Neonatal Handling Research Articles

Early environments, glucocorticoid receptors, and behavioral epigenetics.

In 1985, a brief report published in Behavioral Neuroscience established the link between neonatal handling and concentrations of hippocampal glucocorticoid receptors (GR) in the adult rat, suggesting a neurobiological basis for the attenuated stress reactivity observed in handled versus nonhandled offspring. To celebrate the 30th anniversary of Behavioral Neuroscience, this article explores the research that preceded and followed from this brief but significant publication. Changes in hippocampal GR induced by handling were determined to be the outcome of a cascade of cellular and molecular events involving thyroid hormones, serotonin turnover, and transcription factor binding to the Nr3c1 gene, leading to increased GR mRNA and protein. Though many hypotheses were proposed for the "handling effect," the role of handling-induced changes in maternal care, particularly pup licking/grooming (LG), generated a productive scientific framework for understanding the handling phenomenon. Indeed, LG has since been demonstrated to alter GR levels through the signaling pathways described for handling. Moreover, epigenetic mechanisms have been discovered to play a critical role in the effects of early life experience and particularly in the regulation of Nr3c1. Overall, the research avenues that have evolved from the initial finding of handling-induced changes in GR have broad applications to our understanding of plasticity, resilience, and the transmission of traits across generations.

Neonatal handling prevents anxiety-like symptoms in rats exposed to chronic mild stress: Behavioral and oxidative parameters

This study investigated the influence of neonatal handling on behavioral and biochemical consequences of chronic mild stress (CMS) in adulthood. Male rat pups were submitted to daily tactile stimulation (TS) or maternal separation (MS), from postnatal day 1 (PND1) to postnatal day 21 (PND21), for 10 min/day. In adulthood, half the number of animals were exposed to CMS for 3 weeks and submitted to behavioral testing, including sucrose preference (SP), elevated plus maze (EPM), and defensive burying tasks (DBTs), followed by biochemical assessments. CMS reduced SP, increased anxiety in EPM and DBT, and increased adrenal weight. In addition, CMS decreased plasma vitamin C (VIT C) levels and increased protein carbonyl (PC) levels, catalase (CAT) activity in hippocampus and cortex, and superoxide dismutase (SOD) levels in cortex. In contrast, both forms of neonatal handling were able to prevent reduction in SP, anxiety behavior in DBT, and CMS-induced adrenal weight increase. Furthermore, they were also able to prevent plasma VIT C reduction, hippocampal PC levels increase, CAT activity increase in hippocampus and cortex, and SOD levels increase in cortex following CMS. Only TS was able to prevent CMS-induced anxiety symptoms in EPM and PC levels in cortex. Taken together, these findings show the protective role of neonatal handling, especially TS, which may enhance ability to cope with stressful situations in adulthood.

Early handling modulates outcome of neonatal dexamethasone exposure

Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1–21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1–3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype.

Neonatal handling induces deficits in infant mother preference and adult partner preference

Neonatal handling is an experimental procedure used to understand how early-life adversity can negatively affect neurobehavioral development and place animals on a pathway to pathology. Decreased preference for the maternal odor during infancy is one of many behavioral deficits induced by neonatal handling. Here, we hypothesize that deficits in maternal odor preference may interfere with partner preference in the adult. To test this hypothesis, we assessed infant maternal odor preference and adult partner preference in different reproductive stages in both male and female rats that received neonatal handling. Our results indicate that only neonatally handled females present deficits in maternal odor preference during infancy, but both male and females present deficits in adult partner preference. However, sexual experience was effective in rescuing partner preference deficits in males. These results indicate that, considering infant and adult social interactions, females are more susceptible to the effects of neonatal handling than males.

Neonatal handling and environmental enrichment increase the expression of GAP-43 in the hippocampus and promote cognitive abilities in prenatally stressed rat offspring

Neonatal handling and environmental enrichment have been used to aid the treatment and recovery of a diverse variety of brain dysfunctions. However, the underlying mechanism and the effects on cognitive function following neonatal handling and environmental enrichment are still unclear. In this study, we investigated GAP-43 protein levels in the hippocampus of prenatally stressed rat pups by Western blot on postnatal day (P) 10, P20 and P45. The cognitive ability of prenatally stressed rat pups was tested by using the Morris water maze on P45. GAP-43 protein levels were upregulated on P10 in the prenatal restraint stress (RS) group and the prenatal restraint stress plus neonatal handling and environmental enrichment (RE) group compared to the negative control (NC) group. However, the expression of GAP-43 in RS pups was lower on P20 and P45 than that in NC and RE pups. Exposure to prenatal stress prolonged average latency and total swim distance, but neonatal handling and environmental enrichment could reverse the change. Differences were also observed in the selection of search strategies. These results indicate that neonatal handling and environmental enrichment can improve the spatial learning and memory ability of prenatally stressed offspring, and the possible mechanism is the upregulation of GAP-43.

The Influence of Early Life Interventions on Olfactory Memory Related to Palatable Food, and on Oxidative Stress Parameters and Na+/K+-ATPase Activity in the Hippocampus and Olfactory Bulb of Female Adult Rats

The effects of neonatal handling and the absence of ovarian hormones on the olfactory memory related to a palatable food in adulthood were investigated. Oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of adult pre-puberty ovariectomized female rats handled or not in the neonatal period were also evaluated. Litters were non-handled or handled (10 min/day, days 1-10 after birth). Females from each litter were divided into: OVX (subjected to ovariectomy), sham, and intact. When adults, olfactory memory related to a palatable food (chocolate) was evaluate using the hole-board olfactory task. Additionally, oxidative stress parameters and Na+/K+-ATPase activity were measured in the hippocampus and olfactory bulb. No difference between groups was observed considering olfactory memory evaluation. Neonatal handled rats presented an increase in Na+/K+-ATPase activity in the hippocampus and in the olfactory bulb, compared to non-handled ones. Considering the surgical procedure, there was a decrease in Na+/K+-ATPase and catalase activities in sham and OVX groups, compared to intact animals in the olfactory bulb. We concluded that olfactory memory related to a palatable food in adulthood was not affected by neonatal handling or by pre-puberty surgery, with or without removal of ovaries. The difference observed between groups in catalase and Na+/K+-ATPase activity does not seem to be related to the olfactory memory. Additionally, the increase in Na+/K+-ATPase activity (an enzyme that maintains the neurochemical gradient necessary for neuronal excitability) induced by neonatal handling may be related to neuroplastic changes in the hippocampus and olfactory bulb.

Effects of early life interventions and palatable diet on anxiety and on oxidative stress in young rats

Early life events can change biochemical, endocrine and behavioral aspects throughout the life of an animal. Since there is a strong relationship between stress, neonatal handling and feeding behavior, the aim of this study was to investigate the effects of these three factors on behavioral parameters (anxiety and locomotion), oxidative stress in brain structures (prefrontal cortex and hippocampus) and on plasma glucose. Nests of Wistar rats were handled (10min/day), or not (control groups), on days 1–10 after birth. Males from these groups were divided into 4 subgroups: 1) stressed by isolation in childhood (pre-puberty) and with access to a highly palatable diet 2) stressed by isolation and receiving standard lab chow 3) not isolated and receiving a highly palatable diet and 4) not isolated and receiving standard chow. The animals were kept under these conditions for 7days. Rats receiving the highly palatable diet consumed more food, more calories, gained more weight and had a higher plasma glucose level, but had a lower caloric efficiency than the standard chow groups. Both handling and palatable diet were able to increase food consumption on the first day of isolation. Isolation stress had an anxiogenic effect in the plus maze, which was counteracted by handling. Palatable diet increased time spent in the central area of the open field apparatus and in the open arms of the elevated plus maze, showing an anxiolytic effect. The use of both these conditions, however, does not appear to bring additional protection against the effects of stress during this particular period of life, i.e. pre-puberty. In the prefrontal cortex, handling reduced thiol content and appears to imbalance the antioxidant enzymes system, which is counteracted by a palatable diet. Hippocampus seems to be more sensitive than the prefrontal cortex to early interventions, especially to the highly palatable diet, and both handling and diet appear to imbalance the antioxidant enzyme system. Thus, measurements of antioxidant enzymes activities indicate that handling may endanger some brain structures and that the palatable diet was able to prevent some handling effects on antioxidant enzymes, depending on the brain structure.

Neonatal handling affects learning, reversal learning and antioxidant enzymes activities in a sex-specific manner in rats

Early life experiences have profound influences on behavior and neurochemical parameters in adult life. The aim of this study is to verify neonatal handling-induced sex specific differences on learning and reversal learning as well as oxidative stress parameters in the prefrontal cortex and striatum of adult rats. Litters of rats were non-handled or handled (10min/day, days 1–10 after birth). In adulthood, learning and reversal learning were evaluated using a Y maze associated with palatable food in male and female rats. Morris water maze reversal learning was verified in males. Oxidative stress parameters were evaluated in both genders. Male neonatal handled animals had a worse performance in the Y maze reversal learning compared to non-handled ones and no difference was observed in the water maze reversal learning task. Regarding females, neonatal handled rats had a better performance during the Y maze learning phase compared to non-handled ones. In addition, neonatal handled female animals showed a decreased SOD/CAT ratio in the PFC compared to non-handled females. We conclude that neonatal handling effects on learning and memory in adult rats are sex and task specific. The sex specific differences are also observed in the evaluation of antioxidant enzymes activities with neonatal handling affecting only females.

Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.

Early-life environmental intervention may increase the number of neurons, astrocytes, and cellular proliferation in the hippocampus of rats

Neonatal handling reduces the stress response in adulthood due to a feedback mechanism. The present study analyzed the effects of repeated neonatal environmental intervention (daily handling during the first 10 days after birth) on neuron-, astroglial cell density, and cellular proliferation of the hippocampal (CA1, CA2, and CA3) pyramidal cell layers in female rats. Pups were divided into two groups, nonhandled and handled, which were submitted to repeated handling sessions between postnatal days 1 and 10. Histological and immunohistochemical procedures were used to determine changes in neuron density, astroglial cell density, and cellular proliferation. We found an increase in neuron density in each pyramidal cell layer of the hippocampus (CA1, CA2, and CA3) in female rats (11 and 90 day old) that were handled during the neonatal period. Furthermore, we found an increase in astroglial cell density in both hemispheres of the brain in the handled group. Finally, we observed an increase in cellular proliferation in both hippocampi (CA1, CA2, and CA3) of the brain in female pups (11 days old) handled during the neonatal period. This study demonstrates that an early-life environmental intervention may induce morphological changes in a structure involved with several functions, including the stress response. The results of the current study suggest that neonatal handling may influence the animals' responses to environmental adversities later in life.

Dissociation between neonatal novelty-induced preferential maternal care and enhancement in cognitive, social, and emotional functions

Early life stimulation is known to produce long-lasting changes in the brain and behavior. One such early stimulation method is the neonatal novelty exposure procedure which allows the isolation of the novelty effect from several prominent confounding factors inherent to the neonatal handling procedure. In two previous studies, we found long-lasting novelty effects on different sets of functional measures without accompanying preferential maternal care, even when the observation was made immediately after the novelty manipulation, a time when such preferential care is most likely to be expressed. Here, within a single cohort of Long-Evans male rats, we demonstrate that novelty exposure leads to enhancements across several functional domains, including increased disinhibition to novelty, enhanced spatial and social memory, and reduced aggression, again without the accompaniment of preferential maternal care. These findings extend novelty exposure effects to aggression and replicate previously known novelty exposure effects on spatial and social memory with extension to new developmental stages. Most importantly, these findings do not support the hypothesis that preferential maternal care towards novelty-exposed pups mediates the observed novelty effects. We discuss the possibility that the effects of neonatal novelty exposure are mediated via repeated activation of the hypothalamic–pituitary–adrenal (HPA) axis that serves to inoculate pups for future exposures to novelty and novelty-induced HPA activation and that maternal influence is likely to be expressed via its modulatory role—the mother sets the individual-family specific behavioral and hormonal context to allow the same early life experience to have a family-specific effect.

Neonatal Handling Impairs Spatial Memory and Leads to Altered Nitric Oxide Production and DNA Breaks in A Sex Specific Manner

Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, antioxidant enzymatic activities and DNA breaks in the hippocampus of male and female adult rats. Litters of rats were non-handled or handled (10 min/day, days 1-10 after birth). In adulthood they were subjected to a Morris water maze or used for biochemical evaluations. Female handled rats showed impairment in spatial learning. They also showed decreased NO production, while no effects were observed in these parameters in male rats. No effects were observed on the number of hippocampal NADPH diaphorase positive cells. In the Comet Assay, male handled rats showed increased DNA breaks index when compared to non-handled ones. We conclude that neonatal handling impairs learning performance in a sex-specific manner, what may be related to NO decreased levels.

Interventions in the neonatal environment in rats and their relationship to behavior in adulthood and maternal behavior.

objective of this study was to assess the role of environmental/nest components and maternal behavior after several neonatal interventions on subsequent behavioral responses. Male Wistar rats were subjected to different neonatal interventions and were later evaluated for innate fear-like behavior in adulthood. The experimental groups included nonhandled (i.e., animals were not touched), handled (i.e., animals were separated from their mother, removed from the nest, and handled for 10 min/day), brief maternal separation (i.e., the mother was removed from the homecage for 10 min/day, and the pups remained in their cages without being touched), and tactile stimulation (i.e., the mother was removed from the homecage, and pups were stimulated with a brush for 10 min/day within the nest). The mother's behavior was recorded during the neonatal period, and the male pups were later tested in the open field as adults. The results revealed that only mothers whose pups were handled had an increase in the duration of licking behavior compared with the other groups. In the open field test, we observed decreased behavioral innate fear-like responses in male adults in the handled and brief separation groups compared with the others groups. Our results confirm that interventions during the neonatal period cause stable behavioral changes (decreased innate fear) in adulthood and that absent or excessive tactile stimulation appears to be an important factor. Both repeated disruption of the mother-infant relationship and withdrawal from the environment/nest are factors that exert profound effects on the development of the animals. Keywords: brief separation, neonatal handling, tactile stimulation, innate fear, rats.

Effects of a chronic exposure to a highly palatable diet and its withdrawal, in adulthood, on cerebral Na+,K+-ATPase and plasma S100B in neonatally handled rats

We have previously demonstrated that early environment influences the metabolic response, affecting abdominal fat deposition in adult female rats exposed to a long-term highly caloric diet. In the present study, our goal was to verify the effects of the chronic exposure, in adulthood, to a highly palatable diet (chocolate) on cerebral Na+,K+-ATPase activity and S100B protein concentrations, and the response to its withdrawal in neonatally handled and non-handled rats. We measured the consumption of foods (standard lab chow and chocolate), body weight gain, S100B protein concentrations, as well as cerebral Na+,K+-ATPase activity during chronic exposure and after chocolate withdrawal in adult female rats that had been exposed or not to neonatal handling (10min/day, 10 first days of life). Non-handled rats chronically exposed to chocolate exhibited increased plasma S100B levels, but there was no difference in abdominal fat S100B concentration between groups. Chronic chocolate consumption decreased Na+,K+-ATPase activity in both amygdala and hippocampus in non-handled, but not in handled rats, and this effect disappeared after chocolate withdrawal. Non-handled animals also demonstrated increased frequency of head shaking in the open field after 24h of chocolate withdrawal in comparison to handled ones. These findings suggest that neonatal handling modifies the vulnerability to metabolic and brain alterations induced by chronic exposure to a highly palatable diet in adulthood.

Effects of neonatal handling on playfulness by means of reversal of the desire to play in rats (Rattus norvegicus).

In the present study the authors sought to establish whether the range of effects of neonatal handling stimulation (H), that is, brief daily periods of infant isolation, could be extended to the domain of social motivation. With this aim, the authors studied the innate motivation to engage in rough-and-tumble play (R&T) in adolescent rats (Rattus norvegicus) by means of a reversal design, in which half of the rats were first housed in isolation (Days 1-3), and then in company (Days 4-6), while the other half followed the reverse sequence of housing conditions. Results showed in a clear-cut manner that H fuelled playfulness, as measured by pin and dorsal contact episodes, with (relative) independence of trait-based differences in fearful behavior between handled and nonhandled rats. Given that the different levels of the rat's social brain are apparently sensitive to tactile stimulation in infancy, the authors propose that the vibrant R&T reported here could reflect an enduring alteration of genetically based, motivational systems underlying playfulness and, perhaps, positive social emotions like joy.

Selective effects of neonatal handling on rat brain N-methyl-d-aspartate receptors

Neonatal handling, an experimental model of early life experiences, is known to affect the hypothalamic–pituitary–adrenal axis function thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. A molecule that plays a most critical role in such processes is the N-methyl-d-aspartate (NMDA) receptor, a tetramer consisting of two obligatory, channel forming NR1 subunits and two regulatory subunits, usually a combination of NR2A and NR2B. Since the subunit composition of the NMDA receptor affects brain plasticity, in the present study we investigated the effect of neonatal handling on NR1, NR2A and NR2B mRNA levels using in situ hybridization, and on NR2B binding sites, using autoradiography of in vitro binding of [3H]-ifenprodil, in adult rat limbic brain areas. We found that neonatal handling specifically increased NR2B mRNA and binding sites, while it had no effect on the NR1 and NR2A subunits. More specifically, neonatally handled animals, both males and females, had higher NR2B mRNA and binding sites in the dorsal CA1 hippocampal area, as well as the prelimbic, the anterior cingulate and the somatosensory cortex, compared to the non-handled. Moreover NR2B binding sites were increased in the dorsal CA3 area of handled animals of both sexes. Furthermore, neonatal handling had a sexually dimorphic effect, increasing NR2B mRNA and binding sites in the central and medial amygdaloid nuclei only of the females. The neonatal handling-induced increase in the NR2B subunit of the NMDA receptor could underlie the higher brain plasticity, which neonatally handled animals exhibit.

Early life experience alters behavioral responses to sweet food and accumbal dopamine metabolism

Neonatal handling in rats persistently alters behavioral parameters and responses to stress. Such animals eat more sweet food in adult life, without alterations in lab chow ingestion. Here, we show that neonatally handled rats display greater incentive salience to a sweet reward in a runway test; however they are less prone to conditioned place preference and show less positive hedonic reactions to sweet food. When injected with methylphenidate (a dopamine mimetic agent), non-handled rats increase their sweet food ingestion in the fasted state, while neonatally handled rats do not respond. We did not observe any differences regarding baseline general ambulatory activity between the groups. A lower dopamine metabolism in the nucleus accumbens was observed in handled animals, without differences in norepinephrine content. We suggest that early handling leads to a particular response to positive reinforcers such as palatable food, in a very peculiar fashion of higher ingestion but lower hedonic impact, as well as higher incentive salience, but diminished dopaminergic metabolism in the nucleus accumbens.

Environmental and tactile stimulation modulates the neonatal handling effect on adult rat spatial memory

Handling of rat pups promotes their adult cognitive performance. However, new data suggest that individual components of the handling procedure, like exposure to novelty or tactile stimulation, have distinct lasting effects on behaviour. In this study we examined the interaction of early novelty exposure with a varying amount of tactile stimulation on spatial recognition memory and corticosterone secretion of adult male and female rats. A split litter design was used and the experimental animals were also compared to animal facility reared controls. The experiment was conducted in two phases. In the first phase, we examined the effect of novel or home environment during the 15-min of neonatal handling, following 10 back-strokes. Tactile stimulation of 10 back-strokes combined with novelty exposure, enhanced novel arm discrimination in a Y-maze task in adult rats of both sexes compared to their siblings that stayed at home, as well as to the animal facility reared controls. In the second phase, additional back-stroking (total of 20 back-strokes) reduced the Y-maze performance of males neonatally exposed to novelty, while the same treatment enhanced the performance of their siblings that stayed at home. Basal corticosterone levels, determined 1 week post-Y-maze, were significantly increased only in the novelty exposed/10 back-stroked females compared to same sex non-handled controls. In contrast, 10 back-strokes combined with the home cage environment increased corticosterone in males. Increase to 20 back-strokes reversed the impact of neonatal environment on corticosterone levels.These data suggest that the nature and intensity of the individual components of a mild early life manipulation, like handling, are critical in modifying aspects of adult memory performance and basal adrenocortical function.

Adverse experience during early life and adulthood interact to elevate tph2 mRNA expression in serotonergic neurons within the dorsal raphe nucleus

Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of brain serotonergic systems. These effects could result from genetic influences, adverse early life experiences (ELE), or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to neuropsychiatric disorders. To evaluate the effects of ELE, adverse experiences during adulthood, and potential interactions between these factors on neuronal tryptophan hydroxylase 2 (tph2) mRNA expression, we investigated in rats the effects of maternal separation (MS)(separation from the dam for 180 min/day from postnatal day 2–14; MS180, a model of vulnerability to a depression-like syndrome), neonatal handling (separation from the dam for 15 min/day from postnatal day 2–14; MS15, a model of decreased stress sensitivity), or normal animal facility rearing (AFR) control conditions, with or without subsequent exposure to adult social defeat, on tph2 mRNA expression in the dorsal raphe nucleus (DR). Among rats exposed to social defeat, MS180 rats had increased tph2 mRNA expression in the DR, while MS15 rats had decreased tph2 mRNA expression compared to AFR rats. Social defeat increased tph2 mRNA expression, but only in MS180 rats and only in the “lateral wings” of the DR, a subdivision of the DR that is part of a sympathomotor command center. Overall, these data demonstrate that ELE and stressful experience during adulthood interact to determine tph2 mRNA expression. These changes in tph2 mRNA expression represent a potential mechanism through which adverse ELEs and stressful life experiences during adulthood may interact to increase vulnerability to stress-related psychiatric disease.

Cerebral palsy in eastern Denmark: Declining birth prevalence but increasing numbers of unilateral cerebral palsy in birth year period 1986–1998

The Cerebral Palsy Registry in eastern Denmark has been collecting cases using a uniform data sampling procedure since birth year 1979. Children are included by two child neurologists and an obstetrician. Information on pregnancy, birth, neonatal period, impairments and demographic data are registered. The total cerebral palsy birth prevalence has been significantly decreasing since the birth period 1983–1986 with 3.0 per 1000 live births until the period 1995–1998 with 2.1 per 1000 live births. The overall decrease was seen in preterm infants (<31 weeks) as well as in term infants and despite a simultaneous fall in perinatal and early neonatal mortality in the preterm group. Analysing the subtypes of CP we found a significant increase in the numbers as well as the rate of unilateral CP with a simultaneous fall in the numbers as well as the rate of bilateral CP. The explanation of this rise is not obvious. A change from bilateral periventricular lesions to unilateral is a possibility, but no major change in the neonatal handling could be documented. Regarding associated impairments, developmental delay/learning disabilities as well as motor function assessed by ability to walk (unassisted/assisted), both have changed toward higher percentage of children with unassisted walking and in need of special education.