Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.

Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence.

Early life stress-induced alterations in rat brain structures measured with high resolution MRI.

Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excitability and microstructure. Detailed information on the effects of ELS on rodent brain structural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses. Here, we exposed rats to 24 hours of maternal deprivation (MD) at postnatal day 3, a paradigm known to increase corticosterone levels and thereby activate glucocorticoid receptors in the brain. Using structural magnetic resonance imaging we examined: i) volumetric changes and white/grey matter properties of the whole cerebrum and of specific brain areas; and ii) whether potential alterations could be normalized by blocking glucocorticoid receptors with mifepristone during the critical developmental window of early adolescence, i.e. between postnatal days 26 and 28. The results show that MD caused a volumetric reduction of the prefrontal cortex, particularly the ventromedial part, and the orbitofrontal cortex. Within the whole cerebrum, white (relative to grey) matter volume was decreased and region-specifically in prefrontal cortex and dorsomedial striatum following MD. A trend was found for the hippocampus. Grey matter fractions were not affected. Treatment with mifepristone did not normalize these changes. This study indicates that early life stress in rodents has long lasting consequences for the volume and structural integrity of the brain. However, changes were relatively modest and-unlike behavior- not mitigated by blockade of glucocorticoid receptors during a critical developmental period.

Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation.

Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [postnatal days (PND)26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood. In adulthood, contextual memory formation of MD compared to noMD (i.e., control) male rats was significantly impaired. This impairment was fully prevented by MIF treatment at PND26-PND28, whereas MIF by itself did not affect behavior. A second behavioral test, a rodent version of the Iowa Gambling Task (rIGT), revealed that flexible spatial learning rather than reward-based aspects of performance was impaired by MD; the deficit was prevented by MIF. Neuronal activity as tested by c-Fos staining in the latter task revealed changes in the right hippocampal-dorsomedial striatal pathway, but not in prefrontal areas involved in reward learning. Follow-up electrophysiological recordings measuring spontaneous glutamate transmission showed reduced frequency of miniature postsynaptic excitatory currents in adult CA1 dorsal hippocampal and enhanced frequency in dorsomedial striatal neurons from MD versus noMD rats, which was not seen in MIF-treated rats. We conclude that transient prepubertal MIF treatment normalizes hippocampus-striatal-dependent contextual memory/spatial learning deficits in male rats exposed to early life adversity, possibly by normalizing glutamatergic transmission.

Mifepristone Treatment during Early Adolescence Fails to Restore Maternal Deprivation-Induced Deficits in Behavioral Inhibition of Adult Male Rats.

Early life adversity has a profound impact on brain development and later life health. Animal models have provided insight how early life stress programs stress responsiveness and might contribute to the development of psychiatric disorders. In the present study, the long-term effects of maternal deprivation (MD) on behavioral inhibition and attention were examined in adult male Wistar rats. To this end animals were tested in the 5-choice serial reaction time task (5-choice SRTT). We also explored the potential of a 3-day treatment with the glucocorticoid receptor (GR) antagonist mifepristone during early adolescence to normalize putative behavioral effects of early life stress. Deprivation of the mother for 24 h on postnatal day (PND) 3 led to a modest but significant increase in premature responses in the 5-choice SRTT, but did not affect measures of attention. Body weight was lower in deprived animals from weaning until the start of testing. Early adolescent mifepristone treatment (PND 26-28) did not influence performance on the 5-choice SRTT and did not mitigate the deprivation-related impairment in behavioral inhibition. Our results indicate that MD leads to impaired behavioral inhibition, and that mifepristone treatment during early adolescence does not normalize the behavioral changes caused by early life stress.

Complex Living Conditions Impair Behavioral Inhibition but Improve Attention in Rats.

Rapid adaptation to changes, while maintaining a certain level of behavioral inhibition is an important feature in every day functioning. How environmental context and challenges in life can impact on the development of this quality is still unknown. In the present study, we examined the effect of a complex rearing environment during adolescence on attention and behavioral inhibition in adult male rats. We also tested whether these effects were affected by an adverse early life challenge, maternal deprivation (MD). We found that animals that were raised in large, two floor Marlau(TM) cages, together with 10 conspecifics, showed improved attention, but impaired behavioral inhibition in the 5-choice serial reaction time task. The early life challenge of 24 h MD on postnatal day 3 led to a decline in bodyweight during adolescence, but did not by itself influence responses in the 5-choice task in adulthood, nor did it moderate the effects of complex housing. Our data suggest that a complex rearing environment leads to a faster adaptation to changes in the environment, but at the cost of lower behavioral inhibition.

Age- and sex-dependent effects of early life stress on hippocampal neurogenesis.

Early life stress is a well-documented risk factor for the development of psychopathology in genetically predisposed individuals. As it is hard to study how early life stress impacts human brain structure and function, various animal models have been developed to address this issue. The models discussed here reveal that perinatal stress in rodents exerts lasting effects on the stress system as well as on the structure and function of the brain. One of the structural parameters strongly affected by perinatal stress is adult hippocampal neurogenesis. Based on compiled literature data, we report that postnatal stress slightly enhances neurogenesis until the onset of puberty in male rats; when animals reach adulthood, neurogenesis is reduced as a consequence of perinatal stress. By contrast, female rats show a prominent reduction in neurogenesis prior to the onset of puberty, but this effect subsides when animals reach young adulthood. We further present preliminary data that transient treatment with a glucocorticoid receptor antagonist can normalize cell proliferation in maternally deprived female rats, while the compound had no effect in non-deprived rats. Taken together, the data show that neurogenesis is affected by early life stress in an age- and sex-dependent manner and that normalization may be possible during critical stages of brain development.

Down-regulation of hippocampal BDNF and Arc associated with improvement in aversive spatial memory performance in socially isolated rats.

Rats deprived of social contact with other rats at a young age experience a form of prolonged stress that leads to long-lasting changes in behavioral profile. Such isolation is thought to be anxiogenic for these normally gregarious animals, and the abnormal reactivity of isolated rats to environmental stimuli is thought to be a product of prolonged stress. We now show that isolation of rats at weaning reduced immobility time in the forced swim test, decreased sucrose intake and preference, and down-regulated both brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeletal associated protein (Arc) in the hippocampus. In the Morris water maze, isolated rats showed a reduced latency to reach the hidden platform during training, indicative of an improved learning performance, compared with group-housed rats. The cumulative search error during place training trials indicated a reliable difference between isolated and group-housed rats on days 4 and 5. The probe trial revealed a significant decrease of the average proximity to the target location in the isolated rats suggesting an improvement in spatial memory. Isolated rats also showed an increase in the plasma level of corticosterone on the 5th day of training and increased expression of BDNF and Arc in the hippocampus on both days 1 and 5. These results show that social isolation from weaning in rats results in development of depressive-like behavior but has a positive effect on spatial learning, supporting the existence of a facilitating effect of stress on cognitive function.