Early experience influences adult retention of aversively motivated tasks in normal,but not DSP4-treated rats

Sprague-Dawley rat pups were injected with DSP4 or water within 48 hr of birth and tested as adults in an inhibitory avoidance task and in a Y-maze discrimination reversal task. Half of the animals were also tested as juveniles during postnatal weeks 4–5, in tasks assessing odor preferences and general investigatory behavior. Controls, but not drug-treated adults, which received the juvenile testing, showed significantly better retention on both tasks than either controls or drug-treated animals not tested as juveniles. Neonatal DSP4 significantly reduced norepinephrine concentrations in the hippocampus and frontal cortex, but not the heart. The results suggest that central norepinephrine may modulate the effects of early experience on adult learning.     

Choline supplementation following third-trimester-equivalent alcohol exposure attenuates behavioral alterations in rats

Despite the known adverse consequences of prenatal alcohol exposure, some pregnant women continue to drink alcohol, making it imperative to identify treatments for children with fetal alcohol spectrum disorders. The authors recently reported that perinatal choline supplementation can reduce some fetal alcohol effects (J. D. Thomas, M. Garrison, & T. M. O'Neill, 2004), and the present study examined whether choline supplementation is effective when administered after third-trimester-equivalent ethanol treatment. Rat pups were exposed to 6.0 g/kg/day ethanol during the neonatal brain growth spurt (Postnatal Days [PD] 4-9) and treated with choline chloride (0, 10, 50, or 100 mg/kg) from PD 10-30. Behavioral testing occurred after choline treatment had ceased. Female subjects exposed to ethanol were overactive and exhibited spatial learning deficits, effects that were attenuated with all doses of choline supplementation. These data indicate that choline supplementation can alter brain development following a developmental insult. Moreover, the data suggest that early dietary interventions may reduce the severity of some fetal alcohol effects, even when administered after birth.     

Supplemental choline during the periweaning period protects against trace conditioning impairments attributable to post-training ethanol exposure in adolescent rats

Supplemental choline during early stages of development can result in long-lasting improvements to memory function. In addition, pre- or postnatal choline has been shown to be protective against some of the adverse effects of early alcohol exposure. The present experiment examined whether supplemental choline given to rats would protect against the effects of posttraining alcohol administration on trace fear conditioning. Posttraining alcohol exposure in adolescent rats results in poor performance in this hippocampus-dependent task, although delay conditioning is unaffected. Here, rats were given an s.c. injection of either saline or choline chloride daily on postnatal days (PD) 15-26. On PD 30 subjects were trained in a trace fear conditioning procedure. For the next 3 days animals were administered 2.5 g/kg ethanol or water control, and conditional stimulus (CS)-elicited freezing was measured on PD 34. Results indicated that posttraining alcohol disrupted the expression of trace conditioning and that supplemental choline on PD 15-26 was protective against this effect. That is, choline-treated animals subsequently given posttraining ethanol performed as well as animals not given ethanol. These results indicate that supplemental choline given during the periweaning period protects against ethanol-induced impairments in a hippocampus-dependent learning task. Findings contribute to the growing literature showing improvements in learning and memory in subjects given extra dietary choline during critical periods of brain development.     

Retained elements of early avoidance training and relearning of forgotten operants

In a series of 7 experiments we investigated the possibility that juvenile rats show long-term retention for aspects of early avoidance training and that these retained elements serve to reinforce relearning of the forgotten operants. Rats trained in active or passive avoidance at 23–25 days of age demonstrated the typical juvenile forgetting effect relative to adults after a 28-day interval. However, both juveniles and adults demonstrated marked reductions in locomotor activity prior to retraining which were specific to the apparatus and not dependent on the opportunity to perform an operant during initial training. Juvenile animals given a reminder exposure plus footshock 27 days after training, then single daily nonshock trials (Days 28–30), showed decreasing crossover latencies across days if trained in active avoidance and increasing latencies if trained in passive avoidance. This reappearance of task-appropriate crossover latencies was evident in previously trained juveniles only. Finally, young animals' demonstrated change in crossover latency is associated with subsequent superior acquisition performance, and this change depends upon the presentation of the test trials for its appearance. We suggest that the amelioration of “infantile amnesia” associated with the present procedures is a learning process motivated by Pavlovian components of training which are retained well, by juveniles and adults alike, over intervals typical of ontogeny of memory research.     

5-methoxy-N,N-di(iso)propyltryptamine hydrochloride (Foxy)-induced cognitive deficits in rat after exposure in adolescence

Foxy or Methoxy Foxy (5-methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO-DIPT) is rapidly gaining popularity among recreational users as a hallucinogenic “designer drug.”Unfortunately, much remain unknown about the consequences of its use on neuropsychological development or behavior. During one of two adolescent periods, the rats were given repeated injections of 5 mg/kg or 20 mg/kg of 5-MeO-DIPT or a corresponding volume of isotonic saline. After the animals reached adulthood, they were trained and tested on a number of tasks designed to assess the impact of 5-MeO-DIPT, if any, on spatial memory, presumably involving declarative memory systems as well as a nonspatial task that is considered sensitive to disruptions in nondeclarative memory. Both the 5-MeO-DIPT- and saline-treated rats were able to master spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Regardless of exposure level during adolescence, the performance of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. Detected reductions in serotonin activity in the forebrain similar to the effects of extensively investigated compounds such as methylenedioxymethamphetamine (MDMA), suggest that 5-MeO-DIPT may produce its adverse effects by compromising serotonergic systems in the brain.     

Chronic neonatal nicotine increases anxiety but does not impair cognition in adult rats

Developmental nicotine exposure has been implicated in the association between maternal smoking and adverse outcomes in offspring. The 3rd trimester of human pregnancy is equivalent to the 1st postnatal week in rodents; both are periods of active brain growth during which nicotinic acetylcholine receptors are transiently upregulated. Chronic neonatal nicotine (CNN; 6 mg/kg/day) from postnatal Days 1 to 7 was given orally to rat pups to evaluate long-term behavioral effects. Males and females were tested as adolescents or as young adults. CNN significantly decreased center time, ambulatory behavior, and rearing in the open-field test and decreased the number of entrances and time spent in the open arm of the elevated plus-maze in both sexes and ages. CNN did not change performance in the T maze or in the water maze in adult males or females. Motor coordination was not altered. In summary, CNN had long-term effects on anxiety-like behavior but did not affect spatial learning and memory functions. This finding is particularly important when evaluating the benefits of nicotine-replacement therapies during human pregnancies, which may improve smoking cessation rates but could result in long-term behavioral consequences.     

The effects of prenatal exposure to predictable or unpredictable stress on early development in the rat

Pregnant rats were exposed to different schedules of noise and light stress, and the development of their offspring was studied during the first 2 weeks of life. Motor development was measured by different tests: Righting reflex (Days 2-4); cliff avoidance (Days 4-10); turning on an inclined plane (Days 5-10); and swimming behavior (Days 6-10). Development of motivation-involved behavior was measured with a home-seeking test (Days 6-16). Other developmental landmarks such as acoustic response (Days 12-14) and eye-opening (Days 14-17) were also recorded. Thrice-weekly random stress resulted in a delay in the development of all behaviors studied. Daily stress exposure throughout pregnancy resulted in smaller litters with heavier pups, but otherwise normal behavioral and physical development. Rats exposed to daily stress during the last week of pregnancy only produced litters that did not differ in size and body weight, but that displayed accelerated development of all parameters (except for eye-opening) from Day 6 onwards. It is concluded that the unpredictable nature of prenatal stress is responsible for delays in behavior of offspring.     

Hemodynamic adjustments during free-operant avoidance in dogs with unilateral renal artery stenosis.

To examine blood pressure (BP) and heart rate (HR) during avoidance performance in animals with renal artery stenosis, 10 dogs were prepared with arterial catheters, and subsequently underwent habituation to the experimental apparatus. Following this, 6 of the dogs received ligation of the left renal artery to reduce luminal dia. 50–80%, and habituation was repeated in all dogs. After training on a free-operant avoidance task, the animals were exposed to 5 daily 60 min avoidance sessions consisting of alternating 5 min periods of non-avoidance and avoidance. On 2 days, the dogs received either propranolol (0.3 mg/kg) or phenoxybenzamine (1.0 mg/kg) intra-arterially during the second nonavoidance period. While stenosis of the renal artery was effective in increasing diastolic BP during the second habituation exposure, a permanent BP elevation was not observed. These animals displayed similar pressor responses but larger HR increases than controls during the first and final avoidance periods. Drug effects were minimal. The results suggest that an exaggerated tachycardia may characterize the hemodynamic adjustment to environmental challenges in animals with unilateral renal artery stenosis, as it does in some hypertensive patients.     

Sex differences in appetitive learning of mice

Learning abilities of male and female ddY mice were compared in two appetitive tasks (a lever-press task and an 8-arm radial maze task), and two avoidance tasks (a shuttle box task and a light-dark discrimination T-maze task). In the two types of appetitive learning, male mice were significantly superior to female mice. Sex differences were particularly apparent in the acquisition process. In contrast, there was no significant sex difference in learning of the two avoidance tasks. A sex difference in appetitive learning was not found in juvenile mice prior to sexual maturation, and the mice which had established a lever-press response as juveniles did not show any significant difference in the performance level when tested as adults. Thus, a sex difference appeared only in the acquisition stage of adult mice. These results suggest that there exists a sex difference in motivation level for hunting food but not for feeding, and that it causes a sex difference in appetitive learning.     

Behavioral deficits induced by bingelike exposure to alcohol in neonatal rats: Importance of developmental timing and number of episodes

The importance of the timing and number of episodes of bingelike alcohol exposure in neonatal rats on subsequent behavioral outcomes was evaluated with a parallel bar task and a spatial conditional alternation task. Different groups of Sprague-Dawley rat pups were exposed to alcohol delivered via artificial rearing procedures either on postnatal Days (PD) 4 and 5, on PD 8 and 9, or on both PD 4/5 and 8/9 (Combined), producing daily peak blood alcohol concentrations around 400 mg/dl. Controls included an artificially reared group and a normally reared group. Exposure during PD 4/5 produced significantly more severe motor deficits and significantly more severe reductions in cerebellar and brainstem weights than did exposure on PD 8/9. Combined exposure produced greater deficits on these measures than either of the limited exposures. Significant deficits in the acquisition rates for conditional alternation were found only with the Combined exposure, although both the PD 8/9 and Combined groups committed significantly more within-trial errors. All three alcohol treatments produced significant and comparable reductions in forebrain weight. The type and severity of behavioral and neural deficits induced by neonatal bingelike alcohol exposure depend on the timing and number of exposures. © 1996 John Wiley & Sons, Inc.     

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.     

Age-related differences in avoidance behavior in rats following CS preexposure

Weanling and adult rats were exposed to either 0 or 10 conditioned stimulus (CS) presentations prior to 1-way active-avoidance (AA) training. Although CS exposure retarded avoidance acquisition in the adults, it produced no effect in the pups during avoidance learning. Neither adult nor young rats demonstrated preexposure effects in extinction. A general extinction analysis showed that pups had less resistance to extinction than the adults, despite a comparable avoidance learning criterion between age groups. The lack of preexposure influences on performance by the pups was compared to previous findings of response inhibitory deficits in immature rats. The results were considered in light of selective attention interpretations of latent inhibition.     

Contribution of hippocampal place cell activity to learning and formation of goal-directed navigation in rats

Although extensive behavioral studies have demonstrated that hippocampal lesions impair navigation toward specific places, the role of hippocampal neuronal activity in the development of efficient navigation during place learning remains unknown. The aim of the present study was to investigate how hippocampal neuronal activity changes as rats learn to navigate efficiently to acquire rewards in an open field. Rats were pre-trained in a random reward task where intracranial self-stimulation rewards were provided at random locations. Then, the rats were trained in a novel place task where they were rewarded at two specific locations as they repeatedly shuttled between them. Hippocampal neuronal activity was recorded during the course of learning of the place task. The rats learned reward sites within several sessions, and gradually developed efficient navigation strategies throughout the learning sessions. Some hippocampal neurons gradually changed spatial firing as the learning proceeded, and discharged robustly near the reward sites when efficient navigation was established. Over the learning sessions, the neuronal activity was highly correlated to formation of efficient shuttling trajectories between the reward sites. At the end of the experiment, spatial firing patterns of the hippocampal neurons were re-examined in the random reward task. The specific spatial firing patterns of the neurons were preserved if the rats navigated, as if they expected to find rewards at the previously valid locations. However, those specific spatial firing patterns were not observed in rats pursuing random trajectories.These results suggest that hippocampal neurons have a crucial role in formation of an efficient navigation.     

Age increases vulnerability to bacterial endotoxin-induced behavioral decrements

Peripheral lipopolysaccharide (LPS) or proinflammatory cytokines produce alterations in learning, memory, and other behaviors. Additionally, research has demonstrated that factors such as dose, route of administration, species, strain, gender, and age are important modulatory factors in the effects of endotoxin exposure. Previous research from our laboratory and others indicate that LPS-induced behavioral deficits are greater in older subjects. The current study examined avoidance learning in a negatively reinforced operant procedure (i.e., two-way active avoidance conditioning) following single or repeated intraperitoneal LPS injections in 2- and 12-month-old male C57BL/6J mice. LPS-treated subjects show impaired acquisition of the task regardless of the age of the subject, as these animals performed significantly fewer avoidance responses than controls. However, the effects of LPS administration were more pronounced in the 12-month-old animals, particularly for the subjects given repeated LPS injections. These results support the hypothesis that endotoxin exposure is capable of altering performance in this task in a way that may reflect deficits in learning, and provide evidence that increased age may exacerbate these deleterious behavioral effects.     

Prenatal and neonatal androgen exposure interact to affect sexual differentiation in female rats

Rats were injected with oil on Days 17.5 and 18.5 of pregnancy or with 2 mg of testosterone propionate (TP) on Days 15.5 and 16.5, or Days 17.5 and 18.5, or Days 19.5 and 20.5. The female offspring were given oil or 5 micrograms of TP on Day 25 postconception. Among females exposed to TP only during prenatal ontogeny, a lower proportion of those treated on Days 17.5-18.5 of gestation displayed lordotic behavior than did the control group. Postnatal TP alone did not affect lordosis. However, all groups receiving combined pre- and postnatal TP showed impaired estrous patterns. The development of several components of morphology also was differentially affected by the timing of the androgen exposure. The data suggest that the differentiation of sexual behavior and reproductive morphology in the rat are influenced by an interaction of androgen dependent processes operating at different stages of perinatal ontogeny. Further, there may be an optimal fetal period during which androgenization sensitizes animals to low levels of testosterone circulating during neonatal development.     

Neonatal alcohol exposure impairs acquisition of eyeblink conditioned responses during discrimination learning and reversal in weanling rats

Discrimination and reversal of the classically conditioned eyeblink response depends on cerebellar-brainstem interactions with the hippocampus. Neonatal "binge" exposure to alcohol at doses of 5 g/kg/day or more has been shown to impair single-cue eyeblink conditioning in both weanling and adult rats. The present study exposed neonatal rats to acute alcohol intubations across different developmental periods (postnatal day [PND] 4-9 or PND7-9) and tested them from PND26-31 on discriminative classical eyeblink conditioning and reversal. A high dose of alcohol (5 g/kg/day) dramatically impaired conditioning relative to controls when exposure occurred over PND4-9, but produced mild or no impairments when delivered over PND7-9. These findings support previous claims that developmental exposure period plays a critical role in determining the deleterious effects of alcohol on the developing brain. A lower dose of alcohol (4 g/kg/day) delivered from PND4-9--lower than has previously been shown to affect single-cue eyeblink conditioning--also produced deficits on the discrimination task, suggesting that discrimination learning and acquisition of responding to CS+ during reversal may be especially sensitive behavioral indicators of alcohol-induced brain damage in this rat model.     

Behavioral and neuroendocrine effects in rats of postnatal exposure to low dietary levels of maneb

Several behavioral and neurochemical consequences of neonatal and/or postneonatal exposure to maneb (ethylenebisdithiocarbamate manganese), a popularly used fungicide, were investigated in male rats at dietary levels of 0, .5, 1.0, or 10 ppm. Three different periods of exposure were employed: (1) during the 28-day neonatal period; (2) during the 5 months postweaning; and (3) during both the neonatal and postweaning periods of life. Behaviorally, neonatal exposure to maneb depressed exploratory activity of the 30-day old wealings. As adults, neonatally treated rats demonstrated enhanced learning ability in an operant conditioning procedure. However, no facilitation of learning was found in animals whose exposure to maneb was restricted to only their postweaning period of life. Although unrelated to the behavioral changes, neuroendocrine effects were also found. Regional brain cholinesterase (ChE) activity was reduced in rats exposed to maneb during either the neonatal period alone or during the 5 month postweaning period alone, but continuous exposure to maneb during both the neonatal and postweaning periods did not appreciably affect brain ChE activity. Adult plasma corticosterone levels were elevated by exposure to maneb only postweaning. No such change was found in the neonatally exposed rats.     

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.     

Use of proximal and distal cues in place navigation by mice changes during ontogeny

The ontogeny of the ability of C57BL/6 mice to use different cues for spatial learning was examined in several Morris water maze tasks. In the first two studies, three learning procedures were used, in which only distal cues (place learning), only proximal cues (cue learning), or both proximal and distal cues (cue + place learning) were pertinent to localize the platform. The results indicated that whatever the procedure, 22-day-old mice showed the same capabilities as adults. Moreover, in the cue + place-learning procedure, although the distal cues were not necessary to solve the task, both young and adult mice demonstrated the integration of distal information by exhibiting a strong spatial bias during a probe test. However, in the third experiment, it was shown that nonpertinent proximal cues perturbed 22-day-old mice in a place-learning procedure. Taken together, these results suggest that while even the youngest mice show striking spatial navigation abilities, young mice give greater importance to proximal cues for orientation whereas adults preferentially use distal information. © 1996 John Wiley & Sons, Inc.     

Similarities in the development of place and cue navigation by rats in a swimming pool

The development of place and cue spatial navigation was evaluated in 18-, 19-, and 20-day-old males in the Morris water task (MWT). Past work has suggested that place and cue learning develop at different rates, suggesting that the two aspects of spatial navigation have different neural substrates. In the present study, a new training methodology was used in which animals received spaced training trials, drying and warming in between trials to maintain body temperature, and two probe trial-dependent measures to evaluate spatial memory performance. All ages of rats had lower latencies on the cue task than on the place task. Nevertheless, 18-day-old rats did not learn either task as measured by acquisition latencies and probe trial-dependent measures. The 19- and 20-day-old rats learned both the place and cue tasks as measured by acquisition latency and direct swims to the correct platform location on the probe trial, and both 19- and 20-day-old rats demonstrated a strong spatial bias to the former platform location on the place probe trial but not on the cue probe trial. The finding that developmental onset of place and cue spatial navigation is rapid and complete by day 19 is discussed in relation to contemporary theories of spatial navigation.