Long-term consequences of alcohol use in early adolescent mice: Focus on neuroadaptations in GR, CRF and BDNF.

Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a 5-week two-bottle choice protocol (postnatal day [pd]21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals' age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation and cognition.

Remote memory of drug experiences coexists with cognitive decline and abnormal adult neurogenesis in an animal model of cocaine-altered cognition.

Cocaine addiction is a chronic disorder in which the person loses control over drug use. The past memories of the stimuli associated with the drug are a relevant clinical problem, since they trigger compulsive drug-seeking and drug-taking habits. Furthermore, these persistent drug-related memories seemingly coexist with cognitive decline that predicts worse therapeutic output. Here, we use a new animal model of cocaine-altered cognition that allowed to observe these events in the same individual and study their relationship. Mice were chronically administered cocaine in a conditioned place preference (CPP) apparatus for 14 days, and control mice received saline. After 28 days of cocaine withdrawal, animals were tested for retrieval of remote drug-associated memory as well as for cognitive performance in a battery of tests, including novel object and place recognition and spatial memory. The cocaine-withdrawn mice showed persistent CPP memory while impaired in the cognitive tasks, displaying deficits in reference memory acquisition and working memory. However, the CPP expression was not associated with the defective cognitive performance, indicating that they were concomitant but independent occurrences. After completion of the experiment, adult hippocampal neurogenesis (AHN) was studied as a relevant neurobiological correlate due to its potential role in both learning and drug addiction. Results suggested a preserved basal AHN in the cocaine-withdrawn mice but an aberrant learning-induced regulation of these neurons. This paradigm may be useful to investigate maladaptive cognition in drug addiction as well as related therapies.

Where to place the rewards? Exploration bias in mice influences performance in the classic hole-board spatial memory test.

The classic hole-board paradigm (a square arena with 16 holes arranged equidistantly in a 4 × 4 pattern) assesses both exploration and spatial memory in rodents. For spatial memory training, food rewards are hidden in a fixed set of holes. The animal must not visit (i.e. nose-poke) the holes that are never baited (reference memory; RM) nor re-visit a baited hole within a session (working memory; WM). However, previous exploratory bias may affect performance during reward searching. During habituation sessions with either all holes rewarded or all holes empty, mice intrinsically preferred poking peripheral holes (especially those located in the maze's corners) over centre holes. During spatial memory training, mice progressively shifted their hole pokes and staying time to the central area that contained hidden rewards, while mice exposed to the empty apparatus still preferred the periphery. A group of pseudotrained mice, for whom rewards were located randomly throughout the maze, also increased their central preference. Furthermore, reward location influenced memory measures. Most repeated pokes (WM-errors) were scored in the locations that were most intrinsically appealing to mice (i.e. the corner and wall-baited holes), supporting a strong influence of previous exploratory bias. Regarding RM, finding rewards located in the centre holes, which were initially less preferred, entailed more difficulty and required more trials to learn. This outcome was confirmed by a second experiment that varied the pattern of rewarded holes, as well as the starting positions. Therefore, reward location is a relevant aspect to consider when designing a hole-board memory task.

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, the number of proliferating hippocampal cells were reduced in Trained mice, but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is a useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.

Age and gender differences in spatial perspective taking.

BACKGROUND AND AIMS: It is often necessary in daily experience to change one's point of view to adopt mentally the spatial perspective of other persons, learn the position of different objects in a new environment or even describe an environment to other persons. Hence, the ability to link spatial information from different perspectives seems to be necessary to orient ourselves in the space. Several studies have found gender-related differences in spatial reasoning in younger adults, but little is known about such effects in middle-aged and older adults. METHODS: This research was designed to study how spatial perspective taking is affected by gender and age along the lifespan. The Perspective Taking/Spatial Orientation Test (PPT; Kozhevnikov and Hegarty [1]) was administered to groups of younger, middle-aged, and older adults, with females and males represented in each age group. RESULTS: The performance in the PPT decreased across age groups. All age groups had more errors in items that involved perspective changes of greater than 90º. Males performed better than females on most of the variables; however, no significant differences appeared in the interaction gender × age. CONCLUSION: The present findings showed the relevance of the degree perspective change in visuo-spatial abilities, especially in the older group. In relation with the gender, males outperformed females; however, the interaction gender × age did not show significant differences.

Sex-related differences in young binge drinkers on the neurophysiological response to stress in virtual reality.

Background: Stress is one of the main environmental factors involved in the onset of different psychopathologies. In youth, stressful life events can trigger inappropriate and health-damaging behaviors, such as binge drinking. This behavior, in turn, can lead to long-lasting changes in the neurophysiological response to stress and the development of psychological disorders late in life, e.g., alcohol use disorder. Our aim was to analyze the pattern of neurophysiological responses triggered with the exposition to a stressful virtual environment in young binge drinkers. Methods: AUDIT-3 (third question from the full AUDIT) was used to detect binge drinking (BD) in our young sample (age 18-25 years). According to the score, participants were divided into control (CO) and BD group. Next, a standardized virtual reality (VR) scenario (Richie's Plank) was used for triggering the stress response while measuring the following neurophysiological variables: brain electrical activity by electroencephalogram (EEG) and cortisol levels through saliva samples both measurements registered before and after the stressful situation. Besides, heart rate (HR) with a pulsometer and electrodermal response (EDA) through electrodes placed on fingers were analyzed before, during and after the VR task. Results: Regarding the behavior assessed during the VR task, BD group spent significantly less amount of time walking forward the table and a tendency toward more time walking backwards. There was no statistically significant difference between the BD and the CO group regarding time looking down, but when we controlled the variable sex, the BD women group displayed higher amount of time looking down than the rest of the groups. Neurophysiological measurements revealed that there was not any statistically significant difference between groups in any of the EEG registered measures, EDA response and cortisol levels. Sex-related differences were found in HR response to VR scenario, in which BD women displayed the highest peak of response to the stressor. Also, the change in heartbeat was higher in BD women than men. Conclusion: Unveiling the neurophysiological alterations associated with BD can help us to prevent and detect early onset of alcohol use disorder. Also, from our data we conclude that participants' sex can modulate some stress responses, especially when unhealthy behaviors such as BD are present. Nevertheless, the moment of registration of the neurophysiological variables respect to the stressor seems to be a crucial variable.

Intensity of Physical Activity in Young People: Focus on Emotional, Cognitive, and Healthy Lifestyle-Related Variables.

The college years represent a crucial developmental period in which unhealthy behaviors, including smoking, alcohol consumption, inadequate physical activity (PA), poor sleep quality, and unhealthy nutrition habits are often acquired, influencing the onset or exacerbation of pre-existing mental disturbances such as anxiety, depression, or difficulties in emotion regulation. Our aim was to analyze the effect of the intensity of physical activity (PA) on the emotional, behavioral, and cognitive variables in a sample of young people. We recruited 103 participants (19.85 ± 0.25) who completed several online questionnaires (IPAQ-SF, STAI-t, DERS, UPPS-P, ISP-20, and Mini-IPIP). Subsequently, face-to-face sessions were conducted to assess the cognitive variables and to collect more details about their lifestyle habits, including drug use, sleep quality, and leisure activities. Based on the IPAQ-SF results, we categorized the sample into three groups: light PA (n = 47), moderate PA (n = 29), and vigorous PA (n = 27). Vigorous PA group showed better emotional regulation, lower impulsivity, fewer prefrontal symptoms and unhealthy behaviors, better sleep quality, and more leisure activities. No significant cognitive differences were found. It seems that young people are a vulnerable group with emotional and impulsivity traits and engaging in intense PA appears to be a promising avenue for managing these symptoms. In conclusion, our study suggests that young people are a vulnerable group with emotional and impulsivity traits that may precipitate in future mental disorders. Nevertheless, engaging in PA, particularly at high intensity, appears to be a promising avenue for reducing and managing these symptoms during this critical period of life.

Sex-related differences in the associations between diurnal cortisol pattern and social and emotional loneliness in older adults.

Introduction: Loneliness is a distressful feeling that can affect mental and physical health, particularly among older adults. Cortisol, the primary hormone of the Hypothalamic-Pituitary-Adrenal axis (HPA-axis), may act as a biological transducer through which loneliness affects health. While most previous studies have evaluated the association between loneliness, as a unidimensional construct, and diurnal cortisol pattern, no research has examined this relationship discriminating between social and emotional loneliness in older adults. As sex differences in the negative mental health outcomes of loneliness have been reported, we also investigated whether diurnal cortisol indices and loneliness associations occur in a sex-specific manner. Methods: We analyzed the diurnal cortisol- pattern in 142 community-dwelling, non-depressed, Caucasian older adults (55,6% female) aged 60-90. Social and emotional (family and romantic) loneliness scores were assessed using the Spanish version of the Social and Emotional Loneliness Scale for Adults (SELSA). Five salivary cortisol samples were used to capture key features of the diurnal cortisol pattern, including: awakening and bedtime cortisol levels, awakening response (CAR), post-awakening cortisol output (post-awakening cortisol [i.e., the area under the curve with reference to the ground: AUCG]), total diurnal cortisol release (AUCG), and diurnal cortisol slope (DCS). Results: After controlling for sociodemographic variables, the hierarchical linear multiple regression analyses revealed that in male older adults, higher scores on social and family loneliness were associated with elevated awakening cortisol levels, total diurnal cortisol output, and a steeper diurnal cortisol slope (DCS). However, these associations were not observed in female older adults. In addition, feelings of romantic loneliness were positively associated with bedtime cortisol levels and AUCG in older males. Multilevel growth curve modeling showed that experiencing more social and emotional loneliness predicted higher diurnal cortisol output throughout the day in older male adults. Discussion: The presence of sex differences in the relationship between cortisol indices and loneliness among older adults holds particular significance for diagnostic and screening procedures. Combining loneliness scales as screening tools with diurnal cortisol measures has the potential to be an effective and cost-efficient approach in identifying higher-risk individuals at early stages.

The Relationship between Binge Drinking and Binge Eating in Adolescence and Youth: A Systematic Review and Meta-Analysis.

Adolescence and youth are critical periods in which alcohol consumption is usually initiated, especially in the form of binge drinking. In recent years, it is increasingly common to find adolescents and young people who also present binge behaviors towards unhealthy food with the aim of alleviating their anxiety (emotional eating) and/or because of impulsive personality. Despite the social and health relevance of this issue, it remains scarcely studied and more preventive research needs to be developed. Our meta-analysis study aimed to evaluate the relationship and co-occurrence of both binge behaviors during adolescence and young adulthood to clarify the link between binge drinking and eating. Selective literature search on different online databases was performed. We identified discrete but significant results regarding the direct association between binge drinking and binge eating in correlation coefficients and odds ratio. Future research should focus on the common psychological background and motives behind these problematic behaviors owing to their clinical implications for effective prevention and treatment.

Treadmill Exercise Buffers Behavioral Alterations Related to Ethanol Binge-Drinking in Adolescent Mice.

The binge-drinking pattern of EtOH consumption, which is frequently observed in adolescents, is known to induce several neurobehavioral alterations, but protection strategies against these impairments remain scarcely explored. We aimed to study the protective role of treadmill physical exercise on the deficits caused after repeated cycles of binge-like EtOH exposure in the cognition, motivation, exploration, and emotion of C57BL/6J mice from adolescence to adulthood. Animals were divided into four groups: control group, exercised group, EtOH group, and exercised + EtOH group (20% in tap water). The exercise was performed for 20 min, 5 days/week at 20 cm/s. Then, animals were submitted to several behavioral tasks. Compared to binge-drinking mice, the exercised + EtOH group exhibited diminished anxiolytic-related behaviors in the elevated plus-maze, enhanced exploratory activity in the open field, reduced preference for alcohol odor when another rewarding stimulus was present (social stimulus) and lower latency to start self-cleaning behaviors in the sucrose splash test. In contrast, other measurements such as habituation learning and working memory were not improved by exercise. Besides, exercise was not able to reduce alcohol consumption across the weeks. In conclusion, physical activity during adolescence and early adulthood could buffer certain neurobehavioral alterations associated with binge-drinking, despite not reducing the quantity of consumed alcohol.

Salivary Cortisol Levels Are Associated with Craving and Cognitive Performance in Cocaine-Abstinent Subjects: A Pilot Study.

Cortisol is a glucocorticoid hormone secreted by the adrenal cortex upon the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Assessment of cortisol in saliva has emerged as a reliable way of evaluating HPA function. We examined the relationships between salivary cortisol levels with both craving and cognitive performance, as a possible biomarker of cocaine addiction. Cognitive performance (attention, declarative and working memory, executive functions and recognition of emotions) was assessed in 14 abstinent cocaine-dependent subjects in outpatient treatment and 13 control participants. Three salivary samples were collected at home by all the participants in the morning, afternoon and at bedtime. Patients showed higher levels of cortisol in the morning, as well as higher area under the curve with respect to the ground (AUCg). Regarding cognitive performance, cocaine-abstinent subjects showed worse performance in attention (d2 test), verbal memory (Spanish Complementary Verbal Learning Test, TAVEC) and executive tests (Tower of Hanoi and phonological fluency test) with respect to the control group. Morning cortisol levels and the AUCg index were negatively associated with the age of onset of drug consumption and the AUCg index was also positively associated with craving in our patients' group. Moreover, morning cortisol levels, as well as the AUCg index, were negatively associated with verbal memory performance. Therefore, our pilot study suggests that salivary cortisol measurements could be a good avenue to predict craving level, as well as cognitive status, especially the declarative memory domain.

The presence of a social stimulus reduces cocaine-seeking in a place preference conditioning paradigm.

BACKGROUND: One challenge in the treatment of substance use disorders is to re-engage the interest toward non-drug-related activities. Among these activities, social interaction has had a prominent role due to its positive influence on treatment outcome. AIMS AND METHODS: Our aim was to study whether the presence of a social stimulus during the cocaine-induced conditioned place preference test was able to reduce the time spent in the drug-paired compartment. For that purpose, mice were trained for four days on a conditioned place preference task with one compartment paired with cocaine and the opposite with saline. On the test day, we introduced an unfamiliar juvenile male mouse into the saline-conditioned compartment (inside a pencil cup) to analyse the animal preference towards the two rewarding stimuli (cocaine vs mouse). Additionally, to discard the possible effect of novelty, as well as the housing condition (social isolation) on social preference, we decided to include a novel object during the test session, as well as perform the same conditioned place preference protocol with a group of animals in social housing conditions. RESULTS: The social stimulus was able to reduce the preference for cocaine and enhance the active interaction with the juvenile mouse (sniffing) compared to the empty pencil cup paired with the drug. The introduction of a novel object during the test session did not reduce the preference for the cocaine-paired compartment, and interestingly, the preference for the social stimulus was independent of the housing condition. c-Fos immunohistochemistry revealed a different pattern of activation based on cocaine-paired conditioning or the presence of social stimulus. CONCLUSIONS: These results suggest that social interaction could constitute a valuable component in the treatment of substance use disorders by reducing the salience of the drug.

Effects of pre-reproductive maternal enrichment on maternal care, offspring's play behavior and oxytocinergic neurons.

Potentiating social, cognitive, and sensorimotor stimulations the Environmental Enrichment (EE) increases levels of novelty and complexity experienced by individuals. Growing evidence demonstrates that parental EE experience, even occurring in the pre-reproductive phase, affects behavioral and neural developmental trajectories of the offspring. To discover how the accumulation of early maternal complex experiences may inform and shape the social behavior of the following generation, we examined the effects of pre-reproductive enrichment of dams (post-natal days 21-72) on the play performances of their male and female adolescent offspring. Furthermore, we examined the effects of pre-reproductive enrichment on maternal behavior (during post-partum days 1-10) and male intruder aggression (on post-partum day 11). Since oxytocin modulates maternal care, social bonding, and agonistic behavior, the number of oxytocinergic neurons of the paraventricular (PVN) and supraoptic (SON) nuclei was examined in both dams and offspring. Results revealed that enriched females exhibited higher levels of pup-oriented behaviors, especially Crouching, and initiated pup-retrieval more quickly than standard females after the maternal aggression test. Such behavioral peculiarities were accompanied by increased levels of oxytocinergic neurons in PVN and SON. Moreover, pre-reproductive maternal EE cross-generationally influenced the offspring according to sex. Indeed, male pups born to enriched females exhibited a reduced play fighting associated with a higher number of oxytocinergic neurons in SON in comparison to male pups born to standard-housed females. In conclusion, pre-reproductive EE to the mothers affects their maternal care and has a cross-generational impact on the social behavior of their offspring that do not directly experiences EE. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Neuroplastic and cognitive impairment in substance use disorders: a therapeutic potential of cognitive stimulation.

Drug addiction is a chronic and relapsing disorder in which repeated drug exposure compromises brain neuroplasticity. Brain areas normally involved in learning and goal-directed behaviors become corrupted, which may lead to cognitive deficits that coexist with other addiction symptoms and predict a worse treatment outcome. New learning experiences that are not motivated by drugs may improve both cognitive deficits and drug-induced symptoms by promoting adaptive neuroplastic changes that could alleviate or reverse those involved in addiction. The present review will focus on whether potentiating healthy cognitive function, either by formal cognitive training or non-drug related environmental experiences, could exert beneficial effects in the therapeutics of addiction. Although additional studies are needed, the available clinical and preclinical evidence suggests that cognitive stimulation may provide a valuable adjuvant intervention in drug addiction.

Comprendiendo la adicción desde una perspectiva neuropsicológica / prendiendo la adicción desde una perspectiva neuropsicológica Understanding addiction from a neuropsychological perspective

La concepción de la adicción como una enfermedad crónica con base cerebral se ha hechopredominante en los últimos años. Desde ella, se promueve la idea de que una persona con untrastorno adictivo sufre cambios en la estructura y el funcionamiento de su cerebro haciendoque pierda el autocontrol sobre su comportamiento. Además, desde este modelo biomédico, laspersonas que abusan de las drogas son consideradas enfermas promoviendo su atención médicay su consideración social siendo así, el individuo más propenso a externalizar los motivos de lasrecaídas y de los abandonos y mostrando menos implicación en su rehabilitación. Debido a estasasunciones, en los últimos años han proliferado los estudios que cuestionan este modelo desdeel ámbito metodológico, ético y sociológico. Por ello, en esta revisión pondremos en duda estaperspectiva reduccionista destacando la necesidad de considerar la interrelación entre el cerebroy el entorno para proporcionar una comprensión más amplia e integral de la adicción. Para ello,proponemos que la neuropsicología y su estudio de los procesos cognitivos es la mejor manera deentender tanto el inicio como el curso de los trastornos adictivos. (AU)

The conception of addiction as a chronic brain disease has become prevalent promoting theidea that a person with an addictive disorder undergoes changes in the structure and functioning of his or her brain. Unfortunately, when these brain changes occur, the individual loses selfcontrol over his/her behavior. From this biomedical model of addiction, people who abusedrugs are considered sick promoting their medical care and social consideration. Moreover,from this idea of addiction as a brain disease, the individual is more likely to externalize thereasons for relapses or dropouts during treatment showing little involvement in rehabilitation.Due to these assumptions, in recent years there has been a proliferation of studies questioning this model from methodological, ethical and sociological perspectives. Therefore, in thisreview we will highlight the idea that not everything is in the brain and that we must considerthe interrelationship between the brain and the environment to provide a broader and morecomprehensive understanding of addiction. To this end, we propose that neuropsychologyand its study of cognitive processes is the best way to understand both the onset and thecourse of addictive disorders (AU)

Understanding addiction from a neuropsychological perspective / Comprendiendo la adicción desde una perspectiva neuropsicológica

The conception of addiction as a chronic brain disease has become prevalent promoting theidea that a person with an addictive disorder undergoes changes in the structure and functioning of his or her brain. Unfortunately, when these brain changes occur, the individual loses selfcontrol over his/her behavior. From this biomedical model of addiction, people who abusedrugs are considered sick promoting their medical care and social consideration. Moreover,from this idea of addiction as a brain disease, the individual is more likely to externalize thereasons for relapses or dropouts during treatment showing little involvement in rehabilitation.Due to these assumptions, in recent years there has been a proliferation of studies questioning this model from methodological, ethical and sociological perspectives. Therefore, in thisreview we will highlight the idea that not everything is in the brain and that we must considerthe interrelationship between the brain and the environment to provide a broader and morecomprehensive understanding of addiction. To this end, we propose that neuropsychologyand its study of cognitive processes is the best way to understand both the onset and thecourse of addictive disorders (AU)

La concepción de la adicción como una enfermedad crónica con base cerebral se ha hechopredominante en los últimos años. Desde ella, se promueve la idea de que una persona con untrastorno adictivo sufre cambios en la estructura y el funcionamiento de su cerebro haciendoque pierda el autocontrol sobre su comportamiento. Además, desde este modelo biomédico, laspersonas que abusan de las drogas son consideradas enfermas promoviendo su atención médicay su consideración social siendo así, el individuo más propenso a externalizar los motivos de lasrecaídas y de los abandonos y mostrando menos implicación en su rehabilitación. Debido a estasasunciones, en los últimos años han proliferado los estudios que cuestionan este modelo desdeel ámbito metodológico, ético y sociológico. Por ello, en esta revisión pondremos en duda estaperspectiva reduccionista destacando la necesidad de considerar la interrelación entre el cerebroy el entorno para proporcionar una comprensión más amplia e integral de la adicción. Para ello,proponemos que la neuropsicología y su estudio de los procesos cognitivos es la mejor manera deentender tanto el inicio como el curso de los trastornos adictivos. (AU)

Influence of Pre-reproductive Maternal Enrichment on Coping Response to Stress and Expression of c-Fos and Glucocorticoid Receptors in Adolescent Offspring.

Environmental enrichment (EE) is an experimental setting broadly used for investigating the effects of complex social, cognitive, and sensorimotor stimulations on brain structure and function. Recent studies point out that parental EE experience, even occurring in the pre-reproductive phase, affects neural development and behavioral trajectories of the offspring. In the present study we investigated the influences of pre-reproductive EE of female rats on maternal behavior and adolescent male offspring's coping response to an inescapable stressful situation after chronic social isolation. For this purpose female Wistar rats were housed from weaning to breeding age in enriched or standard environments. Subsequently, all females were mated and housed in standard conditions until offspring weaning. On the first post partum day (ppd 1), mother-pup interactions in undisturbed conditions were recorded. Further, after weaning the male pups were reared for 2 weeks under social isolation or in standard conditions, and then submitted or not to a single-session Forced Swim Test (FST). Offspring's neuronal activation and plastic changes were identified by immunohistochemistry for c-Fos and glucocorticoid receptors (GRs), and assessed by using stereological analysis. The biochemical correlates were measured in the hippocampus, amygdala and cingulate cortex, structures involved in hypothalamic-pituitary-adrenocortical axis regulation. Enriched dams exhibited increased Crouching levels in comparison to standard reared dams. In the offspring of both kinds of dams, social isolation reduced body weight, decreased Immobility, and increased Swimming during FST. Moreover, isolated offspring of enriched dams exhibited higher levels of Climbing in comparison to controls. Interestingly, in the amygdala of both isolated and control offspring of enriched dams we found a lower number of c-Fos immunopositive cells in response to FST and a higher number of GRs in comparison to the offspring of standard dams. These results highlight the profound influence of a stressful condition, such as the social isolation, on the brain of adolescent rats, and underline intergenerational effects of maternal experiences in regulating the offspring response to stress.