Neonatal Handling Research Articles

Schizophrenia-relevant social, attentional and cognitive traits in female RHA vs. RLA rats: effects of neonatal handling

The Roman high- (RHA) and low-avoidance (RLA) rats were bidirectionally selected and bred for, respectively, their rapid vs. extremely poor acquisition in the two-way active avoidance task. Consistent between-strain neurobehavioural differences have been found in anxiety- and stress-linked traits, as well as in schizophrenia-related phenotypes. RLAs display enhanced anxious- and stress-related phenotypes, whereas RHA rats show impulsivity, hyperactivity and attention/cognition-related impairments. Many of these typical behavioural phenotypes have been reported to be positively modulated by environmental treatments such as neonatal handling (NH). However, most studies on the Roman rat strains have been carried out in males. Thus, the present study for the first time focused on the joint evaluation of differences in novel object exploration (NOE), social interaction (SI), prepulse inhibition of the startle response (PPI), and cognitive performance and flexibility in various spatial tasks (using the Morris water maze, MWM) in females of both Roman rat strains. We also aimed at evaluating the long-lasting effects of NH treatment on the RHA vs. RLA profiles in these tests/tasks. Results show that anxiety-related behavior, as measured by the NOE test and self-grooming in the SI test, was increased in RLA rats, and dramatically reduced by NH. In the SI test RLA rats displayed diminished social interaction, which was rescued by NH. RHA females exhibited a deficit of PPI, which was not affected by NH. Spatial tasks in the MWM showed impairments of working memory, reference learning/memory and spatial reversal learning (i.e., cognitive flexibility) in RHA females. Spatial reference learning and cognitive flexibility (i.e., reversal task) showed some improvement in rats (mainly in RHAs) that had received NH during the first three weeks of life. With the exception of the SI test, the pattern of differences between female RHA vs. RLA profiles was overall consistent with what has previously been found in males of both strains, and NH treatment was able to enduringly improve some emotion-related and (spatial) cognitive outcomes in both strains.

C-Fos expression after neonatal handling in social brain regions: Distinctive profile of RHA-rat schizophrenia model on a social preference test

Neonatal handling (NH) is an environmental manipulation that induces long-lasting changes in behavioural, neuroendocrine, and neuroanatomical processes in rodents. We have previously reported that NH treatment increases social interaction preference in an animal model of schizophrenia-relevant features, the Roman high-avoidance (RHA) rats. The present study was aimed at evaluating whether the increase of social behaviour/preference due to NH treatment in RHA rats is associated with differences in c-Fos expression levels in some of the brain areas that integrate the “social brain”. To this aim, we evaluated the performance of adult male rats from both Roman rat strains (RHA vs. RLA –Roman low-avoidance- rats), either untreated (control) or treated with NH (administered during the first 21 days of life) in a social interaction task. For the analyses of c-Fos activation untreated and NH-treated animals were divided into three different experimental conditions: undisturbed home cage controls (HC); rats exposed to the testing set-up context (CTX); and rats exposed to a social interaction (SI) test. It was found that, compared with their RLA counterparts, NH treatment increased social behaviour in RHA rats, and also specifically enhanced c-Fos expression in RHA rats tested for SI in some brain areas related to social behaviour, i.e. the infralimbic cortex (IL) and the medial posterodorsal amygdala (MePD) regions.

Sex differences in hippocampal structural plasticity and glycosaminoglycan disaccharide levels after neonatal handling.

In this study we investigated the effects of a neonatal handling protocol that mimics the handling of sham control pups in protocols of neonatal exposure to brain insults on dendritic arborization and glycosaminoglycan (GAG) levels in the developing brain. GAGs are long, unbranched polysaccharides, consisting of repeating disaccharide units that can be modified by sulfation at specific sites and are involved in modulating neuronal plasticity during brain development. In this study, male and female Sprague-Dawley rats underwent neonatal handling daily between post-natal day (PD)4 and PD9, with brains analyzed on PD9. Neuronal morphology and morphometric analysis of the apical and basal dendritic trees of CA1 hippocampal pyramidal neurons were carried out by Golgi-Cox staining followed by neuron tracing and analysis with the software Neurolucida. Chondroitin sulfate (CS)-, Hyaluronic Acid (HA)-, and Heparan Sulfate (HS)-GAG disaccharide levels were quantified in the hippocampus by Liquid Chromatography/Mass Spectrometry analyses. We found sex by neonatal handling interactions on several parameters of CA1 pyramidal neuron morphology and in the levels of HS-GAGs, with females, but not males, showing an increase in both dendritic arborization and HS-GAG levels. We also observed increased expression of glucocorticoid receptor gene Nr3c1 in the hippocampus of both males and females following neonatal handling suggesting that both sexes experienced a similar stress during the handling procedure. This is the first study to show sex differences in two parameters of brain plasticity, CA1 neuron morphology and HS-GAG levels, following handling stress in neonatal rats.

A comprehensive approach to modeling maternal immune activation in rodents.

Prenatal brain development is a highly orchestrated process, making it a very vulnerable window to perturbations. Maternal stress and subsequent inflammation during pregnancy leads to a state referred to as, maternal immune activation (MIA). If persistent, MIA can pose as a significant risk factor for the manifestation of neurodevelopmental disorders (NDDs) such as autism spectrum disorder and schizophrenia. To further elucidate this association between MIA and NDD risk, rodent models have been used extensively across laboratories for many years. However, there are few uniform approaches for rodent MIA models which make not only comparisons between studies difficult, but some established approaches come with limitations that can affect experimental outcomes. Here, we provide researchers with a comprehensive review of common experimental variables and potential limitations that should be considered when designing an MIA study based in a rodent model. Experimental variables discussed include: innate immune stimulation using poly I:C and LPS, environmental gestational stress paradigms, rodent diet composition and sterilization, rodent strain, neonatal handling, and the inclusion of sex-specific MIA offspring analyses. We discuss how some aspects of these variables have potential to make a profound impact on MIA data interpretation and reproducibility.

Neuroendocrine mechanisms in oxaliplatin-induced hyperalgesic priming.

Stress plays a major role in the symptom burden of oncology patients and can exacerbate cancer chemotherapy-induced peripheral neuropathy (CIPN), a major adverse effect of many classes of chemotherapy. We explored the role of stress in the persistent phase of the pain induced by oxaliplatin. Oxaliplatin induced hyperalgesic priming, a model of the transition to chronic pain, as indicated by prolongation of hyperalgesia produced by prostaglandin E 2 , in male rats, which was markedly attenuated in adrenalectomized rats. A neonatal handling protocol that induces stress resilience in adult rats prevented oxaliplatin-induced hyperalgesic priming. To elucidate the role of the hypothalamic-pituitary-adrenal and sympathoadrenal neuroendocrine stress axes in oxaliplatin CIPN, we used intrathecally administered antisense oligodeoxynucleotides (ODNs) directed against mRNA for receptors mediating the effects of catecholamines and glucocorticoids, and their second messengers, to reduce their expression in nociceptors. Although oxaliplatin-induced hyperalgesic priming was attenuated by intrathecal administration of β 2 -adrenergic and glucocorticoid receptor antisense ODNs, oxaliplatin-induced hyperalgesia was only attenuated by β 2 -adrenergic receptor antisense. Administration of pertussis toxin, a nonselective inhibitor of Gα i/o proteins, attenuated hyperalgesic priming. Antisense ODNs for Gα i 1 and Gα o also attenuated hyperalgesic priming. Furthermore, antisense for protein kinase C epsilon, a second messenger involved in type I hyperalgesic priming, also attenuated oxaliplatin-induced hyperalgesic priming. Inhibitors of second messengers involved in the maintenance of type I (cordycepin) and type II (SSU6656 and U0126) hyperalgesic priming both attenuated hyperalgesic priming. These experiments support a role for neuroendocrine stress axes in hyperalgesic priming, in male rats with oxaliplatin CIPN.

The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities.

This review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.

Sex-dependent worsening of NMDA-induced responses, anxiety, hypercortisolemia, and organometry of early peripheral immunoendocrine impairment in adult 3xTg-AD mice and their long-lasting ontogenic modulation by neonatal handling

The neuroimmunomodulation hypothesis for Alzheimer’s disease (AD) postulates that alterations in the innate immune system triggered by damage signals result in adverse effects on neuronal functions. The peripheral immune system and neuroimmunoendocrine communication are also impaired. Here we provide further evidence using a longitudinal design that also studied the long-lasting effects of an early life sensorial intervention (neonatal handling, from postnatal day 1–21) in 6-month-old (early stages of the disease) male and female 3xTg-AD mice compared to age- and sex-matched non-transgenic (NTg) mice with normal aging. The behavioral patterns elicited by the direct exposure to an open field, and the motor depression response evoked by NMDA (25 mg/kg, i.p) were found correlated to the organometry of peripheral immune-endocrine organs (thymus involution, splenomegaly, and adrenal glands’ hypertrophy) and increased corticosterone levels, suggesting their potential value for diagnostic and biomonitoring.The NMDA-induced immediate and depressant motor activity and endocrine (corticosterone) responses were sensitive to sex and AD-genotype, suggesting worse endogenous susceptibility/neuroprotective response to glutamatergic excitotoxicity in males and in the AD-genotype. 3xTg-AD females showed a reduced immediate response, whereas the NTg showed higher responsiveness to subsequent NMDA-induced depressant effect than their male counterparts. The long-lasting ontogenic modulation by handling was shown as a potentiation of NMDA-depressant effect in NTg males and females, while sex × treatment effects were found in 3xTg-AD mice. Finally, NMDA-induced corticosterone showed sex, genotype and interaction effects with sexual dimorphism enhanced in the AD-genotype, suggesting different endogenous vulnerability/neuroprotective capacities and modulation of the neuroimmunoendocrine system.

Effects of rearing methods on feather-damaging behavior and corticosterone metabolite excretion in the peach-faced lovebird (Agapornis roseicollis Vieillot)

Hand-reared birds are more likely to develop behavioral disorders such as feather-damaging behavior (FDB) than parent-reared birds; this may adversely affect the human–animal bond and lead to poor animal welfare. Therefore, it is important to determine the effects of rearing methods on FDB to improve the welfare of companion birds. We determined the effects of rearing methods on FDB in the peach-faced lovebird (Agapornis roseicollis Vieillot) using a case–control study and by comparing the concentrations of corticosterone metabolites (CM) in bird droppings among the following 3 groups: (1) non-FDB hand-reared (N-HR) birds; (2) FDB hand-reared (FDB-HR) birds; and (3) parent-reared (PR) birds with neonatal handling. The case–control study included sex, age, rearing method, signs of separation anxiety, staple food, fresh food, enrichment, and the presence of conspecifics as potential risk factors for FDB. Droppings were collected once a month over a 3-day period for 2 months, and the CM concentrations in the droppings were determined using a competitive enzyme immunoassay. The prevalence of FDB was higher in the HR birds than in the PR birds. Furthermore, there was no difference in the mean CM concentrations in the droppings between the N-HR and FDB-HR birds; however, the mean CM concentrations in the droppings of these birds were higher than those of the PR birds. The presence of conspecifics resulted in significantly lower CM concentrations in the 3 groups than when conspecifics were absent. These findings suggest that rearing methods influence FDB development and dropping CM concentrations in the peach-faced lovebirds. Therefore, we propose parental rearing with neonatal handling over hand-rearing and maintaining with conspecifics for the welfare of the peach-faced lovebirds.

Early postnatal handling alters social behavior, learning, and memory of pre- and postnatal VPA-induced rat models of autism in a context-based manner

Early life events are known to greatly affect brain development, cortical neurogenesis, and Hypothalamic-pituitary-adrenal activity. Mainly characterized by impairment in social communication, language, and cognitive development, autism spectrum disorder (ASD) refers to a class of neuropsychiatric disorders with numerous genetic and environmental risk factors. In the early handling (EH) method, daily separation of infants from their mother, physical touching, and exposure to a new environment occur. Here, we studied the effect of EH on Social interaction, learning, and memory in rats exposed pre-or post-natally to valproic acid (VPA). Gestational VPA exposure (600 mg/kg) led to some severe autistic-like traits, more notable in the social behavior of the male sex, along with unchanged to partially altered spatial learning and memory function and reduced avoidance memory. In comparison, while causing a sex-dependent increase in spatial memory, subcutaneous injection of VPA (400 mg/kg) in infancy resulted in limited adverse autistic features, including a decrease in males’ social preference, as well as reduced avoidance memory. The results indicated that neonatal handling significantly improved multiple social behavior and memory deficits in prenatally injected rats. In contrast, EH in rats receiving postnatal VPA elicited a restricted advantage on social novelty tendency; while negatively affecting some other social behavior criteria and spatial learning of males and encouraging sex-dependent repetitive behaviors in the social setting. The controversial influence of postnatal handling on juvenile rats of postnatal VPA treatment vs. prenatal VPA treatment opens up the potential for future research on the context-based consequence of early-life handling stress using different behavioral tasks and to benefit therapeutic procedures through understanding the sex- and age-specific neurobiology of short-term environmental manipulation in animal models of autism.

Decreased social interaction in the RHA rat model of schizophrenia-relevant features: Modulation by neonatal handling

The Roman-Low (RLA) and High-Avoidance (RHA) rat strains have been bidirectionally selected and bred, respectively, for extremely poor vs. rapid acquisition of the two-way active avoidance task. Over 50 years of selective breeding have led to two strains displaying many differential specific phenotypes. While RLAs display anxious-related behaviours, RHA rats show impulsivity, and schizophrenia-like positive and cognitive symptoms or phenotypes.Neonatal handling (NH) is an environmental treatment with long-lasting anxiolytic-like and anti-stress effects. NH also reduces symptoms related to schizophrenia, such as pre-pulse inhibition (PPI) impairment and latent inhibition (LI) deficits, and improves spatial working memory and cognitive flexibility.The present work was aimed at exploring whether RHAs also display negative schizophrenia-like symptoms (or phenotypes), such as lowered preference for social interaction (i.e. asociality), and whether NH would reduce these deficits. To this aim, we evaluated naïve inbred RHA and RLA rats in a social interaction (SI) test after either long- or short-term habituation to the testing set up (studies 1–2). In Study 3 we tested untreated and NH-treated RHA and RLA rats in novel object exploration (NOE) and SI tests. Compared with RHAs, RLA rats displayed increased anxiety-related behaviours in the NOE (i.e. higher behavioural inhibition, lesser exploration of the novel object) and SI (i.e. higher levels of self-grooming) tests which were dramatically reduced by NH treatment, thus supporting the long-lasting anxiolytic-like effect of NH. Remarkably, RHA rats showed decreased social preference in the SI test compared with RLAs, evidencing that RHAs would present a relative asociality, which is thought to model some negative symptomatology (i.e. social withdrawal) of schizophrenia. NH increased absolute levels of social behaviour in both strains, but with a more marked effect in RHA rats, especially in the first 5 min of the SI test. Thus, it is hypothesized that, apart from its effects on anxiety-related behaviours, NH might have long-lasting positive effects on behavioural and neurobiological processes that are impaired in schizophrenia.

The Behavior and Postnatal Development in Infant and Juvenile Rats After Ultrasound-Induced Chronic Prenatal Stress.

Fetal development is susceptible to environmental factors. One such factor is exposure to stress during pregnancy. The present study aimed to investigate the effects of chronic prenatal stress (PS) on the development and behavior of rat offspring during infancy and juvenile ages. Existing approaches to modeling prenatal stress on animals do not correlate with the main type of stress in pregnant women, namely psychological stress. We used a new stress paradigm in the experiment, namely, stress induced by exposure to variable frequency ultrasound (US), which acted on pregnant Wistar rats on gestational days 1–21. This type of stress in rodents can be comparable to psychological stress in humans. We assessed physical development, reflex maturation, motor ability development, anxious behavior, response to social novelty, and social play behavior in male and female offspring. Additionally, we investigated maternal behavior and the effect of neonatal handling (NH) on behavior. Prenatal stress did not affect postnatal developmental characteristics in rat pups, but prenatally stressed rats had higher body weight in early and adult age than controls. Prenatal exposure to a stressor increased anxiety in the open-field test (OF), changed social preferences in the social novelty test (SN), and impaired social play behavior in males. Neonatal handling reduced anxiety and restored social behavior, but evoked hyperactive behavior in rat pups. Maternal behavior did not change. Our study demonstrated for the first time that exposure to variable frequency ultrasound during pregnancy influences offspring development and impairs behavior, correlating with the effects of other types of stress during pregnancy in rodents. This supports the idea of using this exposure to model prenatal stress.

Laboratory rats as pets: The potential role of neonatal handling schedule for their life in and after the lab

There are organizations for re-homing animals that are also specialized in re-homing dogs and cats who have been research subjects. Why can’t we do this for more animals and especially for the rats that are used extensively in research and they are not intended to be pets as they are not as common as pets? Even though previous research highlights neonatal handling as an essential process for rearing less stressed and emotionally sensitive adult rats, there is very little information about a specific neonatal handling schedule that could be a crucial factor in promoting their welfare and adoption as pets. The aim of this study is to propose a standardized handling schedule assessment based on implementation of a neonatal handling procedure that mimics maternal behavior, in order to have a positive effect on the rats’ welfare, decreasing their stress responsiveness towards humans and promoting their adoption as pets. DA rats (DA/OlaHsd) were handled during postnatal days 1 (D1) to 21 (D21) (experimental group, n=15) using a handling schedule that imitates rat maternal behavior or received only gold standard neonatal handling (control group, n=14). On D22, blinded researchers evaluated the behaviour of both groups according to their responses to handling. Blinding was used, as to try to eliminate biased results, as to examine the rats' behavior against strangers which is a crucial factor for their suitability as pets. The data were collected through a customized assessment form. The statistical analysis of both groups’ cumulative responses showed that the experimental group had less stressful responses compared to the control group (Mann-Whitney (U) test: U= 13; P < 0.01). This neonatal handling schedule may improve rat welfare during their life in the lab. Also, it could be a method that assists laboratory rats to be adopted as pets after their laboratory life.

Maternal separation with neonatal pain influences later-life fear conditioning and somatosenation in male and female rats

Early life adversity, including that which occurs in a medical setting, has been increasingly shown to have lasting consequences on both physical and mental health. In order to understand the lasting effects of early-life adversity, such as that might occur in the neonatal intensive care unit (NICU), several rodent models have been developed including maternal separation, neonatal handling, and repeated needle prick pain. However, in the clinical scenario, these stressors are often combined. Thus, the current study seeks to observe the lasting impacts of both neonatal pain and maternal separation in a rodent model. Rats were separated from their dam for 6 h per day during the first 7 days of life, during which they were subjected to repeated needle prick pain or handling. A separate group was left undisturbed. All rats were subsequently tested for threat processing using a 3-day Pavlovian fear conditioning model and for somatosensation using measures of mechanical and thermal thresholds. Results indicated that rats subjected to maternal separation and pain had enhanced fear conditioning in adolescence as well as displaying a modest age-independent tactile hypersensitivity compared to undisturbed controls. These data show that experiencing combined neonatal pain and maternal separation may create a latent vulnerability to subsequent stressors.

Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy.

Although clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide targeting β₂-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. By contrast, glucocorticoid receptor antisense oligodeoxynucleotide prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone, and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also, a risk factor for CIPN, early-life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding) and stress-resilient (produced by neonatal handling) phenotypes in adults. Although neonatal limited bedding significantly enhanced CIPN only in female adults, neonatal handling significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the 2 major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Early-life stress affects behavioral and neurochemical parameters differently in male and female juvenile Wistar rats.

Neonatal handling is an early life stressor that leads to behavioral and neurochemical changes in adult rats in a sex-specific manner and possibly affects earlier stages of development. Here, we investigated the effects of neonatal handling (days 1-10 after birth) on juvenile rats focusing on biochemical parameters and olfactory memory after weaning. Male neonatal handled rats performed more crossings on the hole-board task, increased Na+ /K+ -ATPase activity in the olfactory bulb, and decreased acetylcholinesterase activity in the hippocampus versus non-handled males. Female neonatal handled animals increased the number of rearing and nose-pokes on the hole-board task, decreased glutathione peroxidase activity, and total thiol content in the hippocampus versus non-handled females. This study reinforces that early life stress affects behavioral and neurochemical parameters in a sex-specific manner even before the puberty onset.

Neonatal handling increases neurogenesis, BDNF and GR in the hippocampus favoring memory acquisition in rats

Early life is a critical period for the development of the central nervous system (CNS) when the brain undergoes functional organization, neuronal proliferation and migration. This study aimed to evaluate influences and possible interactions of the neonatal handling (NH) on morphologic, biochemical and molecular markers in the hippocampus, as well as on Mu opioid receptors (MOR) immunoreactivity when adolescent rats were exposed to morphine. On postnatal day (PND) 1, male pups were assigned to two experimental groups: unhandled (UH) or neonatal handling (NH), whose procedure was applied from PND2 to PND9. On PND 50, animals were submitted to memory behavioral test, anesthesia and euthanasia for blood collection and hippocampus removal. Animals exposed to NH showed: i) increased levels of proBDNF and brain-derived neurotrophic factor (BDNF); ii) increased memory performance; iii) decreased lipid peroxidation (LP) in plasma and hippocampus; iv) increased antioxidant defenses; v) increased glucocorticoids receptor (GR) levels. Interestingly, our data showed a positive correlation between BDNF and working memory after NH procedure (r2 = 0.73; P = 0.006). Animals submitted to NH showed an increased per se of MOR immunoreactivity regardless of morphine exposure, while this increasing was also observed in the UH group after morphine exposure, even in a small extent. NH beneficial influence during early stage of life can be reflected during the development of the puppies, enhancing memory performance, preventing oxidative events and improving molecular targets in hippocampus. Further experimental studies in addition to clinical ones are needed to validate NH protocol as a therapeutic tool.

Prenatal Ethanol Exposure and Postnatal Environmental Intervention Alter Dopaminergic Neuron and Microglia Morphology in the Ventral Tegmental Area During Adulthood.

Prenatal ethanol exposure (PE) impairs midbrain dopaminergic (DA) neuron function, which might contribute to various cognitive and behavioral deficits, including attention deficits and increased addiction risk, often observed in individuals with fetal alcohol spectrum disorders. Currently, the underlying mechanisms for PE-induced deficits are unclear. PE could lead to neuroinflammation by activating microglia, which play an important role in synaptic function. In the present study, we investigated PE effects on microglial activation and DA neuron density and morphology in the ventral tegmental area (VTA). Since postnatal environmental enrichment can reduce neuroinflammation and ameliorate several PE-induced behavioral deficits, we examined if a postnatal environmental intervention strategy using neonatal handling and postweaning complex housing could reverse PE effects on VTA DA neurons and microglia. Pregnant rats received 0 or 6g/kg/d ethanol by 2 intragastric intubations on gestation days 8 to 20. After birth, rats were reared in the standard laboratory or enriched condition. Male adult rats (8 to 12weeks old) were used for immunocytochemistry. The results showed that PE decreased VTA DA neuron body size in standardly housed rats. Moreover, there was a significant decrease in numbers of VTA microglial branches and junctions in PE rats, suggesting morphological activation of microglia and possible neuroinflammation. The PE effects on microglia were normalized by postnatal environmental intervention, which also decreased the numbers of microglial branches and junctions in control animals, possibly via reduced stress. Our findings show an association between PE-induced morphological activation of microglia and impaired DA neuron morphology in the VTA. Importantly, postnatal environmental intervention rescues possible PE-induced microglial activation. These data support that environmental intervention can be effective in ameliorating cognitive and behavioral deficits associated with VTA DA neuron dysfunctions, such as attention deficits and increased addiction risk.

Severe Perinatal Hypoxic-Ischemic Brain Injury Induces Long-Term Sensorimotor Deficits, Anxiety-Like Behaviors and Cognitive Impairment in a Sex-, Age- and Task-Selective Manner in C57BL/6 Mice but Can Be Modulated by Neonatal Handling.

Perinatal brain injury (PBI) leads to neurological disabilities throughout life, from motor deficits, cognitive limitations to severe cerebral palsy. Yet, perinatal brain damage has limited therapeutic outcomes. Besides, the immature brain of premature children is at increased risk of hypoxic/ischemic (HI) injury, with males being more susceptible to it and less responsive to protective/therapeutical interventions. Here, we model in male and female C57BL/6 mice, the impact of neonatal HI and the protective effects of neonatal handling (NH), an early life tactile and proprioceptive sensory stimulation. From postnatal day 1 (PND1, modeling pre-term) to PND21 randomized litters received either NH or left undisturbed. HI brain damage occurred by permanent left carotid occlusion followed by hypoxia at PND7 (modeling full-term) in half of the animals. The behavioral and functional screening of the pups at weaning (PND23) and their long-term outcomes (adulthood, PND70) were evaluated in a longitudinal study, as follows: somatic development (weight), sensorimotor functions (reflexes, rods and hanger tests), exploration [activity (ACT) and open-field (OF) test], emotional and anxiety-like behaviors [corner, open-field and dark-light box (DLB) tests], learning and memory [T-maze (TM) and Morris Water-Maze (MWM)]. HI induced similar brain damage in both sexes but affected motor development, sensorimotor functions, induced hyperactivity at weaning, and anxiety-like behaviors and cognitive deficits at adulthood, in a sex- and age-dependent manner. Thus, during ontogeny, HI affected equilibrium especially in females and prehensility in males, but only reflexes at adulthood. Hyperactivity of HI males was normalized at adulthood. HI increased neophobia and other anxiety-like behaviors in males but emotionality in females. Both sexes showed worse short/long-term learning, but memory was more affected in males. Striking neuroprotective effects of NH were found, with significantly lower injury scores, mostly in HI males. At the functional level, NH reversed the impaired reflex responses and improved memory performances in hippocampal-dependent spatial-learning tasks, especially in males. Finally, neuropathological correlates referred to atrophy, neuronal densities and cellularity in the affected areas [hippocampal-CA, caudate/putamen, thalamus, neocortex and corpus callosum (CC)] point out distinct neuronal substrates underlying the sex- and age- functional impacts of these risk/protection interventions on sensorimotor, behavioral and cognitive outcomes from ontogeny to adulthood.

Infection control measures in neonatal units: implementation of change in the Gaza-Strip

Introduction: Low-income countries rarely report infection control measures although they are key to reducing mortality and morbidity in healthcare. This audit examined healthcare personnel’s adherence to infection control measures before entry to the NICU and in both minor and major procedures’ bundles. Furthermore, it examined the effect of subsequent authorization and dissemination of infection control guidelines followed by education and training sessions on the adherence of healthcare personnel to infection control policies.Methods: This prospective observational study was conducted in two NICUs at two separate hospitals in the Gaza-Strip, Palestine. The initial observation period was June–August 2016 during which healthcare professionals’ adherence to infection control policies was assessed by direct observation. This was followed by NICU feedback dissemination and on-site educational and training sessions. Then, the reaudit, following the same protocol, was carried out throughout February 2017.Results: There was a statistically significant improvement in the adherence to infection control measures among healthcare personnel. Significant improvements were found in both minor and major procedure infection control protocols’ adherence rates. However, when comparing the general neonatal handling adherence rate between both audits, no significant change was noted.Discussion: This study highlights the effectiveness of using audit feedback and on-site educational and training sessions in the enhancement of adherence to infection control policies, demonstrating significant improvement in areas covered by the staff training program. Therefore, including regular infection control training combined with feedback in the curriculum of healthcare professionals can improve the sustainability of infection control programs. Further studies must examine the impact of such training also on the incidence of healthcare-associated infection rates as well as morbidity and mortality within neonatal units.