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Horses are often still exposed to stressful or inadequate conditions and difficult relationships with humans, despite growing concerns about animal welfare. In the present study, we investigated the impact of different approaches of short-term handling sessions on young Lusitanian horses raised on a high-breed farm, specifically on their later adaptability to humans and stressful environments. Thirty-one foals (3 months old ± 15 days), from both sexes, were separated into three groups, one submitted to 3 consecutive days of handling sessions (Int-H), another to one handling session each month for 3 months (Month-H), and one left undisturbed (control). At 8 months old ± 15 days, all foals were evaluated during behavioral tests (restraint in a stock and forced-person test). Evaluations were based on behavioral observations and physiological assessments. The handled foals (Int-H and Month-H) reacted less to being isolated and restrained and better tolerated human contact and veterinary procedures than the control ones. The handled foals displayed less evasive and negative behaviors toward human approach, but also sought less human contact and did not interact, regardless of the handling timeframe. All animals displayed signs of stress when restrained in the stock, with increased neutrophil counts and CHCM levels in the blood, and no differences in metabolic (CK and LDH) and other hematological parameters. The neutrophil-lymphocyte ratio was significantly higher (p < 0.05) in handled foals than in control ones, suggesting low standards of welfare. Our data suggest that early forced handling decreases fearfulness in new environments; however, it does not improve the horses' relationship with humans, and it decreases welfare.

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Exposure to stressors in early postnatal life induces long-lasting modifications in brain function. This plasticity, an essential characteristic of the brain that enables adaptation to the environment, may also induce impairments in some psychophysiological functions, including learning and memory. Early life stress (ELS) has long-term effects on the hypothalamic-pituitary-adrenal axis response to stressors, and has been reported to lead to neuroinflammation, altered levels of neurotrophic factors, modifications in neurogenesis and synaptic plasticity, with changes in neurotransmitter systems and network functioning. In this review, we focus on early postnatal stress in animal models and their effects on learning and memory. Many studies have reported ELS-induced impairments in different types of memories, including spatial memory, fear memory, recognition (both for objects and social) memory, working memory and reversal learning. Studies are not always in agreement, however, no effects, or sometimes facilitation, being reported, depending on the nature and intensity of the early intervention, as well as the age when the outcome was evaluated and the sex of the animals. When considering processes occurring after consolidation, related with memory maintenance/persistence or transformation, there are a very reduced number of reports. Future studies addressing the mechanisms underlying memory changes for ELS should shed some light on the understanding of the different effects induced by stressors of different types and intensities on cognitive functions.

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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.

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INTRODUCTION: Autism spectrum disorder (ASD) is a complex, behaviorally defined disorder of the immature brain as a result of genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). This syndrome is known for its high prevalence. On the other hand, postnatal manipulations have been shown to affect brain development, cortical neuroscience, and pituitary-adrenal activity. In early handling (EH) procedure, pups are removed from their mother on a daily basis from birth to lactation, are physically touched, and exposed to the (a) new environment. In the present study, the effect of EH on anxiety-like behaviors in rats exposed pre- and post-natally to valproic acid was investigated. METHODS: Pregnant Wistar rats were randomly separated into six groups which are prenatal saline, Prenatal VPA, Prenatal VPA + EH and postnatal saline, Postnatal VPA, Postnatal VPA + EH. VPA administration was performed either on ED12.5 (600 mg/kg, i.p.) or PD 2-4 (400 mg/kg, s.c.). In the groups receiving EH, pups underwent physical handling from PD 1 to 21. On postnatal day 21 all offspring were weaned and the behavioral tests were performed on 30 and 31 days of age. Elevated plus maze and open field tests were used to investigate anxiety-like behaviors. RESULTS: The results revealed that intraperitoneal injection of valrpoic acid (600 mg.kg) during pregnancy significantly reduced OAT% in males (p < 0.01) and females in a non-significant manner (p > 0.05). In comparison, rearing counts of prenatal VPA groups significantly increased in female sex (p < 0.05) in the EPM test. Following postnatal VPA administration (400 mg/kg), decrease in the time spent in central zone occurred in female rats in the open filed (p < 0.05), as well as a significant increase in the number of grooming of the male sex (p < 0.05). Applying Early Handling to male and female Wistar rats receiving prenatal VPA significantly reversed the OAT% fall (p < 0.05). EH in postnatally VPA exposed animals significantly decreased the OAT% and OAE% criteria, while increasing the locomotor activity of the female sex (p < 0.05). Compared with the postnatal VPA group, no significant change was reported in the EPM performance of postnatal VPA + EH group in neither of sexes (p > 0.05). CONCLUSION: The findings of this study suggest that injections of valproic acid during pregnancy lead to anxiety-like behaviors in male offspring, which EH can improve (attenuate) to some extent. VPA injections on the second to the fourth day of infancy did not have a profound effect on anxiety level. Further behavioral studies need to be performed using other devices to investigate anxiety-like behaviors and to determine the mechanisms involved in these behaviors.

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The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring's stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14-16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis.

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In rodents, fragmented and low levels of maternal care have been implicated in age-related cognitive decline and the incidence and progression of Alzheimer's pathology. In contrast, enhancing early postnatal maternal care has been associated with improved cognitive function later in life. Here we examined whether early postnatal handling of mouse pups from postnatal days 2-9 enhanced maternal care and whether this affected cognition and Alzheimer pathology at 5 and 11months of age in the APPswe/PS1dE9 mouse model for Alzheimer's disease. Brief, 15min daily episodes of separating offspring from their dams from postnatal days 2-9 (early handling, EH) increased maternal care of the dam towards her pups upon reunion. At 11 (but not 5) months of age, EH APPswe/PS1dE1 mice displayed significantly reduced amyloid plaque pathology in the hippocampus. At this age, EH also prevented short-term working memory deficits while restoring impairments in contextual fear memory formation in APPswe/PS1dE9 mice. EH did not modulate amyloid pathology in the amygdala, nor did it affect auditory fear conditioning deficits in APPswe/PS1dE9 mice. We conclude that increased levels of maternal care during the early life period delays amyloid accumulation and cognitive decline in an Alzheimer's mouse model, involving the hippocampus, but not to the amygdala. These studies highlight the importance of the early postnatal period in modulating resilience to develop Alzheimer's pathology later in life.

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Stress has been implicated as a risk factor for the severity and progression of sporadic Alzheimer's disease (AD). Early life experiences determine stress responsivity in later life, and modulate age-dependent cognitive decline. Therefore, we examined whether early life experiences influence AD outcome in a bigenic mouse model which progressively develops combined tau and amyloid pathology (biAT mice).Mice were subjected to either early life stress (ELS) or to 'positive' early handling (EH) postnatally (from day 2 to 9). In biAT mice, ELS significantly compromised long term survival, in contrast to EH which increased life expectancy. In 4 month old mice, ELS-reared biAT mice displayed increased hippocampal Aß levels, while these levels were reduced in EH-reared biAT mice. No effects of ELS or EH were observed on the brain levels of APP, protein tau, or PSD-95. Dendritic morphology was moderately affected after ELS and EH in the amygdala and medial prefrontal cortex, while object recognition memory and open field performance were not affected. We conclude that despite the strong transgenic background, early life experiences significantly modulate the life expectancy of biAT mice. Parallel changes in hippocampal Aß levels were evident, without affecting cognition of young adult biAT mice.

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Exposure to chronic stress is associated with an increased incidence of neuropsychiatric dysfunction. The current study evaluated two competing hypotheses, the cumulative stress and the match/mismatch hypothesis of neuropsychiatric dysfunction, using two paradigms relating to exposure to "stress": pre-weaning maternal separation and post-weaning isolation-housing. C57BL/6 offspring were reared under four conditions: typical animal facility rearing (AFR, control), early handling (EH, daily 15 min separation from dam), maternal separation (MS, daily 4 hr separation from dam), and maternal and peer separation (MPS, daily 4 hr separation from dam and from littermates). After weaning, mice were either housed socially (2-3/cage) or in isolation (1/cage) and then tested for prepulse inhibition in adulthood. Isolation-housed MPS subjects displayed greater deficits in prepulse inhibition relative to socially-housed MPS subjects while socially-housed AFR subjects displayed greater deficits in prepulse inhibition relative to isolation-housed AFR subjects. The results indicate that these treatment conditions represent a potentially valuable model for evaluating the match/mismatch hypothesis in regards to neuropsychiatric dysfunction.

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Although numerous animal studies have assessed the impact of maternal separation upon pain sensitivity, overall conclusions are difficult to draw about the literature in light of mixed patterns of findings. In this research, a meta-analysis was performed to assess effects of early maternal separation on sensitivity to nociceptive thermal stimulation in rodent offspring and to identify moderators that might explain variable results between studies. Fifteen studies comprising 19 rodent offspring samples (N=1642) fulfilled all selection criteria. Analyses indicated that rodent offspring exposed to early maternal separation had longer response latencies (RLs) reflecting lower sensitivity to nociceptive thermal stimulation compared to non-separated controls. Heightened effect size heterogeneity was also evident. Moderator analyses indicated variable findings between studies were partially or fully explained by operationalizations of maternal separation (early handling vs. maternal separation), type of noxious stimuli, age of testing, receipt of injections during separation, sex composition of samples, and publication year. Biobehavioral underpinnings of overall group differences and moderator effects are posited in the discussion.

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For rats, maternal mediation of brief and longer term dam-pup separations were thought to account for pup differences in adult "emotionality." In this study, early handling (EH), maternal separation (MS), and maternal peer separation (MPS) groups were compared to an animal facility reared (AFR) group for maternal behavior and offspring adult open-field behavior in C57BL/6 mice. Although MS and MPS dams displayed higher levels of maternal behavior upon reunion, these group differences did not predict offspring open-field behavior. However, when offspring behavior was analyzed as a function of specific aspects of maternal behavior, irrespective of treatment group, pups that received high levels of quiescent nursing and activity, but not licking, were less "emotional." Individual differences in maternal licking of pups predicted variability of "emotional" behavior for AFR and EH pups. Thus, for this strain of mouse, individual and not treatment differences in maternal care predict offspring "emotional" development.

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This study aims at providing an insight into early handling procedures on learning and memory performance in adult female rats. Early handling procedures were started on post-natal day 2 until 21, and consisted in 15 min, daily separations of the dams from their litters. Assessment of declarative memory was carried out in the novel-object recognition task; spatial learning, reference- and working memory were evaluated in the Morris water maze (MWM). Our results indicate that early handling induced an enhancement in: (1) declarative memory, in the object recognition task, both at 1h and 24h intervals; (2) reference memory in the probe test and working memory and behavioral flexibility in the "single-trial and four-trial place learning paradigm" of the MWM. Short-term separation by increasing maternal care causes a dampening in HPA axis response in the pups. A modulated activation of the stress response may help to protect brain structures, involved in cognitive function. In conclusion, this study shows the long-term effects of a brief maternal separation in enhancing object recognition-, spatial reference- and working memory in female rats, remarking the impact of early environmental experiences and the consequent maternal care on the behavioral adaptive mechanisms in adulthood.

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Neonatal handling, an experimental model of early life experiences, is known to affect hypothalamic-pituitary-adrenal (HPA) axis function, thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. AMPA receptors (AMPARs) mediate fast synaptic transmission at excitatory glutamatergic synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPARs are composed of four types of subunits, designated as AMPA glutamate receptor subunits (GluA1, GluA2, GluA3 and GluA4), which combine to form tetramers. The present study addressed the question of whether neonatal handling (15min daily maternal separation from postnatal day 1 (PND1) to PND21) might have an effect on GluA1-4 mRNA levels in adult rat male and female brain using in situ hybridization. We have identified selective sexually dimorphic effects of neonatal handling on the mRNA expression levels of AMPAR subunits in adult rat hippocampus and nuclei of the amygdaloid complex. In the dorsal hippocampus GluA1 mRNA levels were increased in handled males, while they were decreased in handled female animals. In the ventral hippocampus and the amygdaloid complex GluA2 mRNA was lower in handled females, while no effect was observed in handled males. Furthermore, we observed that neonatal handling induced in both sexes decreases of GluA2 mRNA in the dorsal hippocampus, as well as in the somatosensory and occipital cortex, of GluA3 mRNA in most hippocampal areas, amygdaloid complex and cortical regions studied, and of GluA4 mRNA in the ventral hippocampus. These results show that glutamatergic transmission is markedly affected by an early experience. The neonatal handling-induced alterations in AMPAR subunit composition are in line with the increased brain plasticity, the more effective HPA axis function, and in general the more adaptive behavioral phenotype known to characterize the handled animals.

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