Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.

BACKGROUND: Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children. METHODS: The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test. RESULTS: After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake. CONCLUSIONS: At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

Better quality of mother-child interaction at 4 years of age decreases emotional overeating in IUGR girls.

BACKGROUND/OBJECTIVES: While most "fetal programming" area focused on metabolic disease, intrauterine growth restriction (IUGR) is also associated with a preference for less healthy food. Post-natal factors such as strained maternal-child interactions are equally related to obesogenic eating behaviors. We investigated if IUGR and the quality of the mother/child relationship affect emotional overeating in children. SUBJECTS/METHODS: Participants were 196 children from a prospective birth cohort (the MAVAN project). As part of the protocol at 4 years of age, mothers completed the Children Eating Behavior Questionnaire (CEBQ) and mother-child interactions were scored during a structured task. A GLM adjusted for BMI examined the interaction between the "Atmosphere" score (ATM) task, sex and IUGR on the emotional over-eating domain of the CEBQ. RESULTS: There was a significant interaction of BWR vs. sex vs. ATM (P = .02), with no effects of IUGR, sex or ATM. The model was significant for girls with low ATM scores (B = -2.035, P = .014), but not for girls with high (P = 0.94) or boys with high (P = .27) or low (P = .19) ATM scores. Only in IUGR girls, 48 months emotional over-eating correlated with BMI at that age (r = 0.560, P = 0.013) and predicted BMI in the subsequent years (r = 0.654, P = 0.006 at 60 months and r = 0.750, P = 0.005 at 72 months). CONCLUSIONS: IUGR and exposure to a negative emotional atmosphere during maternal-child interactions predicted emotional overeating in girls but not in boys. The quality of mother-infant interaction may be an important target for interventions to prevent emotional overeating and overweight in early development, particularly in girls with a history of IUGR.

Variation in the mu-opioid receptor gene (OPRM1) moderates the influence of maternal sensitivity on child attachment.

The endogenous opioid system is thought to play an important role in mother-infant attachment. In infant rhesus macaques, variation in the µ-opioid receptor gene (OPRM1) is related to differences in attachment behavior that emerges following repeated separation from the mother; specifically, infants carrying at least one copy of the minor G allele of the OPRM1 C77G polymorphism show heightened and more persistent separation distress, as well as a pattern of increased contact-seeking behavior directed towards the mother during reunions (at the expense of affiliation with other group members). Research in adult humans has also linked the minor G allele of the analogous OPRM1 A118G polymorphism with greater interpersonal sensitivity. Adopting an interactionist approach, we examined whether OPRM1 A118G genotype and maternal (in)sensitivity are associated with child attachment style, predicting that children carrying the G allele may be more likely to develop an ambivalent attachment pattern in response to less sensitive maternal care. The sample consisted of 191 mothers participating with their children (n = 223) in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project, a community-based, birth cohort study of Canadian mothers and their children assessed longitudinally across the child's development. Maternal sensitivity was coded from at-home mother-child interactions videotaped when the child was 18 months of age. Child attachment was assessed at 36 months using the Strange Situation paradigm. As predicted, G allele carriers, but not AA homozygotes, showed increasing odds of being classified as ambivalently attached with decreasing levels of maternal sensitivity. Paralleling earlier non-human animal research, this work provides support for the theory that endogenous opioids contribute to the expression of attachment behaviors in humans.

Nature, nurture or nutrition? Impact of maternal nutrition on maternal care, offspring development and reproductive function.

We have previously reported that offspring of mothers fed a high fat (HF) diet during pregnancy and lactation enter puberty early and are hyperleptinaemic, hyperinsulinaemic and obese as adults. Poor maternal care and bonding can also impact offspring development and disease risk.We therefore hypothesized that prenatal nutrition would affect maternal care and that an interaction may exist between a maternal HF diet and maternal care, subsequently impacting on offspring phenotype.Wistar rats were mated and randomized to control dams fed a control diet (CON) or dams fed a HF diet from conception until the end of lactation (HF). Maternal care was assessed by observing maternal licking and grooming of pups between postnatal day (P)3 and P8. Postweaning (P22), offspring were fed a control (­con) or HF (­hf) diet. From P27, pubertal onset was assessed. At ∼P105 oestrous cyclicity was investigated. Maternal HF diet reduced maternal care; HF-fed mothers licked and groomed pups less than CON dams.Maternal fat:lean ratio was higher in HF dams at weaning and was associated with higher maternal plasma leptin and insulin concentrations, but there was no effect of maternal care on fat:lean ratio or maternal hormone levels. Both female and male offspring of HF dams were lighter from birth to P11 than offspring of CON dams, but by P19, HF offspring were heavier than controls. Prepubertal retroperitoneal fat mass was greater in pups from HF-fed dams compared to CON and was associated with elevated circulating leptin concentrations in females only, but there was neither an effect of maternal care, nor an interaction between maternal diet and care on prepubertal fat mass. Pups from HF-fed dams went into puberty early and this effect was exacerbated by a postweaning HF diet.Maternal and postweaning HF diets independently altered oestrous cyclicity in females: female offspring of HF-fed mothers were more likely to have prolonged or persistent oestrus, whilst female offspring fed a HF diet postweaning were more likely to have irregular oestrous cycles and were more likely to have prolonged or persistent oestrus. These data indicate that maternal HF nutrition during pregnancy and lactation results in a maternal obese phenotype and has significant impact on maternal care during lactation. Maternal and postweaning nutritional signals, independent of maternal care, alter offspring body fat pre-puberty and female reproductive function in adulthood, which may be associated with advanced ovarian ageing and altered fertility.

Specific and cumulative lifetime stressors in the aetiology of major depression: A longitudinal community-based population study.

AIMS: Early-life stressful circumstances (i.e. childhood maltreatment) coupled with stressful events later in life increase the likelihood of subsequent depression. However, very few studies have been conducted to examine the specific and cumulative effects of these stressors in the development of depression. There is also a paucity of research that simultaneously considers the role of biological factors combined with psychosocial stressors in the aetiology of depression. Guided by the biopsychosocial model proposed by Engel, the present study aims to examine to what extent the experience of stressors across the lifespan is associated with depression while taking into account the role of genetic predispositions. METHODS: Data analysed were from the Social and Psychiatric Epidemiology Catchment Area of the Southwest of Montreal (ZEPSOM), a large-scale, longitudinal community-based cohort study. A total of 1351 participants with complete information on the lifetime diagnoses of depression over a 10-year follow-up period were included in the study. Stressful events across the lifespan were operationalised as specific, cumulative and latent profiles of stressful experiences. Latent profile analysis (LPA) was used to explore the clustering of studied stressors including childhood maltreatment, poor parent-child relationship, and stressful life events. A polygenetic risk score was calculated for each participant to provide information on genetic liability. Multivariate logistic regression was used to examine the association between specific, cumulative and latent profiles of stressors and subsequent depression. RESULTS: We found that different subtypes of childhood maltreatment, child-parent bonding and stressful life events predicted subsequent depression. Furthermore, a significant association between combined effects of cumulative stressful experiences and depression was found [odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.12-1.28]. Three latent profiles of lifetime stressors were identified in the present study and named as 'low-level of stress' (75.1%), 'moderate-level of stress' (6.8%) and 'high-level of stress' (18.1%). Individuals with a 'high-level of stress' had a substantially higher risk of depression (OR = 1.80, 95% CI: 1.08-3.00) than the other two profiles after adjusting for genetic predispositions, socio-demographic characteristics, and health-related factors. CONCLUSIONS: While controlling for genetic predispositions, the present study provides robust evidence to support the independent and cumulative as well as compositional effects of early- and later-on lifetime psychosocial stressors in the subsequent development of depression. Consequently, mental illness prevention and mental health promotion should target the occurrence of stressful events as well as build resilience in people so they can better cope with stress when it inevitably occurs.

Income disparity in school readiness and the mediating role of perinatal maternal mental health: a longitudinal birth cohort study.

AIMS: There is compelling evidence for gradient effects of household income on school readiness. Potential mechanisms are described, yet the growth curve trajectory of maternal mental health in a child's early life has not been thoroughly investigated. We aimed to examine the relationships between household incomes, maternal mental health trajectories from antenatal to the postnatal period, and school readiness. METHODS: Prospective data from 505 mother-child dyads in a birth cohort in Singapore were used, including household income, repeated measures of maternal mental health from pregnancy to 2-years postpartum, and a range of child behavioural, socio-emotional and cognitive outcomes from 2 to 6 years of age. Antenatal mental health and its trajectory were tested as mediators in the latent growth curve models. RESULTS: Household income was a robust predictor of antenatal maternal mental health and all child outcomes. Between children from the bottom and top household income quartiles, four dimensions of school readiness skills differed by a range of 0.52 (95% Cl: 0.23, 0.67) to 1.21 s.d. (95% CI: 1.02, 1.40). Thirty-eight percent of pregnant mothers in this cohort were found to have perinatal depressive and anxiety symptoms in the subclinical and clinical ranges. Poorer school readiness skills were found in children of these mothers when compared to those of mothers with little or no symptoms. After adjustment of unmeasured confounding on the indirect effect, antenatal maternal mental health provided a robust mediating path between household income and multiple school readiness outcomes (χ2 126.05, df 63, p < 0.001; RMSEA = 0.031, CFI = 0.980, SRMR = 0.034). CONCLUSIONS: Pregnant mothers with mental health symptoms, particularly those from economically-challenged households, are potential targets for intervention to level the playing field of their children.

Nongenomic transmission across generations of maternal behavior and stress responses in the rat.

In the rat, variations in maternal care appear to influence the development of behavioral and endocrine responses to stress in the offspring. The results of cross-fostering studies reported here provide evidence for (i) a causal relationship between maternal behavior and stress reactivity in the offspring and (ii) the transmission of such individual differences in maternal behavior from one generation of females to the next. Moreover, an environmental manipulation imposed during early development that alters maternal behavior can then affect the pattern of transmission in subsequent generations. Taken together, these findings indicate that variations in maternal care can serve as the basis for a nongenomic behavioral transmission of individual differences in stress reactivity across generations.

Effect of neonatal handling on age-related impairments associated with the hippocampus.

In rats, an environmental manipulation occurring early in life resulted in changes in the adrenocortical axis that persisted throughout the entire life of the animals and attenuated certain deficits associated with aging. Rats handled during infancy had a permanent increase in concentrations of receptors for glucocorticoids in the hippocampus, a critical region in the negative-feedback inhibition of adrenocortical activity. Increased receptor concentrations led to greater hippocampal sensitivity to glucocorticoids and enhanced negative-feedback efficacy in the handled rats. Thus, at all ages tested, rats that were not handled secreted more glucocorticoids in response to stress than did handled rats. At later ages, nonhandled rats also showed elevated basal glucocorticoid levels, with the result that there was a greater cumulative exposure to glucocorticoids in nonhandled rats. Increased exposure to adrenal glucocorticoids can accelerate hippocampal neuron loss and cognitive impairments in aging. Hippocampal cell loss and pronounced spatial memory deficits emerged with age in the nonhandled rats, but were almost absent in the handled rats. Previous work showed that glucocorticoid hypersecretion, hippocampal neuron death, and cognitive impairments form a complex degenerative cascade of aging in the rat. The present study shows that a subtle manipulation early in life can retard the emergence of this cascade.

Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress.

Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r's > -0.6). These findings suggest that maternal behavior serves to "program" hypothalamic-pituitary-adrenal responses to stress in the offspring.

Maternal care, hippocampal synaptogenesis and cognitive development in rats.

We report that variations in maternal care in the rat promote hippocampal synaptogenesis and spatial learning and memory through systems known to mediate experience-dependent neural development. Thus, the offspring of mothers that show high levels of pup licking and grooming and arched-back nursing showed increased expression of NMDA receptor subunit and brain-derived neurotrophic factor (BDNF) mRNA, increased cholinergic innervation of the hippocampus and enhanced spatial learning and memory. A cross-fostering study provided evidence for a direct relationship between maternal behavior and hippocampal development, although not all neonates were equally sensitive to variations in maternal care.

Cortisol levels during human aging predict hippocampal atrophy and memory deficits.

Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.

BECon: a tool for interpreting DNA methylation findings from blood in the context of brain.

Tissue differences are one of the largest contributors to variability in the human DNA methylome. Despite the tissue-specific nature of DNA methylation, the inaccessibility of human brain samples necessitates the frequent use of surrogate tissues such as blood, in studies of associations between DNA methylation and brain function and health. Results from studies of surrogate tissues in humans are difficult to interpret in this context, as the connection between blood-brain DNA methylation is tenuous and not well-documented. Here, we aimed to provide a resource to the community to aid interpretation of blood-based DNA methylation results in the context of brain tissue. We used paired samples from 16 individuals from three brain regions and whole blood, run on the Illumina 450 K Human Methylation Array to quantify the concordance of DNA methylation between tissues. From these data, we have made available metrics on: the variability of cytosine-phosphate-guanine dinucleotides (CpGs) in our blood and brain samples, the concordance of CpGs between blood and brain, and estimations of how strongly a CpG is affected by cell composition in both blood and brain through the web application BECon (Blood-Brain Epigenetic Concordance; https://redgar598.shinyapps.io/BECon/). We anticipate that BECon will enable biological interpretation of blood-based human DNA methylation results, in the context of brain.

Infant frontal EEG asymmetry in relation with postnatal maternal depression and parenting behavior.

Right frontal electroencephalogram (EEG) asymmetry associates with negative affect and depressed mood, which, among children, are predicted by maternal depression and poor parenting. This study examined associations of maternal depression and maternal sensitivity with infant frontal EEG asymmetry based on 111 mother-6-month-infant dyads. There were no significant effects of postnatal maternal depression or maternal sensitivity, or their interaction, on infant EEG frontal asymmetry. However, in a subsample for which the infant spent at least 50% of his/her day time hours with his/her mother, both lower maternal sensitivity and higher maternal depression predicted greater relative right frontal EEG asymmetry. Our study further showed that greater relative right frontal EEG asymmetry of 6-month-old infants predicted their greater negative emotionality at 12 months of age. Our study suggested that among infants with sufficient postnatal maternal exposure, both maternal sensitivity and mental health are important influences on early brain development.

Influences of prenatal and postnatal maternal depression on amygdala volume and microstructure in young children.

Maternal depressive symptoms influence neurodevelopment in the offspring. Such effects may appear to be gender-dependent. The present study examined contributions of prenatal and postnatal maternal depressive symptoms to the volume and microstructure of the amygdala in 4.5-year-old boys and girls. Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) at 26 weeks of gestation. Postnatal maternal depression was assessed at 3 months using the EPDS and at 1, 2, 3 and 4.5 years using the Beck's Depression Inventory-II. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 4.5-year-old children to extract the volume and fractional anisotropy (FA) values of the amygdala. Our results showed that greater prenatal maternal depressive symptoms were associated with larger right amygdala volume in girls, but not in boys. Increased postnatal maternal depressive symptoms were associated with higher right amygdala FA in the overall sample and girls, but not in boys. These results support the role of variation in right amygdala structure in transmission of maternal depression to the offspring, particularly to girls. The differential effects of prenatal and postnatal maternal depressive symptoms on the volume and FA of the right amygdala suggest the importance of the timing of exposure to maternal depressive symptoms in brain development of girls. This further underscores the need for intervention targeting both prenatal and postnatal maternal depression to girls in preventing adverse child outcomes.

Does the maternal vaginal microbiota play a role in seeding the microbiota of neonatal gut and nose?

The acquisition and early maturation of infant microbiota is not well understood despite its likely influence on later health. We investigated the contribution of the maternal microbiota to the microbiota of infant gut and nose in the context of mode of delivery and feeding. Using 16S rRNA sequencing and specific qPCR, we profiled microbiota of 42 mother-infant pairs from the GUSTO birth cohort, at body sites including maternal vagina, rectum and skin; and infant stool and nose. In our study, overlap between maternal vaginal microbiota and infant faecal microbiota was minimal, while the similarity between maternal rectal microbiota and infant microbiota was more pronounced. However, an infant's nasal and gut microbiota were no more similar to that of its own mother, than to that of unrelated mothers. These findings were independent of delivery mode. We conclude that the transfer of maternal vaginal microbes play a minor role in seeding infant stool microbiota. Transfer of maternal rectal microbiota could play a larger role in seeding infant stool microbiota, but approaches other than the generally used analyses of community similarity measures are likely to be needed to quantify bacterial transmission. We confirmed the clear difference between microbiota of infants born by Caesarean section compared to vaginally delivered infants and the impact of feeding mode on infant gut microbiota. Only vaginally delivered, fully breastfed infants had gut microbiota dominated by Bifidobacteria. Our data suggest that reduced transfer of maternal vaginal microbial is not the main mechanism underlying the differential infant microbiota composition associated with Caesarean delivery. The sources of a large proportion of infant microbiota could not be identified in maternal microbiota, and the sources of seeding of infant gut and nasal microbiota remain to be elucidated.

Influence of naturally occurring variations in maternal care on prepulse inhibition of acoustic startle and the medial prefrontal cortical dopamine response to stress in adult rats.

In rats, naturally occurring variations in maternal care contribute to the development of individual differences in the behavioral and neuroendocrine responses to stress during adulthood. The dopamine (DA) projection to the medial prefrontal cortex (mPFC) plays an important role in mediating stress responsivity and is thought to be involved also in regulating sensorimotor gating. In the present study, we compared prepulse inhibition (PPI) of acoustic startle as well as the left and right mPFC DA stress responses in the adult offspring of high- and low-licking/grooming (LG) dams. Our data indicate that the offspring of low-LG animals are impaired on measures of PPI compared with high-LG animals. We also observed in low-LG animals a significant blunting of the mPFC DA stress responses that was lateralized to the right hemisphere, whereas in high-LG animals, the left and right mPFC DA stress responses were equally attenuated. Although mPFC levels of DA transporter did not differ between the two groups of animals, mPFC levels of catechol-O-methyl transferase immunoreactivity of low-LG animals were significantly lower than those of high-LG animals. These data provide evidence that variations in maternal care can lead to lasting changes in mPFC DA responsivity to stress and suggest the possibility that such changes in mesocorticolimbic DA function can also lead to deficits in sensorimotor gating.

Maternal care and the development of stress responses.

Studies dating from the 1950s have documented the impact of early life events on the development of behavioral and endocrine responses to stress. Recent findings suggest that these effects are mediated through changes in mother-offspring interactions and have identified central corticotropin-releasing factor systems as a critical target for the effects of variations in maternal care.

Neurotensin receptor levels as a function of brain aging and cognitive performance in the Morris water maze task in the rat.

The present study evaluated whether neurotensin (NT) binding sites were altered in the aged rat brain and if these alterations were related to the cognitive status of the animal. Aged (24-25 months old) Long-Evans rats were behaviorally screened using the Morris water maze task and were classified as either aged, cognitively impaired (AI) or cognitively unimpaired (AU) based on their relative performances in the task compared to young control (Y) animals. Decreases in specific [125I]NT binding were observed in the hippocampal formation, namely the dentate gyrus (DG), as well as in the septum and hypothalamus. Both aged groups also showed significant reductions in specific [125I]NT binding levels compared to the Y animals in the hippocampal CA3 sub-field, with the AI animals exhibiting the lowest levels. In the Substantia Nigra Zona Compacta (SNc) and the ventral tegmental area (VTA), specific [125I]NT binding was decreased as a function of age while binding in the paraventricular nucleus of the hypothalamus (PVNh) was decreased as a function of age and cognitive status. These alterations in the level of specific [125I] NT binding in the aged animals suggest decreases in NT receptor signaling as a function of age and potential involvement of NT-ergic systems in the etiology of age-related cognitive deficits.

Low birth weight associates with hippocampal gene expression.

Birth weight predicts the lifetime risk for psychopathology suggesting that the quality of fetal development influences the predisposition for mental disorders. The connectivity and synaptic network of the hippocampus are implicated in depression, schizophrenia and anxiety. We thus examined the underlying molecular adaptations in the hippocampus as a function of the fetal conditions associated with low birth weight. We used tissues from the non-human primate, Macaca fascicularis, to identify changes in hippocampal gene expression early in postnatal development associated with naturally occurring low compared with normal birth weight. Microarrays were used to analyze gene expression and DNA methylation in the hippocampus of five low- and five normal-birth weight neonates. Real-time PCR was employed to validate differentially expressed genes. Birth weight associated with altered global transcription in the hippocampus. Hierarchical clustering of gene expression profiles from 24,154 probe sets grouped all samples except one by their birth weight status. Differentially expressed genes were enriched in biological processes associated with neuronal projection, positive regulation of transcription and apoptosis. About 4% of the genes with differential expression co-varied with DNA methylation levels. The data suggest that low birth weight is closely associated with hippocampal gene expression with a small epigenetic underpinning by DNA methylation in neonates. The data also provide a potential molecular basis for the developmental origin of an enhanced risk for mental disorders.

Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin.

Postnatal handling increases glucocorticoid receptor expression in the rat hippocampus, thus altering the regulation of hypothalamic synthesis of corticotropin-releasing hormone and the hypothalamic-pituitary-adrenal response to stress. The effect on glucocorticoid receptor gene expression represents one mechanism by which the early environment can exert a long-term effect on neural development. The handling effect on hippocampal glucocorticoid receptor expression is dependent on peripheral thyroid hormone release and the activation of ascending serotonergic pathways. In primary hippocampal cell cultures, serotonin (5-HT) increases glucocorticoid receptor expression, and this effect appears to be mediated by increased cAMP levels. In the current studies we examined the in vivo effects of handling on hippocampal cAMP-protein kinase A (PKA) activity. In 7-d-old rat pups, we found that (1) postnatal handling increased adenylyl cyclase activity and hippocampal cAMP levels, (2) the effect of handling on cAMP levels was completely blocked by treatment with either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or the 5-HT receptor antagonist, ketanserin, and (3) handling also increased hippocampal PKA activity. We then examined the effects of handling on cAMP-inducible transcription factors. Handling rapidly increased levels of the mRNAs for nerve growth factor-inducible factor A (NGFI-A) (zif268, krox24) and activator protein-2 (AP-2) as well as for NGFI-A and AP-2 immunoreactivity throughout the hippocampus. Finally, we found that the effects of handling on NGFI-A and AP-2 expression were significantly reduced by concurrent treatment with either PTU or ketanserin, effects that paralleled those on cAMP formation. NGFI-A and AP-2 have been implicated in the regulation of glucocorticoid receptor expression during development. Thus, these findings suggest that postnatal handling might alter glucocorticoid receptor gene expression via cAMP-PKA pathways involving the activation of NGFI-A and AP-2.