats were decapitated and RPAT was obtained for morphological and immune functional assays and expression of insulin receptor substrate 1 (IRS-1) was assessed in skeletal muscle. Another subset of animals was used to evaluate blood glucose clearance. The results replicated previous findings on energy balance, e.g., increased food intake and reduced body weight gain. There was a significant reduction of RPAT mass (p<0.001), of leptin plasma levels and hypothalamic leptin receptors. Conversely, increased levels of TNF-α and IL-6 and expression of phosphorylated NFκ-ß in the RPAT of SR21 compared to CTL rats (p<0.01, for all parameters). SR21 rats also displayed reduced glucose clearance and IRS-1 expression than CTL rats (p<0.01). The present results indicated that 21days of sleep restriction by the platform method induced metabolic syndrome-related alterations that may be mediated by inflammation of the RPAT.

Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats.

Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression-like and anxiety-like behaviors. The present study evaluated the effect of FO supplementation on Obx-induced depressive-like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and the metabolite 5-hydroxyindoleacetic (5-HIAA) were determined. Obx led to increased anxiety-like and depressive-like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5-HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5-HT and reduced that of 5-HIAA, indicating low 5-HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety-like and depressive-like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5-HT, two major regulators of neuronal survival and long-term plasticity in this brain structure.

Sleep deprivation alters energy homeostasis through non-compensatory alterations in hypothalamic insulin receptors in Wistar rats.

Studies have shown a gradual reduction of sleep time in the general population, accompanied by increased food intake, representing a risk for developing obesity, type II diabetes and cardiovascular disease. Rats subjected to paradoxical sleep deprivation (PSD) exhibit feeding and metabolic alterations, both of which are regulated by the communication between peripheral signals and the hypothalamus. This study aimed to investigate the daily change of 96 h of PSD-induced food intake, body weight, blood glucose, plasma insulin and leptin concentrations and the expression of their receptors in the hypothalamus of Wistar rats. Food intake was assessed during the light and dark phases and was progressively increased in sleep-deprived animals, during the light phase. PSD produced body weight loss, particularly on the first day, and decreased plasma insulin and leptin levels, without change in blood glucose levels. Reduced leptin levels were compensated by increased expression of leptin receptors in the hypothalamus, whereas no compensations occurred in insulin receptors. The present results on body weight loss and increased food intake replicate previous studies from our group. The fact that reduced insulin levels did not lead to compensatory changes in hypothalamic insulin receptors, suggests that this hormone may be, at least in part, responsible for PSD-induced dysregulation in energy metabolism.

Chronic sleep restriction during juvenility alters hedonic and anxiety-like behaviours in a sex-dependent fashion in adolescent Wistar rats.

Chronic reduction of sleep time in children and adolescents has been related to increased incidence of anxiety and depression. In rats, protocols of protracted sleep deprivation or chronic sleep restriction (CSR) are considered a stressor. In previous studies we showed that post-weaning CSR in male rats induces anxiety-like behaviour and changes in neurotransmission in emotion-related brain areas. In the present study we examined whether the effects of this adversity are sex-dependent. Twenty-two litters, containing four males and four females were distributed into control (CTL) and CSR groups. CSR began on postnatal day (PND) 21 and lasted for 21 days; each day the animals were placed onto small platforms immersed in water for 18 h and were allowed to sleep freely in their home-cages for the remaining 6 h. Throughout the CSR, all animals underwent the sucrose splash test once/week to assess their self-care and hedonic behaviours. Body weight was measured on PNDs 21 and 42. At the end of CSR period, the adolescents were allowed to sleep freely for 2 days, after which, behavioural tests began. Within each litter, one male and one female (pair) were not tested and provided blood and brain for determination of basal corticosterone (CORT) levels and hippocampal BDNF. One pair was tested in the sucrose preference test (SPT), one pair on the elevated plus maze (EPM) and one pair in the forced swim test (FST). CORT was measured after all conditions. CSR impaired self-care behaviour and body weight gain in males and females and increased relative adrenal weight only in males. There were no changes in sucrose intake in the SPT; CSR females displayed less immobility in the FST and CSR males displayed more anxiety-like behaviour in the EPM. CORT levels were similar between CTL and CSR males, whilst lower in CSR females than CTL ones in all experimental conditions. No changes in BDNF levels were detected in the dorsal hippocampus of CSR rats. The results indicate that CSR impaired self-care behaviour in both sexes, but only males displayed anxiety-like behaviour, whilst sleep recovery in females appeared to normalise their behaviour.

One Day Away from Mum has Lifelong Consequences on Brain and Behaviour.

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.

Neurobiological mechanisms involved in maternal deprivation-induced behaviours relevant to psychiatric disorders.

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.

Neuroprotective effects of resistance physical exercise on the APP/PS1 mouse model of Alzheimer's disease.

Introduction: Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to AD. Most studies, however, have been conducted with aerobic exercises, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD. Similar to AD patients, double-transgenic APPswe/PS1dE9 (APP/PS1) mice exhibit Αß plaques in the cortex and hippocampus, hyperlocomotion, memory deficits, and exacerbated inflammatory response. Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice. Methods: For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (CTRL), were distributed into three groups: CTRL, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aß plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay. Results: APP/PS1 transgenic sedentary mice showed increased hippocampal Aß plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aß alterations to the CTRL levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Despite these alterations, no memory impairment was observed in APP/PS1 mice in the novel object recognition test. Discussion: Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.