Neonatal Social Isolation Research Articles

Effects of cross-fostering experience on emotion in adolescent Kunming mice

Abstract Parent–infant bonds are critical early postnatal environment in mammals. Unstable parent–infant bonds, such as maternal separation, paternal deprivation, and neonatal social isolation have negative effects on emotion, cognition, addiction, and social behaviours in the animal’s whole lifespan. Another unstable parent–infant bond, cross-fostering, in which pups were randomly exchanged to other parents has mostly focused on kin recognition and anxiety-like behavioural changes in adult. But its effects on adolescence, particularly on autism spectrum disorder, are poorly understood. Whole cross-fostering model was used in the present study. The results showed that with cross-fostering, adolescent Kunming mice buried more marbles, expressed higher levels of anxiety and depression. Cross-fostering attenuated prosocial behaviours and reduced the activity of adolescence when encountering another individual in social interaction test. Taken together, our results demonstrate that experiencing whole cross-fostering in early life is more likely to induce autism-, anxiety-, and depression- like behaviours in adolescence.

Neonatal social isolation increases the proportion of the immature spines in the layer 2/3 pyramidal neurons of the somatosensory cortex

Social isolation during the juvenile period is postulated to leave specific sequelae, such as attention deficits and emotion recognition. Miswiring of the cortical neuronal circuit during postnatal development may underlie such behavioral impairments, but the details of the circuit-level impairment associated with social isolation have not yet been clarified. In this study, we evaluated the possibility that environmental factors may induce alternation in spine characteristics and dynamics. We isolated mice from the mother and siblings from postnatal day 7 to 11 for 6 h per day. Both dynamics and structural properties of spines in the layer 2/3 pyramidal neurons of the somatosensory cortex were measured at postnatal 3 weeks by in vivo two-photon microscopy. We found decrease in the ratio of PSD-95-positive dendritic spines in the mice after social isolation. These mice did not show alteration in spine dynamics. Those results suggest that the neonatal social isolation results in less mature spines, with normal rate of their turnover, which is distinct from spine phenotype seen in multiple models of autism spectrum disorders.

Influence of Pre-Weaning Social Isolation on Post-Weaning Emotion Tendency and Mother–Infant Interactions in Infant Octodon Degus

Our previous research using Octodon degus (degus) revealed that preweaning social isolation negatively affected object exploratory behavior. However, it remains unknown how social isolation affects animal psychology and other behaviors. The present study examined the effects of neonatal social isolation on degu emotion and mother–infant interactions before and after weaning. Because degus have a complex social repertoire, we predicted that they would be sensitive to social isolation and show similarities with humans in their social interaction. Pups in the isolation group were separated from their family seven times for 30 min a day from 8 to 15 days post-birth. Pups in the nonisolation group were reared with their family. At 2, 3, 4, 5, and 6 weeks of age, pups underwent a zero-maze test to measure anxiety and a mother–infant interaction test to assess mother–infant attachment. Isolated pups showed more activity in the zero-maze test than nonisolated pups at 3 weeks of age. We found no significant effects of social isolation on mother–infant interactions. These results suggest that while neonatal social isolation might affect emotion during weaning, it does not influence mother–infant relationships.

Social isolation suppresses actin dynamics and synaptic plasticity through ADF/cofilin inactivation in the developing rat barrel cortex

Exposure to a stressful environment early in life can cause psychiatric disorders by disrupting circuit formation. Actin plays central roles in regulating neuronal structure and protein trafficking. We have recently reported that neonatal isolation inactivated ADF/cofilin, the actin depolymerizing factor, resulted in a reduced actin dynamics at spines and an attenuation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor delivery in the juvenile rat medial prefrontal cortex (mPFC), leading to altered social behaviours. Here, we investigated the impact of neonatal social isolation in the developing rat barrel cortex. Similar to the mPFC study, we detected an increase in stable actin fraction in spines and this resulted in a decreased synaptic AMPA receptor delivery. Thus, we conclude that early life social isolation affects multiple cortical areas with common molecular changes.

Oxytocin and Social Relationships: From Attachment to Bond Disruption.

Social relationships throughout life are vital for well-being and physical and mental health. A significant amount of research in animal models as well as in humans suggests that oxytocin (OT) plays an important role in the development of the capacity to form social bonds, the mediation of the positive aspects of early-life nurturing on adult bonding capacity, and the maintenance of social bonding. Here, we focus on the extensive research on a socially monogamous rodent model organism, the prairie vole (Microtus ochrogaster). OT facilitates mating-induced pair bonds in adults through interaction with the mesolimbic dopamine system. Variation in striatal OT receptor density predicts resilience and susceptibility to neonatal social neglect in female prairie voles. Finally, in adults, loss of a partner results in multiple disruptions in OT signaling, including decreased OT release in the striatum, which is caused by an activation of the brain corticotropin releasing factor (CRF) system. The dramatic behavioral consequence of partner loss is increased depressive-like behavior reminiscent of bereavement. Importantly, infusions of OT into the striatum of adults prevents the onset of depressive-like behavior following partner loss, and evoking endogenous OT release using melanocortin agonists during neonatal social isolation rescues impairments in social bonding in adulthood. This work has important translational implications relevant to the disruptions of social bonds in childhood and in adults.

The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles

Genes and social experiences interact to create variation in social behavior and vulnerability to develop disorders of the social domain. Socially monogamous prairie voles display remarkable diversity in neuropeptide receptor systems and social behavior. Here, we examine the interaction of early-life adversity and brain oxytocin receptor (OTR) density on adult social attachment in female prairie voles. First, pups were isolated for 3 h per day, or unmanipulated, from postnatal day 1–14. Adult subjects were tested on the partner preference (PP) test to assess social attachment and OTR density in the brain was quantified. Neonatal social isolation impaired female PP formation, without affecting OTR density. Accumbal OTR density was, however, positively correlated with the percent of time spent huddling with the partner in neonatally isolated females. Females with high accumbal OTR binding were resilient to neonatal isolation. These results are consistent with the hypothesis that parental nurturing shapes neural systems underlying social relationships by enhancing striatal OTR signaling. Thus, we next determined whether early touch, mimicking parental licking and grooming, stimulates hypothalamic OT neuron activity. Tactile stimulation induced immediate-early gene activity in OT neurons in neonates. Finally, we investigated whether pharmacologically potentiating OT release using a melanocortin 3/4 agonist, melanotan-II (10 mg kg−1 subcutaneously), would mitigate the social isolation-induced impairments in attachment behavior. Neonatal melanotan-II administration buffered against the effects of early isolation on partner preference formation. Thus, variation in accumbal OTR density and early OT release induced by parental nurturing may moderate susceptibility to early adverse experiences, including neglect.

Early deprivation induces competitive subordinance in C57BL/6 male mice

Rodent models have been widely used to investigate the impact of early life stress on adult health and behavior. However, the social dimension has rarely been incorporated into the analysis due to methodological limitations. This study characterized the effects of neonatal social isolation (early deprivation, ED) on adult C57BL/6 mouse behavior in a social context using our recently developed behavioral test protocols for group-housed mice. During the first two postnatal weeks, half of the pups per dam were separated from their dam and littermates for 3h per day (ED group). Post weaning, ED and control pups were electronically tagged and co-housed. At 12weeks, the mixed cohorts were transferred to IntelliCages, equipped with computer-controlled operant chambers. Access to the chambers was used as an index to analyze novel object response, behavioral flexibility, and competitive dominance with minimal experimenter intervention. In general, ED had greater effects on males; ED males exhibited reduced body weight, increased novelty response, and were subordinate to control littermates when competing for reward access. Male ED mice also demonstrated mildly impaired reversal learning. Analyzing gene expression changes in brain regions controlling emotion, stress, spatial memory, and executive function revealed reduced BDNF and c-Fos in hippocampal CA1, enhanced c-Fos in the basolateral amygdala, reduced Map2 while enhanced HSD11β2 in prefrontal cortex of ED males. In male mice, it was suggested that neonatal social isolation results in sustained changes in social behavior with altered function of limbic and frontal cortices.

Evidence That the Periaqueductal Gray Matter Mediates the Facilitation of Panic-Like Reactions in Neonatally-Isolated Adult Rats

Plenty of evidence suggests that childhood separation anxiety (CSA) predisposes the subject to adult-onset panic disorder (PD). As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG). Accordingly, here we examined whether the neonatal social isolation (NSI), a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST) respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2) until weaning (PN21) allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, n = 26) whilst siblings (sham-isolated rats, SHAM, n = 27) and dam were moved to another box in a separate room. Non-handled controls (CTRL, n = 18) remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60) and subjected to sessions of intracranial stimulation (PN65), EPM (PN66) and FST (PN67-PN68). Groups were compared by Fisher's exact test (stimulation sites), likelihood ratio chi-square tests (stimulus-response threshold curves) and Bonferroni's post hoc t-tests (EPM and FST), for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate the DPAG not only in panic attacks but also in separation-anxious children's predispositions to the late development of PD.

P.1.d.005 Modelling negative symptoms of schizophrenia: combined neonatal PCP and social isolation causes social interaction deficits in rats

P.1.d.005 Modelling negative symptoms of schizophrenia: combined neonatal PCP and social isolation causes social interaction deficits in rats

Disrupted cortical function underlies behavior dysfunction due to social isolation

Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress.

Sex difference of the effect of neonatal social isolation on experience driven synaptic delivery of AMPA receptors in rat barrel cortex

Sex difference of the effect of neonatal social isolation on experience driven synaptic delivery of AMPA receptors in rat barrel cortex

Sex difference of the effect of neonatal social isolation on experience driven synaptic delivery of AMPA receptors in rat barrel cortex

Sex difference of the effect of neonatal social isolation on experience driven synaptic delivery of AMPA receptors in rat barrel cortex

Neonatal social isolation alters both maternal and pup behaviors in rats.

The development of emotional behavior is dependent on the early experiences of the infant and the quality of maternal care. In these experiments, the effects of social isolation during the preweaning period on both pup behavior and maternal responsivity were examined. In the first study, the number of ultrasonic vocalizations (USVs) emitted after brief maternal separation was measured in neonatal rats with differing histories of social isolation. The social isolation procedure consisted of 5 days of daily separation from the dam and littermates for either 3 or 6 hr. At both ages tested, socially isolated pups vocalized significantly less than control pups. In the second study, the effects of prior isolation either daily for 5 previous days (Chronic Isolation) or for 4 hr prior to testing (Acute Isolation) were examined in a T-maze choice test. Pup vocalizations in the presence of the dam and dams' maternal behavior were assessed. When the dam was confined to the start box or during the maternal free access period, both Chronic and Acute Isolates vocalized less than pups that had never left the home nest. Dams spent more time with and licked and groomed more frequently and for a longer time both Chronic and Acute Isolates compared to pups that had always been with dams in the home nest. These results suggest that early isolation experience can alter subsequent responses to separation stress in neonatal rats and that maternal behavior is sensitive to the prior experiences of offspring.

The effects of neonatal social isolation on the behavior and endocrine function of Holstein calves

A link between neonatal isolation and increased milk production has been reported for Holstein dairy cattle (Donaldson, 1970; Arave et al., 1985). This research proposes and investigates four mechanisms that might underlie this effect. Three hypotheses were unsupported: neonatal isolation did not affect social dominance, reproductive maturation or socialization to humans. A fourth hypothesis proposes that neonatal isolation, by imposing stress, has organizational effects on hypothalamo-hypophyseal-adrenal axis function. This was supported by behavioral and endocrine evidence. Isolated calves stood more ( P < 0.02) and tended to vocalize and investigate more than controls, evidence of discontent or stress. As yearling heifers, isolates had a higher mean serum cortisol concentration than controls ( P < 0.01) following short-term stressors. Differences in adrenocortical function may, therefore, underlie the effects of neonatal isolation on milk yield, by affecting cows' ability to maintain homeostasis when stressed.