Maternal and littermate deprivation disrupts maternal behavior and social-learning of food preference in adulthood: tactile stimulation, nest odor, and social rearing prevent these effects

Maternal and littermate (social) separation, through artificial rearing (AR), disrupts the development of subsequent maternal behavior and social learning in rats. The addition of maternal-licking-like stimulation during AR, partially reverses some of these effects. However, little is know about the role of social stimuli from littermates and nest odors during the preweaning period, in the development of the adult maternal behavior and social learning. The purpose of this study was to examine the effects of peer- and peer-and-odor rearing on the development of maternal behavior and social learning in rats. Female pups were reared with mothers (mother reared-MR) or without mothers (AR) from postnatal day (PND) 3. AR rats received three different treatments: (1) AR-CONTROL group received minimal tactile stimulation, (2) AR-ODOR females received exposure to maternal nest material inside the AR-isolation-cup environment, (3) AR-SOCIAL group was reared in the cup with maternal nest material and a conspecific of the same-age and same-sex and received additional tactile stimulation. MR females were reared by their mothers in the nest and with conspecifics. In adulthood, rats were tested for maternal behavior towards their own pups and in a social learning task. Results confirm our previous report that AR impairs performance of maternal behavior and the development of a social food preference. Furthermore, social cues from a littermate, in combination with tactile stimulation and the nest odor, reversed the negative effects of complete isolation (AR-CONTROL) on some of the above behaviors. Exposure to the odor alone also had effects on some of these olfactory-mediated behaviors. These studies indicate that social stimulation from littermates during the preweaning period, in combination with odor from the nest and tactile stimulation, contributes to the development of affiliative behaviors.     

Adrenocortical response to stress in fasted and unfasted artificially reared 12-day-old rat pups

Recent studies have compared artificially reared (AR) rats with dam-reared rats on behavioral outcomes but, despite the fact that they are deprived of their mothers during the stress hyporesponsive period (SHRP), little is known about the effects of AR on the development of the stress response. In this study, the corticosterone (CORT) response to a stressor (saline injection ip) on postnatal Day 12 was assessed in rat pups that had been either dam-reared (DR) or artificially reared since Day 5. In the preceding 24 hr, half the pups in the DR group were maternally deprived (DEP). To control for the food deprivation consequent to maternal deprivation in these groups, half the pups in the AR groups also underwent 24-hr food deprivation (DEP). In the nondeprived condition AR pups did not differ from DR pups on untreated CORT levels or on levels at 1-hr poststress (i.e., all rats demonstrated low levels of CORT characteristic of the SHRP). In contrast, both maternally deprived DR pups and food-deprived AR pups exhibited increased untreated CORT levels as well as a significant increase at 30-min poststress, but CORT elevations were lower in the AR groups than in the DR groups. Thus, long-term maternal deprivation through artificial rearing in rats does not affect the reduced CORT levels and reduced CORT responsiveness associated with the SHRP; however, if animals are food deprived, then all show increased basal CORT levels and a greater CORT response to stress, although this response is lower in AR groups than in DR groups. These results suggest that rat pups artificially reared with adequate nutrition will still exhibit the SHRP.     

Absence of behavioral deficits following neonatal undernutrition in the rat

Previous studies of the effects of early undernutrition on behavior in adult rats have confounded underfeeding with maternal deprivation or membership in a large litter. In the present experiment food-deprived rats received full-time maternal care and lived in the same-sized litters as well-fed controls. In contrast to previous findings food-deprived animals in the present study did not differ from controls in the open-field test, in a test of motor coordination, and in 2 learning tasks. However, food-deprived animals were more active than controls in a residential plus maze. Females showed less effect of food deprivation on body growth, but a much greater effect on activity, than males. These findings suggest that early undernutrition when not confounded with social and maternal deprivation may have more restricted effects on adult behavior than has been previously believed.     

Intergenerational effects of complete maternal deprivation and replacement stimulation on maternal behavior and emotionality in female rats

The present study investigated the effects of early rearing experiences on the development of maternal behavior in Sprague-Dawley female rats. Pups from individual litters were assigned to four different groups on Day 3 of life. From days 4 to 20 of life, these were reared artificially, without mother and receiving minimal "licking-like" tactile stimulation (AR-MIN), or maximal stimulation (AR-MAX) or were reared with their mothers (MR-CONTROL and MR-SHAM). At 70-100 days all AR and MR animals were mated and then observed with their own offspring, culled to eight pups. After maternal testing open-field tests were conducted. The female offspring in these litters (all raised by their MR and AR mothers) were reared to adulthood and then observed interacting with their offspring. Results show that in adulthood AR mothers engaged in significantly fewer pup-retrievals and less pup-licking (genital and body), and crouching, but significantly more non-maternal tail-chasing, digging, and hanging/climbing. As well, they were more active in the open field. Comparisons between the two AR groups and the MR groups, showed that most of the differences were between the AR-MIN and MR groups, with the AR-MAX animals showing levels of behavior between the two, and differing from neither. Analyses of covariance indicated that early experience and adult emotional behavior both influence adult maternal behavior, but their effects are independent of one another. A cross-generational effect of artificial rearing was also found. Daughters of AR and MR mothers that were observed after the birth of their own litters in adulthood showed a pattern of behavior that mimicked the pattern shown by their mothers. These results are discussed in terms of the variety of possible behavioral, endocrine, and neurochemical mechanisms that mediate the effects of early experiences on adult maternal behavior.     

Early-life maternal separation and social isolation produce an increase in impulsive action but not impulsive choice

Early life environment, events, and context, such as mother-offspring relationship, can have profound effects on future behavior and physiology. We investigated the effects of long-term maternal and social separation, through artificial rearing, on adult impulsivity. Rats were maternally reared (MR) or artificially reared (AR) and half of the AR rats were provided with replacement somatosensory stimulation intended to simulate maternal licking. There are at least 2 forms of impulsivity and we compared rats on 1 test of impulsive action (differential reinforcement of low rates of responding-DRL-20s) and 2 tests of impulsive choice (delay discounting and fixed consecutive number schedule-FCN). We found that AR rats are more action impulsive; however, this effect can be reduced by maternal licking-like stimulation. In contrast, AR rats did not display an increase in impulsive choice. Overall, these experiments show that early life maternal and social separation have different effects on the 2 forms of impulsivity.     

The effects of early isolation on sexual behavior and c-fos expression in naïve male Long-Evans rats

Previous findings have demonstrated that the maternal environment is important for the development of male sexual behavior. The present study examined the effects of complete early life isolation and replacement 'stroking' stimulation on male sexual behavior and neural activation as seen by Fos immunoreactivity (Fos-IR). Animals were either artificially reared (AR) with minimal (AR-MIN) or maximal (AR-MAX) body simulation, or maternally reared (MR). In adulthood, animals were either given an exposure to an estrous female (EXP) or left undisturbed (NoEXP). No significant effects of early development were found in sexual behavior; however differences in activation in response to this exposure were observed. AR-MIN animals showed lower Fos-IR in the medial preoptic area and the ventromedial hypothalamus compared to MR animals. AR-MAX animals were not significantly different from either condition. These findings demonstrate that although there are no differences in the quality of the first copulatory exposure between AR and MR animals, the brain's response to this exposure differs in sites within the brain that subserve sexual behavior.     

Thymic stress in artificially reared and maternally reared rat pups

It is well documented that the hypothalamic-pituitary-adrenal (HPA) axis influences immunological responses to stress. Maternal factors have been shown to be necessary for appropriate modulation of the HPA axis in the developing rat. The purpose of this study was to determine whether artificially reared (AR) infant rat pups (a procedure whereby infant rats are gastrostomized and reared independently of maternal factors) have an altered function of the HPA axis in terms of thymocyte apoptosis (programmed cell death) and other indices of thymic stress. AR and maternally reared (MR) Long–Evans rat pups were randomized to control, fasted, stressed, and fasted+stressed treatment groups, as well as an unhandled, MR naive group that served as a baseline control. AR rat pups were significantly heavier than MR (p<0.001). AR rat pups had significantly lighter thymuses than did the MR pups (p<0.001) and fasted pups had significantly lighter thymuses than unfasted pups, regardless of whether they were in the AR or MR condition (p<0.005). AR pups had significantly lower thymic cell numbers and a greater percent of necrotic cells than did MR pups. There were no significant effects of rearing condition on the percent of apoptotic thymocytes. The thymocyte alterations observed in this study between the two rearing conditions suggest that AR reduces thymic weight and cell numbers, which may have consequences for the development of adult cellular immunity.     

Artificial rearing of rat pups using rat milk

The contribution of diet and surgery to the brain weight deficits observed in artificially reared rats was investigated. Four day old Long Evans rat pups were assigned to an artificially reared (AR) or mother reared (MR) group. AR pups were encannulated and fed either rat milk (AR-MOM) or replacement formula (AR-MES). MR pups received a sham encannulation (MR-SHAM) or no surgery (MR-CONT) before being returned to their dam for rearing. On day 7 all the animals were killed. Brain weights and visceral organ weights were obtained. There was no significant difference between the MR groups on any measure except stomach weights. AR-MOM pups had larger visceral organ weights than pups in the other groups. AR-MOM and AR-MES pups had similar whole brain weights, smaller than those of the MR pups. However, the cerebellar weights, and to a lesser extent, brainstem weights, showed improvements in the AR-MOM group, over the AR-MES group. Neither the effect of surgery nor of diet alone can account for the organ weight differences that have been described in AR rats. The possibility that normal growth may be primarily dependent on diet at one stage of development, with other factors gaining importance at later stages is discussed.     

Experimental modification of brain weight and behavior in mice: an enrichment study

The effects of environmental enrichment and isolation on cortical weight and learning ability were measured in mice from lines selectively bred for high and low brain weight and from an unselected control line from the same foundation population. Animals from these selected lines differed not only on brain weight, but on discrimination task performance as well. Isolated and enriched animals did not differ in cortical weight, nor was there any significant interaction of rearing conditions with lines. Those animals reared in enrichment were superior to those reared in isolation, both for initial acquisition and for number of reversal tasks performed on a water maze discrimination task. High brain weight animals did not differ from low brain weight animals on initial acquisition across treatment conditions. However, high brain weight animals made significantly more reversals within the testing period. The high, control, and low brain weight animals did not order themselves linearly on the behavioral measures: control line animals performed poorest for both initial acquisition and number of reversals.     

Comparison of the performance of DBA/2 and C57BL/6 mice in transitive inference and foreground and background contextual fear conditioning

DBA/2 mice have altered hippocampal structure and perform poorly in several hippocampus-dependent contextual/spatial learning tasks. The performance of this strain in higher cognitive tasks is less studied. Transitive inference is a hippocampus-dependent task that requires an abstraction to be made from prior rules to form a new decision matrix; performance of DBA/2 mice in this task is unknown, whereas contextual fear conditioning is a hippocampus-dependent task in which DBA/2 mice have deficits. The present study compared DBA/2J and C57BL/6J inbred mice in two different contextual fear conditioning paradigms and transitive inference to test whether similar deficits are seen across these hippocampus-dependent tasks. For background fear conditioning, mice were trained with two paired presentations of an auditory conditioned stimulus (CS, 30 seconds, 85 dB white noise) paired with an unconditioned stimulus (US, 2 seconds, 0.57 mA footshock), the context was a continuous background CS. Mice were tested for contextual learning 24 hours later. Foreground fear conditioning differed in that no auditory CS was presented. For transitive inference, separate mice were trained to acquire a series of overlapping odor discrimination problems and tested with novel odor pairings that either did or did not require the use of transitive inference. DBA/2 mice performed significantly worse than the C57BL/6 in both foreground and background fear conditioning and transitive inference. These results demonstrate that the DBA/2 mice have deficits in higher-cognitive processes and suggest that similar substrates may underlie deficits in contextual learning and transitive inference.     

Pup exposure differentially enhances foraging ability in primiparous and nulliparous rats

The role of maternal experience (i.e., pregnancy and pup exposure) on rats' performance in a foraging task was assessed. Primiparous (P) and nulliparous (N) animals were either exposed to pups for 21 days (+) or received no pup exposure (-). Following habituation trials, all animals were tested in spatial and cued versions of the dry land maze (DLM) for three days (three trials per day). In the spatial DLM, the presence of pups decreased latencies in both N and P groups in Trial 5 and P+ rats exhibited shorter latencies to baited food wells than P- animals on Trial 6. In the subsequent probe trial, P+ animals spent significantly more time in proximity to the previously baited well than P- rats. Pups enhanced performance of both P+ and N+ groups in trial 6 of the cued test. Thus, in the spatial task, the individual components of the maternal experience (e.g., pregnancy, parturition, lactation, and pup exposure) converge to produce behavioral modifications in the DLM spatial and probe tasks that enable the female to care for her offspring, in this case, by enhancing foraging behavior. Further, in one trial of each version of the task, pup exposure enhanced performance in N animals suggesting that, in isolation, pup exposure may be a more important influence on ancillary maternal behavior than the pregnancy itself.     

Brain and behavioral effects of dietary n-3 deficiency in mice: A three generational study

Feeding mice a diet deficient in n-3 fatty acids for three generations resulted in a 53% decrease in docosahexaenoic acid (DHA, 22 : 6n-3) in the brain. Maternal pup retrieval and social learning of a food preference are both tasks based on olfactory function. All dams made contact more readily with pups of their own dietary group, and animals of both dietary groups demonstrated the ability to learn a food preference through exposure to a conspecific that had previously eaten the food. Both groups showed similar ability to learn the location of the hidden platform in the Morris water maze, while the n-3 deficient animals were marginally faster in locating the platform on the cued trial. They were also more active when tested in the open field. While they did not differ in their duration of immobility in a forced swimming test, the deficient animals did have longer paw-lick latencies on a hot plate. Thus, in this study a significant reduction in brain n-3 fatty acid composition, while associated with some indications of change in emotional reactivity, did not impair olfactory function or learning of either a latent or spatial nature.©1994 John Wiley & Sons, Inc.     

The polyunsaturated fatty acids, EPA and DPA exert a protective effect in the hippocampus of the aged rat

Age is characterized by deficits in synaptic function identified by decreased performance of aged animals in spatial learning tasks and reduced ability of animals to sustain long term potentiation (LTP). Several cellular and molecular events are correlated with these deficits, many of which are indicative of age-related neuroinflammatory and oxidative cell stress. It is significant that agents which decrease microglial activation are commonly associated with restoration of function. We set out to examine whether the n-3 polyunsaturated fatty acid docosapentaenoic acid (DPA), which is a metabolite of eicosapentaenoic acid (EPA), could modulate the age-related increase in microglial activation and the associated increase in oxidative changes and therefore impact on synaptic function in aged rats. We demonstrate that docosapentaenoic acid possesses neurorestorative effects and is capable of downregulating microglial activation. The data show that it also decreases the coupled activation of sphingomyelinase and caspase 3, probably because of its ability to decrease age-related oxidative changes, and consequently attenuates the age-related decrease in spatial learning and long-term potentiation.     

The behavioral response to novelty is altered in rats neonatally exposed to cocaine

It has recently been suggested that the effects of in utero cocaine exposure may result in subtle deficits related to a challenging environment, including exposure to novelty or stress. This study used a neonatal drug-exposure model to examine the behavioral response to a novel environment in rodents. Subjects were artificially reared (AR) from postnatal Days 4-10. There were four treatment groups; AR 40 mg/kg/day cocaine, AR 20 mg/kg/day cocaine, AR control group receiving no drug, and a normally reared control. In Experiment 1, subjects were tested for their preference of maternal home-cage or clean wood-chip odors in a T-maze on postnatal Day 15. Subjects from all treatment groups preferred the maternal odor. In Experiment 2, subjects were habituated to four familiar odors and tested with a novel odor in an open field (postnatal Days 16-21). Neonatal exposure to 20 mg/kg/day cocaine led to an overall increase in exploratory behavior during testing, whereas 40 mg/kg/day did not, supporting the hypothesis that developmental exposure to cocaine at some doses may alter the offspring's response to a changing environment.     

Interferon-alpha-induced deficits in novel object recognition are rescued by chronic exercise

The anti-viral drug interferon-alpha (IFN-alpha) is widely-known to induce psychiatric and cognitive effects in patients. Previous work has shown that physical exercise can have a positive effect against brain insult. We investigated the effects of a clinically-comparable treatment regime of IFN-alpha on cognitive function in male Wistar rats and assessed the impact of chronic treadmill running on the deficits generated by IFN-alpha. We found that IFN-alpha induced significant impairments in performance on both spatial novelty and object novelty recognition. Chronic forced exercise did not protect against IFN-alpha-induced learning deficits in reactivity to spatial change, but did restore the capacity for novel object recognition in IFN-alpha-treated animals.     

Maternally separated rats show deficits in maternal care in adulthood

Although there is considerable research on the phenomenology, neuroendocrinology, neuroanatomy, and sensory control of maternal behavior, little is known about the influences of early postnatal and postweaning experiences on the development of maternal behavior. The purpose of this study was to assess how early life separation from the mother rat affects development of the offspring's juvenile and adult maternal behavior. From postnatal Days 1 to 17, 3 female rats within each litter were separated (SEP) from the mother and the rest of the litter for 5 hr daily while 3 of their sisters were not maternally separated (NSEP). On postnatal Day 21, all subjects were weaned and randomly assigned to one of three juvenile conditions. One female from both SEP and NSEP groups was either isolated (I), given a social conspecific (S), or given 1- to 4-day-old pups (P) for 5 consecutive days. Maternal behavior of SEP and NSEP animals was assessed and recorded on each of the 5 days. Once all animals reached adulthood, they were mated, gave birth, and were assessed for their maternal behavior. We found that the effects of maternal separation on juvenile maternal-like behaviors were minimal. On the other hand, maternal separation reduced adult maternal licking and crouching over pups. In addition, there was a significant interaction between postnatal and juvenile experience on maternal crouching in maternal animals. These results are discussed in terms of the variety of possible behavioral, endocrine, and neurochemical mechanisms that mediate the effects of early life experiences on adult maternal behavior.     

Chronic lithium treatment magnifies learning in rats

Recent electrophysiological work shows that chronic lithium treatment increases long-term potentiation (LTP) in neurons of the hippocampus, and LTP is thought to be the major neurophysiological basis for the development of learning and memory. This suggests that lithium might enhance learning and memory. Available studies have mainly assessed memory using aversive conditioning paradigms, but very little is available on the effect of lithium on learning. Since lithium may diminish anxiety or negative affect in adult rats, which would hinder aversive learning, the present study used three different positive reinforcement spatial cognitive tasks to determine whether chronic lithium affects learning. Each task differed in complexity, in the type of learning required, and in the reward received. For 4 weeks prior to, and throughout all learning assessments, rats had continual access to lithium chow or to a control chow diet. After 4 weeks’ access to their designated chow diet, rats began conditioning in the hole-board spatial discrimination or T-maze delayed alternation tasks in a counterbalanced fashion. They immediately began conditioning in the opposite task once completing the first. This was then followed with social place-preference conditioning, after 24-h isolation from their home-cage social partner. Chronic lithium increased learning in all three paradigms, regardless of the reward received. Indeed, both food and social interaction supported enhanced learning. Thus the learning effect was not merely due to an effect of lithium on food palatability. Importantly, clinically relevant serum lithium levels were evidenced at the time of testing. Lithium also marginally enhanced memory as well. Thus chronic lithium treatment may improve learning and memory in Alzheimer’s disease, and do so not only by blocking the formation of beta-amyloid and neurofibrillary tangles as suggested by previous research, but also by enhancing mechanisms involved in basal learning and memory formation, such as hippocampal synaptic plasticity.     

Incubator rearing of infant rats without the mother: Effects on adult emotionality and learning

Eight newborn rats, from 3 litters, were separated from the mother and reared during the usual 3-week nursing period in an artificial environment which included an incubator, a warm, moist, pulsating surrogate mother, and special feeding procedures. The incubator animals showed some superiority over mother-reared littermates in performance on the Hebb-Williams test; and, on measures taken in the open field, the incubator animals showed a greater change over trials. Contrary to previous experimental results, our findings indicate that, at least in the rat, maternal deprivation may affect behavioral patterns but does not necessarily and inevitably result in a deficit in adult behavior.     

Effects of posttrial vasopressin injections on appetitively motivated learning in rats

Sixty male rats, maintained on 23-hr food deprivation were trained on two types of appetitive tasks: bar press responding under a CRF schedule, and under a differentially reinforced (light+, dark?) schedule. Performance of rats treated with lysine vasopressin, injected immediately after each training session, was compared to that of control animals injected with saline. In the CRF stage, treated animals reached learning criterion significantly later than did control rats, and made significantly fewer bar presses. During acquisition and extinction of a light-dark discrimination, learning and retention were not altered by vasopressin, though the number of bar presses was significantly decreased, and a differential effect was found according to previous CRF performance. The results are discussed considering the hypothesis of a facilitatory effect of vasopressin on memory processes.     

Motor and cognitive deficits in the heterozygous leaner mouse, a Cav2.1 voltage-gated Ca2+ channel mutant

The leaner mutation in mice affects the Ca(v)2.1 voltage-gated calcium channel alpha(1A)-subunit gene (Cacna1a), causing a reduction in calcium currents predominantly in Purkinje cells. This reduction in calcium currents causes severe progressive cerebellar ataxia, beginning around postnatal day 10, in homozygous leaner mice (tg(la)/tg(la)), while their heterozygous littermates (tg(la)/+) present no obvious behavioral deficits. In humans, heterozygous mutations in the Cacna1a orthologous gene produce a broad range of neurological manifestations. To evaluate the phenotypic status of the tg(la)/+ animals, we assessed motor performance and cognition, at different ages, in these mutant mice. We were able to observe age-dependent impairment in motor and cognitive tasks; balance and motor learning deficits were found in demanding tasks on the rotarod and on the hanging wire test, while spatial learning and memory impairment was observed in the Morris water maze. Progressive dysfunction in escape reflexes, indicative of neurological impairment, was also present in tg(la)/+ animals. Although not presenting major motor alterations, tg(la)/+ mice show age-dependent motor and cognitive deficits.