Isolation-reared Animals Research Articles

Negative visuospatial priming in isolation-reared rats: Evidence of resistance to the disruptive effects of amphetamine.

Negative visuospatial priming (NP) represents a quantifiable measure of inhibitory information processing that is disrupted in several neurodevelopmental and psychiatric disorders, including schizophrenia. We developed a novel rodent NP task to investigate mechanisms underlying NP and its role in various disorders, and to test potential therapeutics. In the present studies, we further characterized this novel paradigm by investigating whether NP is disrupted in rats reared in isolation, a developmental manipulation that produces a range of abnormalities in behavior, neurochemistry, and brain structure that mirror aspects of schizophrenia pathology. We also further explored the role of monoaminergic signaling in NP and the effects of isolation rearing by challenging both socially reared and isolation-reared rats with D-amphetamine during the NP task. Although fewer isolation-reared animals learned the complex NP task, those that learned exhibited unaffected NP compared with socially reared rats. Consistent with previous reports, D-amphetamine impaired NP and increased motor impulsivity in socially reared rats. In contrast, D-amphetamine did not affect NP or motor impulsivity in isolation-reared rats. These data confirm a monoaminergic influence on NP behavior and indicate that rats reared in isolation have altered dopaminergic sensitivity.

Isolation rearing effects on probabilistic learning and cognitive flexibility in rats

Isolation rearing is a neurodevelopmental manipulation that produces neurochemical, structural, and behavioral alterations in rodents that in many ways are consistent with schizophrenia. Symptoms induced by isolation rearing that mirror clinically relevant aspects of schizophrenia, such as cognitive deficits, open up the possibility of testing putative therapeutics in isolation-reared animals prior to clinical development. We investigated what effect isolation rearing would have on cognitive flexibility, a cognitive function characteristically disrupted in schizophrenia. For this purpose, we assessed cognitive flexibility using between- and within-session probabilistic reversal-learning tasks based on clinical tests. Isolation-reared rats required more sessions, though not more task trials, to acquire criterion performance in the reversal phase of the task, and were slower to adjust their task strategy after reward contingencies were switched. Isolation-reared rats also completed fewer trials and exhibited lower levels of overall activity in the probabilistic reversal-learning task than did the socially reared rats. This finding contrasted with the elevated levels of unconditioned investigatory activity and reduced levels of locomotor habituation that isolation-reared rats displayed in the behavioral pattern monitor. Finally, isolation-reared rats also exhibited sensorimotor gating deficits, reflected by decreased prepulse inhibition of the startle response, consistent with previous studies. We concluded that isolation rearing constitutes a valuable, noninvasive manipulation for modeling schizophrenia-like cognitive deficits and assessing putative therapeutics.

Juvenile social experience regulates central neuropeptides relevant to emotional and social behaviors

Stressful social experiences during early-life can increase the risk of developing neuropsychiatric disorders associated with anxiety, mood, and personality. Early neglect also alters peripheral arginine vasopression (AVP) and oxytocin (OXT). We hypothesized that a lack of social stimuli should adversely affect developmental AVP and OXT systems. To test this idea, we examined changes of central AVP- and OXT-immunoreactive (ir) cell number as well as its related behaviors in socially isolated rats. Animals were weaned at 23 days of age, divided into group- or isolation-reared conditions, and maintained for at least 2 weeks. At 38–48 days of age, animals were sacrificed for immunohistochemistry, or used for two behavioral tests: elevated plus-maze test and social recognition test. The results from immunohistochemistry showed that isolation-reared males have decreased AVP-ir cells in the paraventricular nucleus hypothalamus (PVH), medial parvicellular part, ventral zone, and that isolation-reared females have decreased OXT-ir cells in the PVH, medial parvicellular part, dorsal zone, when compared with group-reared counterparts. The results from behavioral assessment showed that isolation-reared animals have difficulty with social recognition, and that isolation-reared males, but not females, have anxiogenic profile. The present study demonstrates that post-weaning social isolation results in decrease of male AVP-ir cells and female OXT-ir cells in the PVH parvocellular divisions, and supports the idea that juvenile social environment may play a critical role in neuronal and behavioral development.

Early life social isolation alters corticotropin-releasing factor responses in adult rats

Stress induced by early life social isolation leads to long-lasting alterations in stress responses and serotonergic activity. Corticotropin-releasing factor (CRF) is a neurotransmitter that mediates stress responses and alters serotonergic activity. We tested the hypothesis that the stress of early life isolation enhances responses to CRF in adulthood by determining the effect of CRF infusions into the dorsal raphe nucleus (dRN) on 5-HT release in the nucleus accumbens (NAc) of adult rats using in vivo microdialysis. Juvenile male rats were either isolated or housed in groups of three for a 3-week period beginning on postnatal day 21 after which, all rats were group-reared for an additional 2 weeks. Following the isolation/re-socialization procedure, infusion of 100 ng CRF into the dRN decreased 5-HT release in the NAc of group-reared rats. This treatment did not significantly affect 5-HT release in the NAc of isolation-reared animals. In contrast, infusion of 500 ng CRF into the dRN transiently increased 5-HT release in the NAc of both group-reared and isolated animals with isolated animals showing a more prolonged serotonergic response. Western blot and immunofluorescent staining for CRF receptors in the dRN showed that CRF2 receptor levels were increased in the dRN of isolation-reared animals when compared with group-reared rats. Taken together, the results suggest that isolation during the early part of development causes alterations in both CRF receptor levels and CRF-mediated serotonergic activity. These effects may underlie the increased sensitivity to stress observed in isolates.

Isolation-Induced Changes in Ultrasonic Vocalization, Fear-Potentiated Startle and Prepulse Inhibition in Rats

Isolation causes important changes in the behavioral reactivity of rats to environmental stimuli. These changes include deficit in sensorimotor gating and altered fear-like responses to aversive stimuli. Measures of ultrasound vocalizations at 20–22 kHz when rats are exposed to threatening conditions, such as novelty, have been taken as a good measure of fear. The fear-potentiated startle to loud sounds and the prepulse inhibition tests have been considered reliable indicators of anxiety and attention impairments, respectively. Rats reared under conditions of isolation from weaning display clear deficits in prepulse inhibition. Taking into account that housing condition changes the emotional state of the animals, we evaluated in this work the performance of rats in the fear-potentiated startle test, prepulse inhibition and emission of ultrasound vocalizations to novelty when isolated for 10 days and after resocialization for 1 week in comparison to grouped rats. Isolated rats showed greater reactivity to loud sounds in the fear-potentiated startle test than grouped animals. They also emitted less ultrasound vocalizations at 20–22 kHz than grouped animals when exposed to a novel environment. In contrast to the well-known deficit in prepulse inhibition displayed by isolation-reared animals, in the present study isolation for 10 days caused a significant increase in prepulse inhibition. Resocialization was not able to counteract the effects of isolation in all three tests. The results suggest that the emotional state of the animals is altered by 10 days of isolation; they do not vocalize characteristically as grouped rats when submitted to novelty; unconditioned responses to loud sounds are enhanced and increased prepulse inhibition is shown rather than a deficit as largely documented in studies with isolation-reared animals. It is suggested that the assessment of the emotional state of the animals is a prerequisite in the evaluation of prepulse inhibition. The level of defensive reactivity displayed by isolated animals is crucial for the functioning of sensory gating and, by extension, to the expression of prepulse inhibition.

Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation.

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.

Enhanced Neurotensin Neurotransmission Is Involved in the Clinically Relevant Behavioral Effects of Antipsychotic Drugs: Evidence from Animal Models of Sensorimotor Gating

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Isolation-rearing of rats produces deficits as adults in the serotonergic innervation of hippocampus

Isolation-rearing of rats causes a variety of behavioral changes, including anxiety, learning deficits and sensory changes related to schizophrenia. Similar changes are seen following loss of serotonin during development. Thus, the effects of isolation-rearing on behavior may be due to changes in serotonin. Sprague-Dawley rats were raised in groups of four (social animals) or in isolation, from postnatal day 22 until postnatal day 64. The hippocampi were examined immunochemically for changes in serotonin. Our findings show that serotonin terminals are lost throughout the CA regions of hippocampus, where there is also an associated loss of dendrites, but not in the molecular layer of the dentate gyrus. Thus, some of the brain and behavioral changes seen in isolation-reared animals could be due to loss of serotonin.

Fighting, nonagonistic social behavior, and exploration in isolation-reared rats

Sixty hooded Long-Evans rats were assigned to one of three conditions: isolation-rearing (from 14–30 days of age), brief isolation (from 28–30 days of age), and normal (no isolation). From day 14 to day 21, the isolation-reared animals were maintained in an incubator set at 35°C to prevent hypothermia and were separated from each other by Plexiglas. They learned to nourish themselves by lapping milk that continuously flowed down one side of the enclosure. Thereafter, they were housed in standard hanging wire cages. Unlike previous studies of isolation at this age, there were no significant weight differences between the isolation-reared group and the two control groups. At 30 days of age, the three groups were compared on fighting (serious and play), nonagonistic social behaviors (following and crawling under), and exploratory behavior (open-field ambulation). The isolation-reared group was significantly different from the normal group on all measures (isolates were higher on all measures except exploration). The isolation-reared animals showed significantly more serious fighting (aggression) than the brief isolation animals, whereas these two groups did not differ on other behaviors. This methodology allows for the study of isolation-rearing without the nutritional confounds found in previous research and shows an effect on aggression that is not accounted for by recent isolation. Aggr. Behav. 25:211–223, 1999. © 1999 Wiley-Liss, Inc.

The Disruption of Prepulse Inhibition by Social Isolation in the Wistar Rat: How Robust Is the Effect?

Postweaning isolation rearing in rats is shown to have consequences for the expression of numerous behaviors. The present studies investigated isolation-induced disruptions of the prepulse inhibition (PPI) response in the Wistar rat strain, as a function of exposure of the animals to locomotor activity testing. Further, repeated testing of PPI was investigated to examine the robustness of the isolation-induced disruptions. The results indicate that experimentally naive isolation-reared animals exhibit disruptions in the PPI response that are retained in a second test 7 days later. The disruptions obtained are shown to be consistent across all pulse frequencies examined and independent of effects on startle. Exposure to activity testing, however, either before or after the measurement of PPI, abolished the isolation-induced disruption of PPI in a subsequent test. In contrast, locomotor activity testing consistently revealed a hyperactivity response in isolation-reared animals that was not influenced by the temporal occurrence of the testing. The findings are discussed relative to the interpretation of data emerging from studies where both activity testing and PPI are performed in the same animals, and in the relation to the use of PPI in isolation-reared animals as representing a nonpharmacological animal model of schizophrenia.

Social Isolation in the Rat Produces Developmentally Specific Deficits in Prepulse Inhibition of the Acoustic Startle Response Without Disrupting Latent Inhibition

A series of experiments examined the effects of 8 weeks of social isolation on spontaneous locomotor activity, prepulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI) in a conditioned suppression paradigm, and basal and d-amphetamine stimulated dopamine (DA) release in the ventral striatum, as measured by in vivo microdialysis. Both isolation-reared animals (those isolated from the weaning age) and isolation-housed animals (those isolated as adults) were hyperactive when placed in a novel environment. Social isolation also led to deficits in PPI of the acoustic startle response that were specific to isolation-reared animals. Isolation rearing was without effect on the expression of LI but did lead to an enhanced response to systemic d-amphetamine in terms of striatal DA release. The data are discussed with respect to the involvement of ventral striatal DA mechanisms in the expression of PPI and LI, differences in the impact of social isolation in young and adult animals, and the utility of social isolation model as a nonlesion, nonpharmacologic means of perturbing ventral striatal DA function.

Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia

Schizophrenic patients exhibit deficits in the prepulse inhibition of startle, an operational measure of the sensorimotor gating deficits that are theorized to contribute to cognitive disorganization. In rats, the activation of mesolimbic dopamine (DA) disrupts prepulse inhibition, providing a useful model of the similar deficits in sensorimotor gating in schizophrenic patients. Rats reared in isolation exhibit neurochemical and behavioral abnormalities suggestive of hyperactivity in mesolimbic DA systems. In the present studies, rats reared in social groups or in isolation were tested in startle response paradigms using 120 or 105 dB acoustic pulses, some of which were preceded (100 msec) by prepulses that were 2, 4, 8, or 16 dB above the 65 dB background. Isolation-reared animals were hyperreactive only in response to the initial few startle stimuli. The amount of prepulse inhibition was decreased significantly in isolation-reared animals, particularly when midrange 8 dB prepulses were used. A subsequent study replicated the effect of isolation rearing on prepulse inhibition and suggested that the deficit in sensorimotor gating exhibited by isolation-reared animals may be normalized by the administration of the DA antagonist raclopride (0.05 mg/kg). Hence, isolation rearing provides a nonpharmacological way to induce in rats a deficit in sensorimotor gating that is exhibited by schizophrenic patients.

Effect of isolation rearing on 5-HT agonist-induced responses in the rat

Rats were reared from weaning (21 days of age) either in isolation or in social groups of five for 30 days and were then tested for spontaneous locomotor activity and 7 days later for 5-hydroxytryptamine (5-HT) agonist-induced behaviour. Isolation-reared animals displayed locomotor hyperactivity when placed in a novel environment. 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg IP) and 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) (0.32 mg/kg SC) elicited various components of the "5-HT behavioural syndrome" in both groups of animals, with forepaw treading and flat body posture being significantly more pronounced in isolation-reared animals. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg IP), a 5-HT2 selective agonist, produced a significantly greater number of back muscle contractions in isolation-reared animals but there was no difference between the two groups in the number of wet-dog shakes produced. Forepaw treading and flat body posture are thought to be mediated by 5-HT1A receptor activation, and stimulation of this receptor by either 5-MeODMT or 8-OH-DPAT produced greater responding in isolation-reared rats, suggesting supersensitivity of the post-synaptic 5-HT1A receptor. Wet-dog shakes are thought to be mediated by 5-HT2 and other (none-5-HT) receptors while back muscle contractions have been shown to be mediated by 5-HT2 receptors, indicating that there is also an increase in 5-HT2 receptor responsiveness in the socially-isolated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Social Deprivation on the Social Behavior of Mice (Mus musculus)

104 ddY mice had been reared in two conditions since weaning. 48 animals were group-reared with 4 to 6 animals pergroup, whereas 56 were isolation-reared. 9 weeks after rearing, encounter tests were conducted at which four unfamiliar animals from the same rearing condition were simultaneously released at the four corners of a square open-field. Their social behaviors listed in Table 1 were observed by the random scanning method for twenty minutes.The results indicated that the isolation-reared animals rarely showed the behavioral sequences of “Sniff 1 (sniffing others in one way) → Allogroom→ Genital-sniff” and “Attack→ Upright” (Fig. 1). As a whole the isolated animals showed more attacks, Fights, and less Grooms, Genital-sniffs and Sniff 1s than the group-reared animals did (Fig. 2). Looking at the results of the group-reared animals in more detail (Fig. 3), it was noticed that in most cases when Attacks occurred only the first-ranked animals (Rank 1) exclusively did Attacks following little or no Fight. The median value of Attacks showed by the group-reared Rank 1 animals was not less than that of the isolated animals. However, the most noticeable characteristics of the group-reared mice was their constant Grooms and Genital-sniffs whether of not they engaged in a high amount of Attacks.Considering the effect of isolation on aggression it would be difficult to conclude that isolated animals are more aggressive than group-reared animals from the results of the four animals encounter test the authors used. The clearest effect of isolation seems to be the lack of Allogrooms and Genital-sniffs which are necessary to regulate social relationships. This proves that isolated animals lack social communication skills. In other words, these social behaviors need to be learned in social contexts so as to be used skillfully.

Effects of group-rearing or partial isolation on later social behaviour of calves

Calves were either isolated, spatially but not visually, or group-reared for eight months and then kept together. Rank orders based upon competitive interactions were similar at eight and 20 months. Almost all group-reared animals were higher in rank than all isolation-reared animals. The most frequent nearest neighbour associations were between group-reared animals especially those from the same rearing group. Also frequent at eight months were associations between calves which had been isolated in adjacent pens. Isolation-reared animals associated infrequently with group-reared animals and spent more time alone. Body weight was not correlated with rearing conditions or with behavioural measures. Increase, or decrease, in rank between eight and 20 months was associated with faster, or slower, than average weight gain.

Changes in cortical dendritic branching subsequent to partial social isolation in stumptailed monkeys.

Stumptailed monkeys were reared from 1 week after birth to 6 months of age in either a colony condition with the mother or in partial social isolation that allowed visual contact with the colony animals, but not physical contact. At 6 months of age the animals were killed and selected areas of the neocortex stained by the Golgi-Cox method. Relatively nonspiney cells of Layer IV were drawn and analyzed for complexity of dendritic branching. Isolation-reared animals had significantly decreased branching complexity in Motor I cortex when compared to the control animals. A transform of the data that related the number of branches to the number of previous branches showed a slight rearing effect in Somatosensory I cortex with the deprived animals having a lower rate of branching than the controls. We conclude that social isolation also includes a motoric deprivation that could account for these data.