Neonatal Serotonin Depletion Induces Hyperactivity and Anxiolytic-like Sex-Dependent Effects in Adult Rats.

The serotoninergic system plays an important role in the ontogeny of the mammalian central nervous system, and changes in serotonin production during development may lead to permanent changes in brain cytoarchitecture and function. The present study investigated the programming effects of neonatal serotonin depletion on behavior and molecular components of the serotoninergic system in adult male and female rats. Subcutaneous para-chlorophenylalanine (pCPA) administration (100 mg kg-1) was performed daily on postnatal days 8-16 to deplete brain serotonin content. During adulthood, elevated plus-maze, open field, social interaction, forced swimming, and food, saline, and sucrose intake tests were performed. Relative expression of serotonin neurotransmission components in several brain areas was determined by qPCR. Additionally, serotonin immunofluorescence and neuropeptide mRNA expression were assessed in dorsal raphe (DRN) and paraventricular (PVN) nuclei, respectively. Rat performance in behavioral tests demonstrated a general increase in locomotor activity and active escape behavior as well as decreased anxiety-like behavior after neonatal brain serotonin depletion. The behavioral programming effects due to neonatal serotonin depletion were more pronounced in females than males. At the gene expression level, the mRNA of Tph1 and Tph2 were lower in DRN while Htr2c was higher in the amygdala of pCPA-treated males, while Htr1a, Htr2c, Oxt, Avp, Crh, and Trh were not different in any treatments or sex in PVN. The results indicate that neonatal serotonin depletion has long-term consequences on locomotion and anxiety-like behavior associated with long-lasting molecular changes in the brain serotoninergic system in adult rats.

Maternal Deprivation Increases Anxiety- and Depressive-Like Behaviors in an Age-Dependent Fashion and Reduces Neuropeptide Y Expression in the Amygdala and Hippocampus of Male and Female Young Adult Rats.

Maternal deprivation for 24 h produces an immediate increase in basal and stress-induced corticosterone (CORT) secretion. Given the impact of elevated CORT levels on brain development, the goal of the present study was to characterize the effects of maternal deprivation at postnatal days 3 (DEP3) or 11 (DEP11) on emotional behavior and neuropeptide Y immunoreactivity (NPY-ir) in the basolateral amygdala (BLA) and dorsal hippocampus (dHPC) of male and female rats. Litters were distributed in control non-deprived (CTL), DEP3, or DEP11 groups. In Experiment 1, within each litter, one male and one female were submitted to one of the following tests: novelty suppressed feeding (NSF), sucrose negative contrast test (SNCT), and forced swimming test (FST), between postnatal days 52 and 60. In Experiment 2, two males and two females per litter were exposed to the elevated plus maze and 1 h later, perfused for investigation of NPY-ir, on PND 52. The results showed that DEP3 rats displayed greater anxiety-like behavior in the NSF and EPM, compared to CTL and DEP11 counterparts. In the SNCT, DEP3 and DEP11 males showed less suppression of the lower sucrose concentration intake, whereas all females suppressed less than males. Both manipulated groups displayed more immobility in the FST, although this effect was greater in DEP3 than in DEP11 rats. NPY-ir was reduced in DEP3 and DEP11 males and females in the BLA, whereas in the dHPC, DEP3 males showed less NPY-ir than DEP11, which, in turn, presented less NPY-ir than CTL rats. Females showed less NPY-ir than males in both structures. Because the deprivation effects were more intense in DEP3 than in DEP11, in Experiment 3, the frequency of nursing posture, licking-grooming, and interaction with pups was assessed upon litter reunion with mothers. Mothers of DEP11 litters engaged more in anogenital licking than mothers of DEP3 litters. The present results indicate that maternal deprivation changed affective behavior with greater impact in the earlier age and reduced the expression of NPY in emotion-related brain areas. The age-dependent differential effects of deprivation on maternal behavior could, at least in part, explain the outcomes in young adult rats.

Contextual exploration previous to an aversive event predicts long-term emotional consequences of severe stress.

Traumatic stress can lead to long-term emotional alterations, which may result in Posttraumatic Stress Disorder (PTSD). Fear reactions triggered by conditioned cues and exacerbated emotional arousal in face of non-conditioned stimuli are among the most prominent features of PTSD. We hypothesized that long-term emotional alterations seen in PTSD may depend on the strength of context-trauma association. Here, we investigated the contribution of previous contextual exploration to the long-term emotional outcomes of an intense foot shock in rats. We exposed male Wistar rats to a highly stressful event (foot shock, 2 mA, 1 sec) allowing them to explore or not the chamber prior to trauma. We, then, evaluated the long-term effects on emotionality. Fear was assessed by the time spent in freezing behavior either upon re-exposure to trauma context or upon exposure to an unknown environment made potentially more aversive by presentation of an acoustic stimulus. Behaviors on the elevated-plus-maze and acoustic startle response were also assessed. The possibility to explore the environment immediately before the aversive event led to differential long-term emotional effects, including a heightened freezing response to re-exposure to context, blunted exploratory behavior, fear sensitization and exacerbation of the acoustic startle response, in contrast to the minor outcomes of the foot shock with no prior context exploration. The data showed the strong contribution of contextual learning to long-term behavioral effects of traumatic stress. We argue that contextual representation contributes to the robust long-term behavioral alterations seen in this model of traumatic stress.

Instrumental learning: an animal model for sleep dependent memory enhancement.

The relationship between learning and sleep is multifaceted; learning influences subsequent sleep characteristics, which may in turn influence subsequent memory. Studies in humans indicate that sleep may not only prevent degradation of acquired memories, but even enhance performance without further practice. In a rodent instrumental learning task, individual differences occur in how fast rats learn to associate lever pressing with food reward. Rats habitually sleep between learning sessions, and may differ in this respect. The current study assessed if the instrumental leaning paradigm could serve as a model to study sleep-dependent memory enhancement. Male Wistar rats performed 2 sessions of instrumental learning per day for 1-3 days. Electroencephalography was recorded both before and after the sessions. Sleep deprivation (3 h) was applied between the first and second session in a subgroup of rats. Measurements comprised the number of lever presses in each session, slow wave sleep (SWS) duration, Rapid Eye Movement Sleep (REMS) duration and sleep spindles. Baseline sleep parameters were similar for fast and slow learning rats. Task-exposure increased REMS-duration. The increase in REMS-duration was observed specifically after sessions in which learning occurred, but not after a later session. Sleep deprivation during the 3h period between the initial two sessions interfered with performance enhancement, but did not prevent this in all rats. Our considered movement control protocol induced partial sleep deprivation and also interfered with performance enhancement. The classic instrumental learning task provides a practical model for animal studies on sleep-dependent memory enhancement.

Opposite effects of early maternal deprivation on neurogenesis in male versus female rats.

BACKGROUND: Major depression is more prevalent in women than in men. The underlying neurobiological mechanisms are not well understood, but recent data shows that hippocampal volume reductions in depressed women occur only when depression is preceded by an early life stressor. This underlines the potential importance of early life stress, at least in women, for the vulnerability to develop depression. Perinatal stress exposure in rodents affects critical periods of brain development that persistently alter structural, emotional and neuroendocrine parameters in adult offspring. Moreover, stress inhibits adult hippocampal neurogenesis, a form of structural plasticity that has been implicated a.o. in antidepressant action and is highly abundant early postnatally. We here tested the hypothesis that early life stress differentially affects hippocampal structural plasticity in female versus male offspring. PRINCIPAL FINDINGS: We show that 24 h of maternal deprivation (MD) at PND3 affects hippocampal structural plasticity at PND21 in a sex-dependent manner. Neurogenesis was significantly increased in male but decreased in female offspring after MD. Since no other structural changes were found in granule cell layer volume, newborn cell survival or proliferation rate, astrocyte number or gliogenesis, this indicates that MD elicits specific changes in subsets of differentiating cells and differentially affects immature neurons. The MD induced sex-specific effects on neurogenesis cannot be explained by differences in maternal care. CONCLUSIONS: Our data shows that early environment has a critical influence on establishing sex differences in neural plasticity and supports the concept that the setpoint for neurogenesis may be determined during perinatal life. It is tempting to speculate that a reduced level of neurogenesis, secondary to early stress exposure, may contribute to maladaptation of the HPA axis and possibly to the increased vulnerability of women to stress-related disorders.