Cellular mechanisms underlying the effects of an early experience on cognitive abilities and affective states

In the present study we investigated the effects of neonatal handling, an animal model of early experience, on spatial learning and memory, on hippocampal glucocorticoid (GR), mineralocorticoid (MR) and type 1A serotonin (5-HT1A) receptors, as well as brain derived neurotrophic factor (BDNF), and on circulating leptin levels, of male rats. METHOD: Spatial learning and memory following an acute restraint stress (30 min) were assessed in the Morris water maze. Hippocampal GR, MR and BDNF levels were determined immunocytochemically. 5-HT1A receptors were quantified by in vitro binding autoradiography. Circulating leptin levels, following a chronic forced swimming stress, were measured by radioimmunoassay (RIA). Data were statistically analyzed by analysis of variance (ANOVA). RESULTS: Neonatal handling increased the ability of male rats for spatial learning and memory. It also resulted in increased GR/MR ratio, BDNF and 5-HT1A receptor levels in the hippocampus. Furthermore, leptin levels, body weight and food consumption during chronic forced swimming stress were reduced as a result of handling. CONCLUSION: Neonatal handling is shown to have a beneficial effect in the males, improving their cognitive abilities. This effect on behavior could be mediated by the handling-induced increase in hippocampal GR/MR ratio and BDNF levels. The handling-induced changes in BDNF and 5-HT1A receptors could underlie the previously documented effect of handling in preventing "depression". Furthermore, handling is shown to prevent other maladaptive states such as stress-induced hyperphagia, obesity and resistance to leptin

Increased Anxiety-Related Behavior, Impaired Cognitive Function and Cellular Alterations in the Brain of Cend1-deficient Mice

Cend1 is a neuronal-lineage specific modulator involved in coordination of cell cycle exit and differentiation of neuronal precursors. We have previously shown that Cend1−/− mice show altered cerebellar layering caused by increased proliferation of granule cell precursors, delayed radial granule cell migration and compromised Purkinje cell differentiation, leading to ataxic gait and deficits in motor coordination. To further characterize the effects of Cend1 genetic ablation we determined herein a range of behaviors, including anxiety and exploratory behavior in the elevated plus maze (EPM), associative learning in fear conditioning, and spatial learning and memory in the Morris water maze (MWM). We observed significant deficits in all tests, suggesting structural and/or functional alterations in brain regions such as the cortex, amygdala and the hippocampus. In agreement with these findings, immunohistochemistry revealed reduced numbers of γ amino butyric acid (GABA) GABAergic interneurons, but not of glutamatergic projection neurons, in the adult cerebral cortex. Reduced GABAergic interneurons were also observed in the amygdala, most notably in the basolateral nucleus. The paucity in GABAergic interneurons in adult Cend1−/− mice correlated with increased proliferation and apoptosis as well as reduced migration of neuronal progenitors from the embryonic medial ganglionic eminence (MGE), the origin of these cells. Further we noted reduced GABAergic neurons and aberrant neurogenesis in the adult dentate gyrus (DG) of the hippocampus, which has been previously shown to confer spatial learning and memory deficits. Our data highlight the necessity of Cend1 expression in the formation of a structurally and functionally normal brain phenotype

Denial of Reward in the Neonate Shapes Sociability and Serotonergic Activity in the Adult Rat

BACKGROUND: Manipulations of the early environment are linked to long-lasting alterations of emotionality and social capabilities. Denial of rewarding mother-pup interactions in early life of rats could serve as model for child neglect. Negative consequences for social competence in later life, accompanied by changes in the serotonergic system would be expected. In contrast, rewarding mother-pup contact should promote adequate social abilities. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats trained in a T-maze during postnatal days 10-13 under denial (DER) or permission (RER) of maternal contact were tested for play behavior in adolescence and for coping with defeat in adulthood. We estimated serotonin (5-HT) levels in the brain under basal conditions and following defeat, as well as serotonin receptor 1A (5-HT1A) and serotonin transporter (SERT) expression. DER rats exhibited increased aggressive-like play behavior in adolescence (i.e. increased nape attacks, p<0.0001) and selected a proactive coping style during defeat in adulthood (higher sum of proactive behaviors: number of attacks, flights, rearings and defensive upright posture; p = 0.011, p<0.05 vs RER, non-handled-NH). In adulthood, they had lower 5-HT levels in both the prefrontal cortex (p<0.05 vs RER) and the amygdala (p<0.05 vs NH), increased 5-HT levels following defeat (PFC p<0.0001) and decreased serotonin turnover (amygdala p = 0.008). The number of 5-HT1A immunopositive cells in the CA1 hippocampal area was increased (p<0.05 DER, vs RER, NH); SERT levels in the amygdala were elevated (p<0.05 vs RER, NH), but were lower in the prefrontal cortex (p<0.05 vs NH). CONCLUSIONS/SIGNIFICANCE: Denial of expected maternal reward early in life negatively affects sociability and the serotonergic system in a complex manner. We propose that our animal model could contribute to the identification of the neurobiological correlates of early neglect effects on social behavior and coping with challenges, but also in parallel with the effects of a rewarding early-life environment

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

Sleep is an essential ubiquitous biological process, a periodical state of quiescence in which there is minimal processing of sensory information and no interaction with conspecifics or the environment. Despite relevant research on sleep structure and testing of numerous endogenous sleep-affecting chemicals, questions as to the precise mechanisms and functions of sleep remain without satisfactory responses. The purpose of this review is to report on current evidence as regards the effect of several endogenous and exogenous hormones, hormonal agents, and neuropeptides on sleep onset or wake process, when administered in humans in specific doses and via different routes. The actions of several peptides are presented in detail. Some of them (growth hormone releasing hormone, ghrelin, galanin, neuropeptide Y) seem to promote sleep, whereas others (corticotropin, somatostatin) impair its continuity

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

Sleep is an essential ubiquitous biological process, a periodical state of quiescence in which there is minimal processing of sensory information and no interaction with conspecifics or the environment. Despite relevant research on sleep structure and testing of numerous endogenous sleep-affecting chemicals, questions as to the precise mechanisms and functions of sleep remain without satisfactory responses. The purpose of this review is to report on current evidence as regards the effect of several endogenous and exogenous hormones, hormonal agents, and neuropeptides on sleep onset or wake process, when administered in humans in specific doses and via different routes. The actions of several peptides are presented in detail. Some of them (growth hormone releasing hormone, ghrelin, galanin, neuropeptide Y) seem to promote sleep, whereas others (corticotropin, somatostatin) impair its continuity

Effects of an early experience of reward through maternal contact or its denial on laterality of protein expression in the developing rat hippocampus.

Laterality is a basic characteristic of the brain which is detectable early in life. Although early experiences affect laterality of the mature brain, there are no reports on their immediate neurochemical effects during neonatal life, which could provide evidence as to the mechanisms leading to the lateralized brain. In order to address this issue, we determined the differential protein expression profile of the left and right hippocampus of 13-day-old rat control (CTR) pups, as well as following exposure to an early experience involving either receipt (RER) or denial (DER) of the expected reward of maternal contact. Proteomic analysis was performed by 2-dimensional polyacrylamide gel electrophoresis (PAGE) followed by mass spectroscopy. The majority of proteins found to be differentially expressed either between the three experimental groups (DER, RER, CTR) or between the left and right hemisphere were cytoskeletal (34%), enzymes of energy metabolism (32%), and heat shock proteins (17%). In all three groups more proteins were up-regulated in the left compared to the right hippocampus. Tubulins were found to be most often up-regulated, always in the left hippocampus. The differential expression of β-tubulin, β-actin, dihydropyrimidinase like protein 1, glial fibrillary acidic protein (GFAP) and Heat Shock protein 70 revealed by the proteomic analysis was in general confirmed by Western blots. Exposure to the early experience affected brain asymmetry: In the RER pups the ratio of proteins up-regulated in the left hippocampus to those in the right was 1.8, while the respective ratio was 3.6 in the CTR and 3.4 in the DER. Our results could contribute to the elucidation of the cellular mechanisms mediating the effects of early experiences on the vulnerability for psychopathology, since proteins shown in our study to be differentially expressed (e.g. tubulins, dihydropyrimidinase like proteins, 14-3-3 protein, GFAP, ATP synthase, α-internexin) have also been identified in proteomic analyses of post-mortem brains from psychiatric patients

Effect of different early life experiences on basal and stress induced (resident-intruder test) levels of serotonin (5HT) and the ratio, 5-hydroxyindoleacetic acid (5-HIAA)/5-HT, as a measure of serotonin turnover in the prefrontal cortex (A) and amygdala (B).

<p>Bars represent means ± S.E.M of amount of monoamines (ng) per mg of tissue. Post-hoc tests on two-way ANOVA, #, p<0.05 DER, RER≠NH at basal condition; *, p<0.05, RER≠DER, post-hoc, §, p<0.05, Basal≠Resident-Intruder, one-way ANOVA.</p

Effect of different early life experience (DER vs RER) in comparison to no experience (NH) during the neonatal period on play-fighting behavior in adolescence.

<p>Data in the left part of the graph are means ± S.E.M. of number of nape attacks, pinning and supine behaviors and on the right means ± S.E.M. of duration of general exploration during the 10 min of interaction. #, p<0.05, DER,RER≠NH; *, p<0.05, RER≠DER, post-hoc, one-way ANOVA.</p