The effects of early handling on latent inhibition in male and female rats

Latent inhibition (LI) is a behavioral paradigm in which repeated exposure to stimuli not followed by meaningful consequences renders these stimuli ineffective for subsequent learning. The development of LI is considered to reflect learning not to attend to, ignore, or tune out irrelevant stimuli. The present study investigated the differences in the development of LI between handled and nonhandled males and females. Infantile handled (Days 1-22) and nonhandled, male and female Wistar rats were tested in maturity in the LI paradigm. The LI procedure consisted of two stages: pre-exposure, where animals received 60 presentations of the to-be-conditioned stimulus (tone) and test, where the animals acquired a two-way active avoidance response with the tone serving as the warning signal. Handled animals reached higher percentage of avoidance responses as compared with nonhandled animals. Latent inhibition was obtained in both the handled and the nonhandled females, but only the handled males showed the LI effect. Nonhandled males failed to develop LI. The results indicate that the effects of handling are evident in learning tasks that do not involve motivational-emotional variables, i.e., learning to ignore irrelevant stimuli; handling differentially affects males and females, with a much greater impact on males and the nonhandling procedure has significant deleterious consequences on adult behavior.     

Differential effects of handling on exploration in male and female rats

In this study, sex differences in the exploratory behavior of handled and nonhandled animals were measured under conditions of both high and low stimulus variation. The apparatus used was a hole-board, which provided an exploratory response independent of ambulation. Significant effects of handling were found: nonhandled animals decreased head-dipping over days whereas handled animals maintained a high rate. Sex differences were also observed: patterns of head-dipping for males and females differed over days depending on whether objects were present (high stimulus variation) or absent (low stimulus variation) under the hole-board; females also head-dipped for longer durations than males when objects were present; further, males and females showed completely opposite patterns of exploration depending on handling treatment and on level of stimulus variation. We conclude that handling differentially affects males and females, particularly as level of stimulus variability changes.     

Infantile handling and sex differences in shock-elicited aggressive responding of hooded rats

Infantile handled (Days 1-20) and nonhandled, male and female Long Evans hooded rats were tested at maturity (90-100 days) over 10 daily sessions for aggressive response to footshock. Individual jump and flinch thresholds for reactivity to shock, as well as paired aggressive responding to shock, were not significantly influenced by the handling procedure, although handled females ultimately adopted higher levels of fighting than nonhandled females. Handled rats were heavier than nonhandled rats of the same sex before and after testing for social aggression. Males fought significantly more than females; the discrepancy increased with additional sessions of paired exposure to shock. Male and female fight trends over sessions were linear and positive with a greater acceleration for males. The results were interpreted as indicative of a social learning variable occurring with repeated aggressive contact and primarily affecting males.     

A neuroleptic-like effect of ceronapril on latent inhibition.

Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early handling influences on behavioral and physiological responses during active avoidance

The effects of early handling on behavioral and physiological responses of the rat during active avoidance learning were investigated. Handled and nonhandled males and females were run in a 2-way shuttlebox task with an unconditioned stimulus of either .5 mA or .8 mA. Animals exposed to .8 mA showed a higher corticosterone response, a shorter response latency, and increased defecation. Early handling did not affect performance of the task, however handling did alter the patterns of the plasma corticosterone response over the course of avoidance training. Handled females showed less elevation of plasma corticosterone than nonhandled females, but all females showed a decrease in corticosterone over the course of avoidance learning. All males showed the drop in corticoids if run at .5 mA shock, but only handled males showed this change at .8 mA shock.     

Effects of neonatal handling on the behavior and prolactin stress response in male and female rats at various ages and estrous cycle phases of females

Neonatal handling induces behavioral and hormonal changes, characterized by reduced fear in novel environments, and lesser elevation and faster return to basal levels of plasma corticosterone, prolactin and adrenaline, in response to stressors in adulthood. The present study aimed to analyze the effects of neonatal handling from Days 1 to 10 postnatal on prolactin response to ether stress in male and female rats at three life periods: neonatal, peripubertal and adulthood. Moreover, adult females were tested in two different phases of the estrous cycle, i.e., diestrus and estrus. In another set of experiments, the behavior of peripubertal and adult males and females in estrus and diestrus was analyzed in the elevated plus maze test. Pups were either handled for 1 min (handled group) or left undisturbed (nonhandled group) during the first 10 days after delivery. In adults, in the handled females in diestrus, stress induced a lesser increase in plasma prolactin compared with nonhandled ones, as in males. However, in estrus, handled females showed no difference in the prolactin response to stress. In the elevated plus maze, handled females in diestrus, but not in estrus, showed higher locomotor activity compared with nonhandled ones. Peripubertal male and female rats handled during the neonatal period showed no difference in behavior in the elevated plus maze compared with nonhandled animals. Early-life stimulation can induce long-lasting behavioral and stress-related hormonal changes, but they are not stable throughout life and phases of the estrous cycle.     

Early handling effects on neophobia and conditioned taste aversion

The purpose of this study was to determine whether early handling, a manipulation which affects both behavioral and pituitary-adrenal responsiveness to novel and aversive situations, will affect responses in adult rats confronted with novel substances (neophobia) or with substances associated with illness (conditioned taste aversion). We found that (1) early handling reduces the neophobia shown by adult animals and that handled animals appear better able to distinguish between a preferred and a nonpreferred substance. (2) Handling reduces the magnitude of the initial taste aversion and also increases the rate of recovery of drinking to pretoxicosis levels. (3) These behavioral differences between handled and nonhandled animals are not due to differential pituitary-adrenal responses to LiCl. (4) Early handling does affect the conditioned elevation of plasma corticoids upon reexposure to milk under a Forced Extinction procedure. In this situation nonhandled animals show greater corticoid elevations than handled animals. (5) Manipulation of the number of exposures to a substance prior to pairing that substance with LiCl affects the magnitude of both the aversion and the elevation of plasma corticoids which are produced upon reexposure. As number of preexposures increase, both the magnitude of the aversion and the elevation of corticoids decrease.     

Corpus callosum: interactive effects of infantile handling and testosterone in the rat

Previous research found that the corpus callosum of male rats is larger than that of females; handling rats in infancy enhances this sex difference; and female rat pups, when handled in infancy and given 1 injection of testosterone propionate (TP) on Day 4 of life, will have callosa as large as those of males. In 2 experiments, male pups were castrated on Day 1 or received sham surgery; female pups were injected with TP on Day 4 or received an oil injection. Litters were handled or nonhandled. The previous finding that females, when handled and given TP in infancy, have a larger callosum was confirmed; however, a TP effect when administered to nonhandled females was not found. Because handling is known to cause a corticosterone release, these findings were interpreted as evidence of a developmental interaction between adrenal and gonadal hormones at the cortical level.     

Neonatal handling increases fear and aggression in lactating rats

Neonatal handling reduces fear in male and cycling female rats, but increases maternal aggressive behavior against intruders to the nest area. Present study aimed to analyze the effects of neonatal handling on the maternal aggressive behavior and the activity in the open field with a predator of lactating rats on the 8th and the 18th postpartum days (periods of high and low aggressiveness). As pups, animals were divided into two groups: nonhandled (no neonatal manipulation) and handled (handling for 1 min during the first 10 days after delivery). As adults, females of both groups were impregnated and tested against a male intruder for aggressive behavior and in the open field with a cat inside a wire-meshed cage. Results showed that on the 8th day frequency of aggressive behaviors of handled females was higher than that of the nonhandled ones, but on the 18th day, no significant difference was detected. Surprisingly, in the open field test, handled females showed decreased locomotion and increased freezing on the 8th day compared to the nonhandled ones. The opposite relationship between increased aggressiveness with reduced fear is observed in the nonhandled control females in early and late lactation periods. However, neonatal handling abolishes this relationship. Apparently, the increased aggressiveness in neonatal handled lactating females does not depend on a decrease in fear. Our findings support the hypothesis that long lasting effects of early life stimulation is a dynamic function depending on the behavioral system and the period of life analyzed. Moreover, they caution the relationship between aggressive behavior and fear.     

Regular handling early in the nursing period eliminates fear responses toward human beings in wild and domestic rabbits

The effect of early handling has been of special interest as there is accumulating evidence that the experimenter might be considered as a predator by the animals, resulting in an undesirable level of fear in experimental studies. The aims of the present study were (a) a systematic investigation of the effect of regular daily handling on the fear reaction toward human beings both in domestic and in wild type rabbits, (b) to measure the long-term consequences of the handling, (c) to investigate whether the effective handling is linked to the nursing period, and (d) to see whether the effectivity of handling is confined to a sensitive period in the rabbit. We found that both domestic and wild rabbits are sensitive to human handling, especially when it is performed near the time of nursing. There was a sensitive period, the 1st week postpartum, in the effectiveness of handling. The animals handled in the sensitive period readily and repeatedly approached the observer, indicating the lack of fear. The effect of handling seemed long- lasting as handled females raised to adulthood were superior to nonhandled individuals in their breeding performance. These results indicate that reduced fear of humans can be achieved via handling and this might be a prerequisite for studying the unbiased behavior of animals via direct observation.     

Postnatal handling attenuates certain neuroendocrine, anatomical, and cognitive dysfunctions associated with aging in female rats

Hippocampal degeneration with aging is associated with increased hypothalamic-pituitary-adrenal (HPA) activity and, in male rats, both are attenuated by postnatal handling. Considering the important sex differences in the effects of handling and in HPA responses to stress in older rats, we have examined the effects of postnatal handling on aging in females. Female, Long-Evans rats were handled (H) during the first 3 weeks of life and later compared with nonhandled (NH) controls at various ages. Handling resulted in permanently increased hippocampal type II, glucocorticoid receptor binding. Relative to H females, NH females showed increased basal corticosterone levels in later life and hypersecreted corticosterone following stress at all ages examined. Both effects are similar to those reported in males. However, unlike males, H and NH females did not differ in corticosterone levels achieved during stress, a finding that may be related to sex-dependent effects of handling on pituitary transcortin receptors. There were no differences in hippocampal neuron density in 6-month-old animals. However, the older NH animals showed considerable neuron loss in the CA1 and CA3 hippocampal cellfields. There was little or no neuron loss in the H animals. Finally, the NH animals exhibited age-related spatial memory impairments, such that by 24 months of age the performance of the NH females was profoundly worse than that of the younger NHs and same-aged H animals. These data suggest that early handling permanently alters CNS systems that regulate hypothalamic-pituitary-adrenal (HPA) function, although the effect may depend on the gender of the animal. In both males and females, however, handling appears to prevent (or minimize) increased adrenal secretion in later life and to attenuate hippocampal cell loss and spatial memory impairments.     

Effects of pre- and postnatal stimulation on developmental,emotional, and cognitive aspects in rodents: a review

Interactions between the organism and its environment, during pregnancy as well as during the postnatal period, can lead to important neurobehavioral changes. We briefly review the literature, and successively present the main results from our laboratory concerning the behavioral effects of prenatal stress, differential rearing conditions, and postnatal handling. We show that submitting primiparous DA/HAN rats to an acute emotional stress (exposure to a cat) at gestational day10, 14, or 19 leads to greatly increased mortality of pups and to decreased body weight of surviving animals. The effects of such a stressor on emotional reactivity are less obvious. Cognitive processes are impaired depending on the learning task. Enriched environments restore abnormal behaviors (emotional reactivity, motor skills, motor and spatial learning) due to brain trauma or genetic deficiencies. In any case, environmental enrichment does prevent or slow down aging effects. The effects of postnatal handling noted when using classical tests of emotional reactivity also are clear when defensive reaction paradigms are used. Furthermore, pregnant females that are early handled are less anxious than nonhandled females. We hypothesize that, when subjected to a stressor, the offspring of early-handled females would be protected from the deleterious effects of this stress compared to pups of nonhandled females.     

Prenatal ethanol exposure and spatial navigation: effects of postnatal handling and aging

Prenatal ethanol exposure results in spatial navigation deficits in young and mid-aged animals. In contrast, postnatal handling attenuates spatial deficits that emerge with age in animals that are not handled. Therefore, we investigated the ability of handling to attenuate spatial deficits in animals prenatally exposed to ethanol (E). Sprague-Dawley male offspring from E, pair-fed (PF), and control (C) groups were handled (H) or nonhandled (NH) from 1 to 15 days of age and tested on the Morris water maze at 2 or 13 to 14 months of age. In young animals, H-E males had longer latencies to locate the submerged platform, and E animals, across handling conditions, showed altered search patterns compared to their PF and C counterparts. Mid-aged animals had longer latencies than young animals, with no differences among E, PF, and C animals. However, corticosterone levels were higher in mid-aged E than in C males. Handling did not attenuate impairments associated with either prenatal ethanol exposure or aging.     

Visual exploratory behavior as a function of early handling, sex, and level of auditory prestimulation

Previous research has indicated that preexposing animals to intense stimulation leads to subsequent decrements in exploratory behavior. The present study was an attempt to determine if early handling could “buffer” animals against intense stimulation effects. At birth, rat pups were assigned to either a handling or a nonhandling condition. As adults, they received either intense, moderate, or no stimulation prior to being allowed 3 min of visual exploration. The predictions were: (1) handled animals will show significantly more exploration than nonhandled animals; (2) intensely stimulated animals will show significantly less exploration than animals receiving lower amounts of stimulation; (3) handled animals, under intense stimulation, will show significantly more exploration than nonhandled animals under intense stimulation. The results supported the 2nd and 3rd predictions. The first prediction was supported, but was complicated by a Sex x Handling interaction.     

Conditioned hippocampal cellular response to a behaviorally silent conditioned stimulus.

Multiunit activity (MUA) was chronically recorded in the hippocampal CA3 field of rats using a blocking paradigm with conditioned suppression of lever pressing for food as the measure of conditioning. In Experiment 1, a classical blocking paradigm demonstrated the good conditionability of 2 stimuli (a light and a tone) and their respective ability to block each other. In Experiment 2, MUA was recorded in CA3 cells in rats submitted to a similar paradigm. Four groups received either tone (groups B and B1) or click (groups BC and B1C) conditioned stimulus (CS) presentations that were followed immediately by an electrical footshock (unconditioned stimulus, US). The rats were then given either 40 (groups B and BC) or 1 (groups B1 and B1C) tone + light-footshock presentations. During test sessions, the animals showed MUA responses to the added CS (light), with no conditioned suppression of lever presses occurring during CS presentations. The results of Experiment 3 strongly suggest that hippocampal increase in cellular activity to the light appeared at the first compound trial presentation. Conditioning to the light obtained by increasing the US intensity after the single compound trial suggests that the hippocampal response reflects a redundant CS-US association (light-shock). Long-term retention tests given 45 days after the end of conditioning revealed that behavioral and hippocampal responses could still be detected but only in response to the stimulus that had elicited a behavioral response during learning.     

Infantile (handling) stimulation and behavior in young Roman high- and low-avoidance rats.

The effect of infantile handling stimulation on exploratory and emotional behavior of Roman high- and low-avoidance (RHA/Verh and RLA/Verh) weanling rats was investigated. Postnatally handled and nonhandled, 4-week-old males and females from both psychogenetically selected lines were exposed to a hexagonal tunnel maze, including an illuminated central arena. Postnatal handling increased exploratory behavior and decreased emotional reactivity as expressed by increased entries into the central arena and a reduction in defecations in both lines of rats. These effects were more pronounced in the RLA/Verh rats. In agreement with earlier studies using nonselected adult rats, the females of both lines (especially those from the RHA/Verh line) were more sensitive than males to the positive influences of early stimulation.     

Programming life histories: Effects of maternal and environmental variables upon open-field behavior

Open-field behavior was studied as a function of three classes of variables: maternal characteristics, rearing environment, and sexual experience. Mothers of experimental subjects were either handled or nonhandled in infancy. Subjects were born and reared to weaning either in maternit cages or in Hebb-type free environments and were placed after weaning into either a laboratory cage or free enviroment. Sexual experience consisted either of bearing and raising a litter or no sexual experience. The results confirmed previous findings that offspring of mothers handled in infancy arc significantly less active in the open field than the offspring of nonhandled mothers. The maternal handling variable also interacted significantly with breeding experience: for rats which had not been bred, those raised by nonhandled mothers were more active than those raised by handled mothers; for females with breeding experience the reverse was true. Overall, thosc femalcs which had reared a litter were more active and defecated more than their nonbred littermates.     

The effect of early handling is dependent upon the state of the rabbit (Oryctolagus cuniculus) pups around nursing.

We investigated the behavior toward humans in 4-week-old pups and adult rabbits handled daily at different times around the nursing visits during their 1st week of life. The timing of handling significantly influenced its efficiency in altering the subsequent behavior of rabbits. Animals handled around nursing readily approached a human hand when tested at weaning. Other pups, handled either 6, 12, or 18 hr after nursing, avoided the human hand. Our results show that there is a narrow sensitive period for successful stimulation, because only those rabbits that were handled within the interval starting 15 min before and ending 30 min after nursing became tame. The effect of early handling proved to be long-lasting because nonhandled rabbits tested as adults were afraid of humans and showed behavioral elements of avoidance, while the handled ones behaved fearlessly in the open field. The effect of handling proved to be specific toward humans because both handled and nonhandled animals showed avoidance toward a stuffed fox.     

Neonatal handling reduces the number of cells in the locus coeruleus of rats

Neonatal handling induces long-lasting effects on behaviors and stress responses. The objective of the present study was to analyze the effects of neonatal handling (from the 1st to the 10th day after delivery) on the number of cells and volume of locus coeruleus (LC) nucleus in male and female rats at 4 different ages: 11, 26, 35, and 90 days. Results showed significant reductions in the number of cells and the volume of the LC nucleus in neonatally handled males and females compared with nonhandled rats. Environmental stimulation early in life induced a stable structural change in a central noradrenergic nucleus, which could be one of the causal factors for the behavioral and hormonal alterations observed in adulthood.     

Latent inhibition as a function of schizotypality and gender: implications for schizophrenia.

In three within-subject experiments, we demonstrated that preexposure to an irrelevant stimulus interfered with performance when that stimulus subsequently predicted the correct location of a target stimulus. This latent inhibition-like effect (LI) was manifest in response time measures, but not errors. As with other related paradigms, LI was a function of an interaction between schizotypy-level and gender. Low schizotypal females and high schizotypal males exhibited significant LI, while high schizotypal females and low schizotypal males failed to produce LI effects. The results, similar to findings with schizophrenic patients, suggest a sexual dimorphism of cognitive dysfunction in schizophrenia, particularly in regard to the processing of irrelevant stimuli.