Spatial Discrimination Reversal Research Articles

Impacts of neonatal methylmercury on behavioral flexibility and learning in spatial discrimination reversal and visual signal detection tasks

Early postnatal development in rodents is sensitive to neurotoxic effects of the environmental contaminant, methylmercury. While juvenile and adolescent exposure also produce long-term impairments in behavior, the outcome of neonatal exposure is less understood. Neural development during the neonatal period in rodents is akin to that seen in humans during the third trimester of pregnancy but methylmercury exposure occurring during the neonatal period has not been modeled, partly because breast milk is a poor source of bioavailable methylmercury. To examine this developmental period, male Long-Evans rats were exposed to 0, 80, or 350 µg/kg/day methylmercuric chloride from postnatal days 1–10, the rodent neonatal period. As adults, behavioral flexibility, attention, memory, and expression of the dopamine transporter in these rats was assessed. Rats exhibited changes in behavioral flexibility assessed in a spatial discrimination reversal procedure. Those rats exposed to the highest dose of methylmercury displayed subtly altered patterns of perseveration compared to control animals. During acquisition of the attention/memory procedure, rats exposed to this dose also had slower acquisition, and achieved lower overall accuracy during training, compared to controls despite neither attention nor memory being affected once the task was acquired. Finally, dopamine transporter expression in the striatum, prefrontal cortex, and hippocampus was unchanged in these adult rats. The results of this study replicate the trend of findings seen with exposure during gestation or during adolescence.

Sex differences in learning flexibility in an avian brood parasite, the shiny cowbird

Females of brood parasitic shiny cowbirds, Molothrus bonariensis, search and prospect host nests, synchronizing parasitism with host laying. This behavior is sex-specific, as females perform this task without male's assistance. Host nests must be removed from the female’s memory "library" after being parasitized, to avoid repeated parasitism, or when they become unavailable because of predation. Thus, females must adjust their stored information about host nest status more dynamically than males, possibly leading to differences in learning flexibility. We tested for sex differences in a visual (local cues) and a spatial discrimination reversal learning task, expecting females to outperform males as an expression of greater behavioral flexibility. Both sexes learned faster the spatial than the visual task during both acquisition and reversal. In the visual task there were no sex differences in acquisition, but females reversed faster than males. In the spatial task there were no sex differences during either acquisition or reversal, possibly because of a ceiling effect: both sexes learned too fast for differences in performance to be detectable. Faster female reversal in a visual but not spatial task indicates that the greater behavioral flexibility in females may only be detectable above some level of task difficulty.

Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice.

Adolescence is associated with the continued maturation of dopamine neurotransmission and is implicated in the etiology of many psychiatric illnesses. Adolescent exposure to neurotoxicants that distort dopamine neurotransmission, such as methylmercury (MeHg), may modify the effects of chronic d-amphetamine (d-AMP) administration on reversal learning and attentional-set shifting. Male C57Bl/6n mice were randomly assigned to two MeHg-exposure groups (0 ppm and 3 ppm) and two d-AMP-exposure groups (saline and 1 mg/kg/day), producing four treatment groups (n = 10-12/group): control, MeHg, d-AMP, and MeHg + d-AMP. MeHg exposure (via drinking water) spanned postnatal days 21-59 (the murine adolescent period), and once daily intraperitoneal injections of d-AMP or saline spanned postnatal days 28-42. As adults, mice were trained on a spatial-discrimination-reversal (SDR) task in which the spatial location of a lever press predicted reinforcement. Following 2 SDRs, a visual-discrimination task (extradimensional shift) was instated in which the presence of a stimulus light above a lever predicted reinforcement. Responding was modeled using a logistic function, which estimated the rate (slope) of a behavioral transition and trials required to complete half a transition (half-max). MeHg, d-AMP, and MeHg + d-AMP exposure increased estimates of half-max on the second reversal. MeHg exposure increased half-max and decreased the slope term following the extradimensional shift, but these effects did not occur following MeHg + d-AMP exposure. MeHg + d-AMP exposure produced more perseverative errors and omissions following a reversal. Adolescent exposure to MeHg can modify the behavioral effects of chronic d-AMP administration. (PsycINFO Database Record

Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels

RationaleImpairments in behavioral flexibility lie at the core of anxiety and obsessive-compulsive disorders. Few studies, however, have investigated the neural substrates of natural variation in behavioral flexibility and whether inflexible behavior is linked to anxiety and peripheral markers of stress and monoamine function.ObjectiveThe objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task.MethodsRats were trained on a reversal learning task prior to blood sampling, anxiety assessment, and the behavioral evaluation of selective monoamine oxidase-A (MAO-A) and MAO-B inhibitors, which block the degradation of serotonin (5-HT), dopamine (DA), and noradrenaline (NA).ResultsPerseveration correlated positively with 5-HT levels in blood plasma and inversely with trait anxiety, as measured on the elevated plus maze. No significant relationships were found between perseveration and the stress hormone corticosterone or the 5-HT precursor tryptophan. Reversal learning was significantly improved by systemic administration of the MAO-A inhibitor moclobemide but not by the MAO-B inhibitor lazabemide. Moclobemide also increased latencies to initiate a new trial following an incorrect response suggesting a possible role in modulating behavioral inhibition to negative feedback. MAO-A but not MAO-B inhibition resulted in pronounced increases in 5-HT and NA content in the orbitofrontal cortex and dorsal raphé nuclei and increased 5-HT and DA content in the basolateral amygdala and dorsomedial striatum.ConclusionsThese findings indicate that central and peripheral monoaminergic mechanisms underlie inter-individual variation in behavioral flexibility, which overlaps with trait anxiety and depends on functional MAO-A activity.

Chronic cocaine exposure in adolescence: Effects on spatial discrimination reversal, delay discounting, and performance on fixed-ratio schedules in mice

Adolescence is marked by the continued development of the neural pathways that support choice and decision-making, particularly those involving dopamine signaling. Cocaine exposure during adolescence may interfere with this development and manifest as increased perseveration and delay discounting in adulthood, behavioral processes that are related to drug addiction. Adolescent mice were exposed to 30mg/kg/day of cocaine (n=11) or saline vehicle (n=10) for 14days and behavior was assessed in adulthood. In Experiment 1, performance on a spatial-discrimination-reversal procedure was evaluated. In the first two sessions following the first reversal, cocaine-exposed mice produced more preservative errors relative to controls. In Experiment 2, cocaine-exposed mice displayed steeper delay discounting than saline-exposed mice, effects that were reversed by acute cocaine administration. Experiment 3 examined responding maintained by a range of fixed-ratio schedules of reinforcement. An analysis based on a theoretical framework called Mathematical Principles of Reinforcement (MPR) was applied to response-rate functions of individual mice. According to MPR, differences in response-rate functions in adulthood were due to a steepening of the delay-of-reinforcement gradient, disrupted motoric capacity (lower maximum response rates), and enhanced reinforcer efficacy for the adolescent cocaine- compared with saline-exposed mice. Overall, these experiments suggest that chronic exposure to cocaine during adolescence may impair different features of ‘executive functions’ in adulthood, and these may be related to distortions in the impact of reinforcing events.

Spatial discrimination reversal and incremental repeated acquisition in adolescent and adult BALB/c mice

Adolescence is characterized by neural and behavior development that includes increases in novel experiences and impulsive choice. Experimental rodent models can characterize behavior phenotypes that typify adolescence. The present experiment was designed to characterize differences between adolescent (post-natal day (PND) 34–60) and adult (PND 70–96) BALB/c mice using a response-initiated spatial discrimination reversal (SDR) and incremental repeated acquisition of response chains (IRA) procedures. During SDR, adolescents omitted more trials and were slower to initiate trials than adults, but the age groups did not differ on accuracy and perseveration measures. During IRA, adolescents displayed poorer overall performance (measured by progress quotient), lower accuracy at individual chain links, and completed fewer long response chains (>3 links) than adults. In both procedures (SDR and IRA), the poorer performance of adolescents appeared to be related to the use of a response device that was spatially removed from reinforcer delivery. These results indicate that SDR and IRA performance can be established during the brief rodent adolescent period but that these two age groups’ performances differ. We hypothesize that adolescent behavior is more sensitive than adult behavior to the spatiotemporal distance between response device and location of reinforcer delivery.

Administration of Memantine During Withdrawal Mitigates Overactivity and Spatial Learning Impairments Associated with Neonatal Alcohol Exposure in Rats

Prenatal alcohol exposure can disrupt central nervous system development, manifesting as behavioral deficits that include motor, emotional, and cognitive dysfunction. Both clinical and animal studies have reported binge drinking during development to be highly correlated with an increased risk of fetal alcohol spectrum disorders (FASD). We hypothesized that binge drinking may be especially damaging because it is associated with episodes of alcohol withdrawal. Specifically, we have been investigating the possibility that NMDA receptor-mediated excitotoxicity occurs during alcohol withdrawal and contributes to developmental alcohol-related neuropathology. Consistent with this hypothesis, administration of the NMDA receptor antagonists MK-801 or eliprodil during withdrawal attenuates behavioral alterations associated with early alcohol exposure. In this study, we investigated the effects of memantine, a clinically used NMDA receptor antagonist, on minimizing ethanol-induced overactivity and spatial learning deficits. Sprague-Dawley pups were exposed to 6.0g/kg ethanol via intubation on postnatal day (PD) 6, a period of brain development that models late gestation in humans. Controls were intubated with a calorically matched maltose solution. During withdrawal, 24 and 36hours after ethanol exposure, subjects were injected with a total of either 0, 20, or 30mg/kg memantine. The subjects' locomotor levels were recorded in open field activity monitors on PDs 18 to 21 and on a serial spatial discrimination reversal learning task on PDs 40 to 43. Alcohol exposure induced overactivity and impaired performance in spatial learning. Memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Thus, memantine may be neuroprotective when administered during ethanol withdrawal. These data have important implications for the treatment of EtOH's neurotoxic effects and provide further support that ethanol withdrawal significantly contributes to FASD.

Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner

Alcohol is a known teratogen that is estimated to affect 2–5% of the births in the U.S. Prenatal alcohol exposure can produce physical features such as facial dysmorphology, physiological alterations such as cell loss in the central nervous system (CNS), and behavioral changes that include hyperactivity, cognitive deficits, and motor dysfunction. The range of effects associated with prenatal alcohol exposure is referred to as fetal alcohol spectrum disorders (FASD). Despite preventative measures, some women continue to drink while pregnant. Therefore, identifying interventions that reduce the severity of FASD is critical. This study investigated one such potential intervention, vitamin D3, a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D3 nutritional supplement, could serve as a means of mitigating alcohol-related learning deficits. Using a rat model of FASD, cholecalciferol was given before, during, and after 3rd trimester equivalent alcohol exposure. Three weeks after cholecalciferol treatment, subjects were tested on a serial spatial discrimination reversal learning task. Animals exposed to ethanol committed significantly more errors compared to controls. Cholecalciferol treatment reduced perseverative behavior that is associated with developmental alcohol exposure in a dose-dependent manner. These data have important implications for the treatment of FASD and suggest that cholecalciferol may reduce some aspects of FASD.This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the dopaminergic development and survival. Altered expression of Nurr1 has been suggested as a potential genetic risk factor for dopamine-related brain disorders, including schizophrenia. In support of this, recent experimental work in genetically modified mice shows that mice with a heterozygous constitutive deletion of Nurr1 show a facilitation of the development of schizophrenia-related behavioral abnormalities. However, the behavioral characterization of this Nurr1-deficient mouse model remains incomplete. This study therefore used a comprehensive behavioral test battery to evaluate schizophrenia-relevant phenotypes in Nurr1-deficient mice. We found that these mice displayed increased spontaneous locomotor activity and potentiated locomotor reaction to systemic treatment with the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). In addition, male but not female Nurr1-deficient mice showed significant deficits in the prepulse inhibition and prepulse-elicited reactivity. However, Nurr1 deletion did not induce overt abnormalities in other cardinal behavioral and cognitive functions known to be impaired in schizophrenia, including social interaction and recognition, spatial recognition memory or discrimination reversal learning. Our findings thus suggest that heterozygous constitutive deletion of Nurr1 results in a restricted phenotype characteristic of schizophrenia symptomatology, which primarily relates to motor activity, sensorimotor gating and responsiveness to the psychomimetic drug MK-801. This study further emphasizes a critical role of altered dopaminergic development in the precipitation of specific brain dysfunctions relevant to human psychotic disorder.

The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats

BackgroundThe third trimester in human fetal development represents a critical time of brain maturation referred to as the “brain growth spurt”. This period occurs in rats postnatally, and exposure to ethanol during this time can increase the risk of impairments on a variety of cognitive and motor tasks. It has been proposed that one potential mechanism for the teratogenic effects of ethanol is NMDA receptor-mediated excitotoxicity during periods of ethanol withdrawal. In neonatal rats, antagonism of NMDA receptors during ethanol withdrawal, with drugs such as MK-801 and eliprodil, has been shown to mitigate some of the behavioral deficits induced by developmental ethanol exposure. The current study examined whether memantine, an NMDA receptor antagonist and a drug used clinically in Alzheimer's patients, would attenuate impairments associated with binge ethanol exposure in neonatal rats. MethodsOn postnatal day 6, rats were exposed to 6g/kg ethanol via intubation with controls receiving an isocaloric maltose dextrin solution. Twenty-one hours following the ethanol binge, rats received intraperitoneal injections of memantine at 0, 10, 15, or 20mg/kg. Ethanol's teratogenic effects were assessed using multiple behavioral tasks: open field activity, parallel bars and spatial discrimination reversal learning. ResultsEthanol-treated rats were overactive in the open field and were impaired on both reversal learning and motor performance. Administration of 15 or 20mg/kg memantine during withdrawal significantly attenuated ethanol's adverse effects on motor coordination, but did not significantly alter activity levels or improve the spatial learning deficits associated with neonatal alcohol exposure. ConclusionThese results indicate that a single memantine administration during ethanol withdrawal can mitigate motor impairments but not spatial learning impairments or overactivity observed following a binge ethanol exposure during development in the rat.

Association, inhibition, and object permanence in dogs' (Canis familiaris) spatial search.

The relative role of associative processes and the use of explicit cues about object location in search behavior in dogs (Canis familiaris) was assessed by using a spatial binary discrimination reversal paradigm in which reversal conditions featured: (1) a previously rewarded location and a novel location, (2) a previously nonrewarded location and a novel location, or (3) a previously rewarded location and a previously nonrewarded location. Rule mediated learning predicts a similar performance in these different reversal conditions whereas associative learning predicts the worst performance in Condition 3. Evidence for an associative control of search emerged when no explicit cues about food location were provided (Experiment 1) but also when dogs witnessed the hiding of food in the reversal trials (Experiment 2) and when they did so in both the prereversal and the reversal trials (Experiment 3). Nevertheless, dogs performed better in the prereversal phase of Experiment 3 indicating that their search could be informed by the knowledge of the food location. Experiment 4 confirmed the results of Experiments 1 and 2, under a different arrangement of search locations. We conclude that knowledge about object location guides search behavior in dogs but it cannot override associative processes.

Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist

The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801 disrupts reversal learning in developing rats, as reported in an earlier work by Chadman et al., but it is not known whether NMDA-receptor function within the dmSTR plays a role in this effect. In Experiment 1, reversal learning was dose-dependently impaired following bilateral dmSTR administration of MK-801 (either 2.5 or 5.0 microg) only during the reversal phase relative to saline in postnatal day (P) 26 rats. In Experiment 2, separate groups of P26 rats were trained on the same reversal learning task, but were administered bilateral dmSTR infusions during acquisition only (MK-SAL), reversal only (SAL-MK), both phases (MK-MK), or neither phase (SAL-SAL). The MK-801 effect was specific to the reversal training phase. The drug did not alter acquisition of the initial discrimination. Analysis of the pattern of errors indicates that dmSTR MK-801 treatment increased perseveration of the choice response trained in acquisition. NMDA receptors in the dmSTR play a role in reversal learning in the weanling rat.

Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Systemic administration of MK-801, an NMDA-receptor antagonist, impairs reversal learning in weanling rats [Chadman, K.K., Watson, D.J., & Stanton, M.E. (2006). NMDA-receptor antagonism impairs reversal learning in developing rats. Behavioral Neuroscience, 120(5), 1071–1083]. The brain systems responsible for this effect are not known in either adult or young animals. This study tested the hypothesis that hippocampal NMDA receptors are engaged in weanling-age rats during spatial discrimination reversal training in a T-maze. In Experiment 1, 26-day-old Long-Evans rats (P26) showed a dose-related impairment on this task following bilateral intrahippocampal administration of either 2.5 or 5.0 μg MK-801 or saline vehicle during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but received intrahippocampal MK-801 (2.5 μg) during acquisition, reversal, both, or neither. MK-801 failed to impair acquisition, ruling out nonspecific “performance effects” of the drug. MK-801 impaired reversal irrespective of drug treatment during acquisition. NMDA-receptor antagonism in the hippocampus is sufficient to account for the previously reported effects of systemic MK-801 on reversal of T-maze position discrimination.

Spatial and visual discrimination reversals in adult and geriatric rats exposed during gestation to methylmercury and n − 3 polyunsaturated fatty acids

Fish contain essential long chain polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), an omega-3 (or n − 3) PUFA, but are also the main source of exposure to methylmercury (MeHg), a potent developmental neurotoxicant. Since n − 3 PUFAs support neural development and function, benefits deriving from a diet rich in n − 3s have been hypothesized to protect against deleterious effects of gestational MeHg exposure. To determine whether protection occurs at the behavioral level, female Long-Evans rats were exposed, in utero, to 0, 0.5, or 5 ppm of Hg as MeHg via drinking water, approximating exposures of 0, 40, and 400 μg Hg/kg/day and producing 0, 0.29, and 5.50 ppm of total Hg in the brains of siblings at birth. They also received pre- and postnatal exposure to one of two diets, both based on the AIN-93 semipurified formulation. A “fish-oil” diet was high in, and a “coconut-oil” diet was devoid of, DHA. Diets were approximately equal in α-linolenic acid and n − 6 PUFAs. As adults, the rats were first assessed with a spatial discrimination reversal (SDR) procedure and later with a visual (nonspatial) discrimination reversal (VDR) procedure. MeHg increased the number of errors to criterion for both SDR and VDR during the first reversal, but effects were smaller or non-existent on the original discrimination and on later reversals. No such MeHg-related deficits were seen when the rats were retested on SDR after 2 years of age. These results are consistent with previous reports and hypotheses that gestational MeHg exposure produces perseverative responding. No interactions between diet and MeHg were found, suggesting that n − 3 PUFAs do not guard against these behavioral effects. Brain Hg concentrations did not differ between the diets, either. In geriatric rats, failures to respond were less common and response latencies were shorter for rats fed the fish-oil diet, suggesting that exposure to a diet rich in n − 3s may lessen the impact of age-related declines in response initiation.

Spatial and visual discrimination reversals in adult and geriatric rats exposed during gestation to methylmercury and n−3 polyunsaturated fatty acids

Spatial and visual discrimination reversals in adult and geriatric rats exposed during gestation to methylmercury and n−3 polyunsaturated fatty acids

Gestational exposure to methylmercury and selenium: Effects on a spatial discrimination reversal in adulthood

Selenium, a nutrient, and methylmercury, a developmental neurotoxicant, are both found in fish. There are reports that selenium sometimes ameliorates methylmercury's neurotoxicity, but little is known about the durability of this protection after low-level gestational exposure. Developmental methylmercury exposure disrupts behavioral plasticity, and these effects extend well into adulthood and aging. The present experiment was designed to examine interactions between developmental low-level methylmercury and nutritionally relevant dietary selenium on discrimination reversals in adulthood. Female rats were exposed, in utero, to 0, 0.5, or 5 ppm mercury as methylmercury via drinking water, approximating mercury exposures of 0, 40, and 400 μg/kg/day. They also received both prenatal and postnatal exposure to a diet containing selenium from casein only (0.06 ppm) or 0.6 ppm selenium, creating a 2 (chronic Se) × 3 (gestational MeHg) full factorial design, with six to eight rats per cell. Behavior was evaluated with a spatial discrimination procedure using two levers and sucrose reinforcers. All groups acquired the original discrimination similarly. Rats exposed to low selenium (0.06 ppm), regardless of MeHg exposure, required more sessions to complete the first reversal and made more omissions during this reversal than high selenium (0.6 ppm) animals, but the two diet groups did not differ on subsequent reversals. Rats exposed to MeHg, regardless of selenium exposure, made more errors than controls on the first and third reversals, which was away from the original discrimination. MeHg-exposed animals also had shorter choice latencies than controls during the first session of a reversal. Low selenium increased the number of omissions during a reversal, whereas high MeHg exposure produced perseverative responding (errors) on the lever that was reinforced during the original discrimination. However, there was no interaction between selenium and MeHg exposure.

Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning deficits.

Prenatal exposure to alcohol can disrupt brain development, leading to a variety of behavioral alterations, including learning deficits. We have postulated that some central nervous system damage may be due to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity that occurs during ethanol withdrawal. Consistent with this hypothesis, we previously demonstrated that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal attenuates ethanol-related learning deficits using an animal model of fetal alcohol effects. However, MK-801 binds to the phencyclidine site, which affects all NMDA receptor subtypes and can cause adverse side effects and toxicity. Eliprodil is a more selective NMDA receptor antagonist that acts at the polyamine modulatory site of NMDA receptors. The purpose of this study was to determine if administration of eliprodil during ethanol withdrawal would reduce the severity of learning deficits associated with developmental alcohol exposure. Male rat pups were randomly assigned to ethanol-exposed or control treatments. On postnatal day (PD) 6, during a period of brain development similar to that of the mid-third trimester in humans, subjects were exposed to 6.0 g/kg ethanol or isocaloric maltose solutions via oral gavage. Twenty-four hours after the end of the ethanol treatment, during ethanol withdrawal, all subjects received an intraperitoneal injection of one of three doses of eliprodil (5, 10, or 25 mg/kg) or vehicle. On PD 40, all subjects were tested on a serial spatial discrimination reversal learning task. Ethanol-exposed subjects treated with vehicle committed a significantly greater number of errors compared to controls. Administration of eliprodil during ethanol withdrawal significantly decreased the number of errors in the ethanol-exposed groups, but had no significant effect on the performance of controls. These data support the hypothesis that NMDA receptor-mediated excitotoxicity during ethanol withdrawal contributes to fetal alcohol effects.

Contextual modulation of spatial discrimination reversal in developing rats

Reversal of discrimination learning is influenced by manipulation of the training context. In adult and developing rats, contextual changes made between acquisition and reversal aid the learning of the new discrimination, possibly by serving to release proactive interference from the originally acquired discrimination (M. E. Bouton & D. C. Brooks, 1993; N. Spear, G. Smith, R. Bryan, & W. Gordon, 1980). The present study sought to examine this effect in an appetitive T-maze task, as a function of different contextual manipulations. Rats of three ages, Postnatal Day (PND) 19, PND23, and PND30, were tested for their ability to acquire and reverse a position habit in a T-maze. Contextual changes were made between acquisition and reversal sessions and consisted of one of three manipulations: (a) texture; the texture of the maze floor was changed via the addition or subtraction of wire mesh; (b) maze; subjects were reversed in a different maze that was identical in construction to the training maze, but differed in spatial location; (c) texture and maze; subjects were shifted to the new maze, the floor of which differed in texture from the training maze but was otherwise identical in construction. Results showed that the texture-maze combination was an effective aid to reversal learning at all ages tested. The texture alone, however, was not effective at any age. The maze alone also was an effective cue for reversal, but proved to have the greatest effect for PND30 subjects. During ontogeny, the contextual modulation of reversal learning is importantly influenced by the nature and the salience of the contextual cue.

Perinatal choline supplementation attenuates behavioral alterations associated with neonatal alcohol exposure in rats

Children exposed to alcohol prenatally suffer from a variety of behavioral alterations, including hyperactivity and learning deficits. Given that women continue to drink alcohol during pregnancy, it is critical that effective interventions and treatments be identified. Previously, we reported that early postnatal choline supplementation can reduce the severity of learning deficits in rats exposed to alcohol prenatally. The present study examined whether choline supplementation can reduce the severity of behavioral alterations associated with alcohol exposure during the third trimester equivalent brain growth spurt. Male neonatal rats were assigned to one of three treatment groups. One group was exposed to alcohol (6.6 g/kg/day) from postnatal days (PD) 4–9 via an artificial rearing procedure. Artificially reared and normally reared control groups were included. One half of subjects from each treatment received daily subcutaneous injections of a choline chloride solution from PD 4–30, whereas the other half received saline vehicle injections. On PD 31–34, after choline treatment was complete, activity level was monitored and, on PD 40–42, subjects were tested on a serial spatial discrimination reversal learning task. Subjects exposed to alcohol were significantly hyperactive compared to controls. The severity of ethanol-induced hyperactivity was attenuated with choline treatment. In addition, subjects exposed to ethanol during the neonatal period committed a significantly greater number of perseverative-type errors on the reversal learning task compared to controls. Exposure to choline significantly reduced the number of ethanol-related errors. Importantly, these behavioral changes were not due to the acute effects of choline, but were related to long-lasting organizational effects of early choline supplementation. These data suggest that early dietary interventions may reduce the severity of fetal alcohol effects.

Administration of Low Doses of MK‐801 During Ethanol Withdrawal in the Developing Rat Pup Attenuates Alcohol's Teratogenic Effects

Background Alcohol exposure during development can produce severe and long‐lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor‐mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK‐801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK‐801's ability to mitigate ethanol's teratogenic effects.Methods Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge‐like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty‐one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK‐801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18–19, activity level was monitored, and on PD 40–42, serial spatial discrimination reversal learning was assessed.Results Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol‐induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05–0.5 mg/kg) of MK‐801 during withdrawal. The performance of ethanol‐exposed subjects treated with the high dose of MK‐801 (1.0 mg/kg) did not differ from that of the Ethanol Only group.Conclusions These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.