Eyeblink classical conditioning and interpositus nucleus activity are disrupted in adult rats exposed to ethanol as neonates

Neonatal exposure to ethanol in rats, during the period of brain development comparable to that of the human third trimester, produces significant, dose-dependent cell loss in the cerebellum and deficits in coordinated motor performance. These rats are also impaired in eyeblink conditioning as weanlings and as adults. The current study examined single-unit neural activity in the interpositus nucleus of the cerebellum in adults following neonatal binge ethanol exposure. Group Ethanol received alcohol doses of 5.25 g/kg/day on postnatal days 4–9. Group Sham Intubated underwent acute intragastric intubation on postnatal days 4–9 but did not receive any infusions. Group Unintubated Control (from separate litters) did not receive any intubations. When rats were 3–7 mo old, pairs of extracellular microelectrodes were implanted in the region of the interpositus nucleus. Beginning 1 wk later, the rats were given either 100 paired or 190 unpaired trials per day for 10 d followed by 4 d of 100 conditioned stimulus (CS)-alone trials per day. As in our previous study, conditioned response acquisition in Group Ethanol rats was impaired. In addition, by session 5 of paired acquisition, Group Sham Intubated and Group Unintubated Control showed significant increases in interpositus nucleus activity, relative to baseline, in the CS–unconditioned stimulus interval. In contrast, Group Ethanol failed to show significant changes in interpositus nucleus activity until later in training. These results indicate that the disruption in eyeblink conditioning after early exposure to ethanol is reflected in alterations in interpositus nucleus activity.     

Neonatal amphetamine exposure and hippocampus-mediated behaviors

Previous studies linking amphetamine use during pregnancy to changes in the behavioral development of affected infants have greatly increased society’s level of concern regarding amphetamine use by women of reproductive age. The aim of this study was to investigate whether exposure to d-amphetamine sulfate during the brain growth spurt, the most dynamic period of brain development, alters hippocampus-mediated behaviors during both pre-adolescence and young adulthood. Sprague–Dawley rat pups were intragastrically administered a milk formula containing 0, 5, 15 or 25 mg/kg/day of amphetamine from postnatal day (PD) 4–9. Following weaning, the effects of neonatal amphetamine exposure on hippocampus-mediated behaviors were assessed using the open-field, the water maze, and the conditioned taste aversion behavioral tasks. Results from these behavioral tests revealed that while amphetamine exposure during the brain growth spurt alters behaviors in open-field testing, it does not interfere with performance in either the water maze or the conditioned taste aversion paradigm. These results offer speculation that the effects of neonatal amphetamine exposure on hippocampus-mediated behaviors may be related to interactions between the “temporal” (time of drug exposure) and “regional” (different regions of the hippocampus) vulnerability issues.     

Using Eyeblink Classical Conditioning as a Test of the Functional Consequences of Exposure of the Developing Cerebellum to Alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Using eyeblink classical conditioning as a test of the functional consequences of exposure of the developing cerebellum to alcohol

Exposure of the developing brain to alcohol produces profound Purkinje cell loss in the cerebellum, and deficits in tests of motor coordination. However, the precise relationship between these two sets of findings has been difficult to determine. Eyeblink classical conditioning is known to engage a discrete brainstem-cerebellar circuit, making it an ideal test of cerebellar functional integrity after developmental alcohol exposure. In eyeblink conditioning, one of the deep cerebellar nuclei, the interpositus nucleus, as well as specific Purkinje cell populations, are sites of convergence for CS and US information. A series of studies have shown that eyeblink conditioning is impaired in both weanling and adult rats given binge-like exposure to alcohol as neonates, and that these deficits can be traced, at least in part, to impaired activation of cerebellar interpositus nucleus neurons and to an overall reduction in the deep cerebellar nuclear cell population. Because particular cerebellar cell populations are utilized in well-defined ways during eyeblink conditioning, conclusions regarding specific changes in the mediation of behavior by these cell populations are greatly strengthened. Further studies will be directed towards the impact of early exposure to alcohol on the functionality of specific Purkinje cell populations, as well as towards brainstem areas that process the tone CS and the somatosensory US.     

Varenicline ameliorates ethanol-induced deficits in learning in C57BL/6 mice

Ethanol is a frequently abused drug that impairs cognitive processes such as learning. Varenicline, an α4β2 nicotinic receptor partial agonist and α7 nicotinic receptor full agonist prescribed for smoking cessation, has been shown to decrease ethanol consumption. The current study investigated whether varenicline could ameliorate ethanol-induced deficits in learning and whether varenicline alters blood alcohol concentration in C57BL/6 mice. Conditioning consisted of two auditory conditioned stimulus (CS; 30 s, 85 dB white noise)—foot shock unconditioned stimulus (US; 2 s, 0.57 mA) pairings. For all studies, saline or ethanol (1.0, 1.5, 2.0 g/kg i.p.) was administered 15 min before training, and saline or varenicline (0.05, 0.1, 0.2 mg/kg i.p.) was administered 60 min before either training or testing. For blood alcohol analysis, saline or varenicline (0.1 mg/kg) was administered 60 min before collection, and saline or ethanol (1.0, 1.5, 2.0 g/kg) was administered 15 min before collection. Varenicline dose-dependently ameliorated ethanol-induced conditioning deficits for all three doses of ethanol when administered before training but not when administered 24 h later, before testing. In addition, varenicline did not alter blood alcohol concentration. The smoking cessation aid varenicline may have therapeutic uses for treating ethanol-associated disruptions in cognitive processes.     

Scopolamine Selectively Disrupts the Acquisition of Contextual Fear Conditioning in Rats

Muscarinic cholinergic antagonism produces learning and memory deficits in a variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia for contextual fear conditioning, but do not impact fear conditioning to discrete cues. In order to examine the effects of muscarinic antagonism in this paradigm, rats were given scopolamine (1 mg/kg) either before or for 3 days after a Pavlovian fear-conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone was assessed by measuring freezing in separate tests. It was found that pretraining, but not posttraining, scopolamine severely impaired contextual fear conditioning; tone conditioning was not affected under either condition (cf., Young, Bohenek, & Fanselow,Neurobiology of Learning and Memory,63,174–180, 1995).     

Memory and brain volume in adults prenatally exposed to alcohol

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n=26; Alcohol-related Neurodevelopmental Disorder, n=36; and Dysmorphic, n=30) were imaged using structural MRI with brain volume calculated for multiple regions of interest. Memory was measured using the Verbal Selective Reminding Memory Test and its nonverbal counterpart, the Nonverbal Selective Reminding Memory Test, which each yielding measures of learning and recall. For both Verbal and Nonverbal Recall and Slope, linear trends were observed demonstrating a spectrum of deficits associated with prenatal alcohol exposure. Dysmorphic individuals performed significantly poorer than unexposed controls on 5 of 6 memory outcomes. Alcohol-exposed individuals demonstrated significantly lower total brain volume than controls, as well as lower volume in a number of specific regions including hippocampus. Mediation analyses indicated that memory performance associated with effects of prenatal alcohol exposure was mediated from dysmorphic severity through hippocampal volume, particularly right hippocampus. These results indicate that the association between the physical effects of prenatal alcohol exposure and deficits in memory are mediated by volumetric reduction in specific brain regions.     

Long-term effects of prior cocaine exposure on Morris water maze performance

Cocaine addiction is associated with long-term cognitive alterations including deficits on tests of declarative/spatial learning and memory. To determine the extent to which cocaine exposure plays a causative role in these deficits, adult male Long-Evans rats were given daily injections of cocaine (30 mg/kg/day x 14 days) or saline vehicle. Three months later, rats were trained for 6 sessions on a Morris water maze protocol adapted from Gallagher, Burwell, and Burchinal [Gallagher, M., Burwell, R., & Burchinal, M. (1993). Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral Neuroscience, 107, 618-626]. Rats given prior cocaine exposure performed similarly to controls on training trials, but searched farther from the platform location on probe trials interpolated throughout the training sessions and showed increased thigmotaxis. The results demonstrate that a regimen of cocaine exposure can impair Morris water maze performance as long as 3 months after exposure. Although the impairments were not consistent with major deficits in spatial learning and memory, they may have resulted from cocaine-induced increases in stress responsiveness and/or anxiety. Increased stress and anxiety would be expected to increase thigmotaxis as well as cause impairments in searching for the platform location, possibly through actions on ventral striatal dopamine signaling.     

Paired-Associate Learning in Attention-Deficit/Hyperactivity Disorder as a Function of Hyperactivity-Impulsivity and Oppositional Defiant Disorder

A paired-associate learning (PAL) test was administered to 22 community volunteers without disruptive disorders and 197 children (7.5–13.5 years-old) presenting with the inattentive and combined subtypes of attention-deficit/hyperactivity disorder (ADHD) either in combination with or without oppositional defiant disorder (ODD). Participants were screened for learning disorders. In comparison to non-ADHD participants, children with ADHD achieved worse PAL and made errors rated as more acoustically and less semantically similar to the correct paired associates. These deficits were not related to hyperactivity–impulsivity or comorbid ODD. These results suggest that ADHD children are less competent at PAL and use less efficient learning strategies than their non-ADHD peers.     

Effects of moderate chronic ethanol consumption on hippocampal nicotinic receptors and associative learning

A number of studies have reported that ethanol exposure induces changes in different brain systems. The hippocampus is a brain region that is very vulnerable to ethanol exposition, which functionally results in impairment of learning and memory processes reported in heavy drinkers. Hippocampal nicotinic receptors are involved in learning and memory. In this study, we determined the effects of ethanol on the main hippocampal subtypes of neural nicotinic receptors (α7 and α4β2) in rats non-selected for alcohol consumption, in order to check for possible changes on these receptors that could be linked with alterations in learning acquisition. Binding assays were carried out with [³H]methyllycaconitine ([³H]MLA) to study the α7 and [³H]nicotine to study α4β2 receptors. Auto-shaping, continuous ratio and extinction procedures were used as behavioral tests. The results show that moderate chronic ethanol consumption for 10 weeks produces: (a) a decrease of both hippocampal nicotinic receptor subtypes without alterations in affinity; (b) no differences in behavioral performance between control rats and ethanol-drinking rats in auto-shaping and continuous ratio; (c) an improvement of performance of extinction paradigm. These results indicate that chronic ethanol consumption, at moderate levels, induces changes in hippocampal nicotinic receptors but does not impair acquisition and performance of new associative learning and even improves some kind of paradigms. These results may have implications in the biochemical basis of interactions between alcohol and nicotine and the effects of these drugs on behavior.     

Children's cognitive ability from 4 to 9 years old as a function of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence

This study examined the effects of prenatal cocaine exposure, environmental risk, and maternal verbal intelligence on children's cognitive ability. Gender and age were examined as moderators of potential cocaine exposure effects. The Stanford-Binet IV intelligence test was administered to 231 children (91 cocaine exposed, 140 unexposed) at ages 4, 6, and 9 years. Neonatal medical risk and other prenatal exposures (alcohol, cigarettes, and marijuana) were also examined for their unique effects on child IQ. Mixed models analysis indicated that prenatal cocaine exposure interacted with gender, as cocaine-exposed boys had lower composite IQ scores. Age at assessment did not moderate this relation, indicating that cocaine-exposed boys had lower IQs across this age period. A stimulating home environment and high maternal verbal IQ also predicted higher composite IQ scores. Cocaine-exposed boys had lower scores on the Abstract/Visual Reasoning subscale, with trends for lower scores on the Short-Term Memory and Verbal Reasoning subscales, as exposure effects were observed across domains. The findings indicate that cocaine exposure continues to place children at risk for mild cognitive deficits into preadolescence. Possible mechanisms for the Exposure x Gender interaction are discussed.     

Continuity and Change in Emotional Reactivity in Rhesus Monkeys Throughout the Prepubertal Period

We examined continuity and change in emotional reactiviy as assessed by hypothalamic–pituitary–adrenal (HPA) activity in rhesus monkeys. Plasma samples were obtained from mother-peer–reared and surrogate-peer–reared monkeys and assayed for cortisol concentrations at 5 time points in infancy. Both plasma and saliva samples were collected for cortisol assay from the same monkeys as 1-, 2-, and 3-year-old juveniles, respectively. Plasma cortisol concentrations increased during the first 5 months of life and decreased from 1 to 3 years of age. Females consistently had higher plasma cortisol concentrations than males. Plasma cortisol concentrations were lower in surrogate-peer–reared than mother-peer–reared monkeys during the first month of life. Juvenile plasma cortisol concentrations were significantly correlated with infant cortisol levels at all but the earliest time point. Analysis of salivary cortisol from a subset of animals showed a similar age-related decline and the presence of a significant rearing effect, with lower concentrations in surrogate-peer–reared juveniles, but no sex difference. Salivary and plasma cortisol concentrations in these animals were significantly correlated.     

A multisource exploration of the friendship patterns of children with and without learning disabilities

Friendship patterns of 117 children with learning disabilities (LD) and 115 children without LD in Grades 4–8 were examined. In comparison with children without LD, boys with LD had fewer mutual friends, children with LD had more friends with learning problems and more younger friends, and children with LD in Grades 4–6 had less stable relationships. With regard to friendship quality, children with LD reported higher levels of conflict, lower levels of validation, and more problems with relationship repair than did children without LD. The findings were discussed in terms of factors that have been found to enhance friendship such as proximity and similarity, and the social skills difficulties that have been associated with learning disabilities.     

Learning in a task of complex auditory streaming and identification

Adult humans were studied for improvements in their ability to segregate natural whole speech in background noise, in 6 test sessions spaced with a very wide range of inter-session interval (ISI) ranging from minutes to weeks apart so as to examine the effect of this parameter on initial (early) and late components of perceptual learning. Improvements were found even with spacings of 3 weeks between the punctate task sessions. All subjects showed similar total learning amounts but there were sex- and ISI-dependent differences in learning patterns, which we indexed by dividing the overall exponentially-decreasing learning pattern into an early phase between the first two sessions and a later phase between the second and sixth sessions. Males tested at all ISIs and females tested at short (2, 5 and 15 min) and long (1–21 days) ISIs showed small amounts of early-phase learning and large amounts of late-phase learning. However, females tested at intermediate (30 min and 1 h) ISIs showed only early learning, i.e., faster learning given that the total learning was the same. This sex- and ISI-specific deviant pattern could be changed to the standard pattern by interposing an overnight interruption that included sleep amongst test sessions. Thus, improvement in this complex auditory streaming and identification task can occur even with very brief and widely-spaced exposure, generally through a standard pattern of slower overall learning, but also through a sex- and ISI-specific deviant pattern of very rapid early learning which can be modulated by interposed delay unlike the standard pattern.     

Impaired sequential and partially compensated probabilistic skill learning in Parkinson's disease

The striatal dopaminergic dysfunction in Parkinson's disease (PD) has been associated with deficits in skill learning in numerous studies, but some of the findings remain controversial. Our aim was to explore the generality of the learning deficit using two widely reported skill learning tasks in the same group of Parkinson's patients. Thirty-four patients with PD (mean age: 62.83 years, SD: 7.67) were compared to age-matched healthy adults. Two tasks were employed: the Serial Reaction Time Task (SRT), testing the learning of motor sequences, and the Weather Prediction (WP) task, testing non-sequential probabilistic category learning. On the SRT task, patients with PD showed no significant evidence for sequence learning. These results support and also extend previous findings, suggesting that motor skill learning is vulnerable in PD. On the WP task, the PD group showed the same amount of learning as controls, but they exploited qualitatively different strategies in predicting the target categories. While controls typically combined probabilities from multiple predicting cues, patients with PD instead focused on individual cues. We also found moderate to high correlations between the different measures of skill learning. These findings support our hypothesis that skill learning is generally impaired in PD, and can in some cases be compensated by relying on alternative learning strategies.     

Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder

Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discriminative learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger cues. Importantly, this discrimination deficit was driven by enhanced startle-potentiation to the learned safety cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety cues.     

Time stamp in conditioned place avoidance can be set to different circadian phases

We have reported that the expression of conditioned place avoidance (CPA) in the golden hamster is regulated in a circadian pattern such that the preference is exhibited strongly at the circadian time of prior training but not at other circadian times [Cain, S. W., Chou, T., & Ralph, M. R. (2004a). Circadian modulation of performance on an aversion-based place learning task in hamsters. Behavioural Brain Research, 150(1–2), 201–205]. In that study, animals that were trained at a specific circadian time to discriminate between a “safe” context and one paired with foot shock, showed strong avoidance of the paired context at 24 and 48 h following the last training session, and showed no avoidance at 32 and 40 h following training. In the present study, we hypothesized that this “time stamp” effect is settable to any circadian phase. This was tested by training animals at one of two times of day (ZT13 or ZT4) and testing whether a time stamp would be observed, with avoidance occurring only when training and testing times match. Results confirmed our hypothesis, suggesting that the time stamp in the performance of learned tasks can be set to any circadian phase. Such an ability may allow animals in nature to predict the recurrence of 24 h events, regardless of the time of day the event was encountered.     

Anticipation of ball location in low and high-skill performers: a developmental perspective

Objectives: To study how visual anticipatory capabilities develop in high and low-skill tennis players and the role of years of practice (i.e. experience). It was expected that with accumulated experience differences will increase with skill-level, in particular under conditions of fast visual exposure which results in minimal environmental information exposure.Method: Eighty tennis players divided into 4 age categories and 2 skill levels (high and low) were selected according to 4 criterion which ensured appropriate representation of skill-level and experience in tennis. Age categories were 8–11, 11–14, 14–18, and >18. Years of experience in the game were 2.12, 4.17, 6.5, and 12.4 years respectively. Players observed filmed segments of tennis strokes on a monitor, which varied in temporal occlusion conditions from −480 ms prior to ball-racquet contact to 320 ms after contact. After each exposure they were asked to indicate the final ball location. The radial, lateral, and depth distances were averaged for age and skill level.Design: A temporal occlusion paradigm was used in this study. The film was prepared with a camera positioned in the receiver's court. Eight strokes which best represent the game of tennis were chosen. Forty-eight segments were viewed and errors were calculated for each exposure.Result: High-skill tennis players gained more from practice and experience in developing visual anticipatory skills, but their perceptual advantage was not consistent across all stroke conditions, being at its greatest number in conditions of maximal temporal constraints.Conclusions: Differences in visual anticipatory capabilities exist between different skill levels at the outset of their development. These differences increase with experience, mainly after 6–7 years. Greater knowledge base does not always guarantee a superior anticipation of upcoming events and choosing the best decision.     

Emergence of a cue strategy preference on the water maze task in aged C57B6 x SJL F1 hybrid mice

The effects of age on cue learning, spatial reference memory, and strategy preference were assessed in B6 × SJL F1 mice by using the Morris water maze. This mouse strain is of particular interest because it is the background strain for a common transgenic model of Alzheimer's disease, the Tg2576 mouse, which develops plaques and other neurobiological markers of pathology beginning at 8 mo and increasing in severity with advanced age. In the current study, 12- and 23-mo-old C57B6 × SJL F1 mice were serially trained in cue and place versions of the Morris water maze task. At the completion of training, mice received a strategy probe test in which place (hidden) and cue (visible) strategies were in competition. Cue and spatial learning ability was maintained between 12 and 23 mo of age; however, on the strategy preference probe test, the 23-mo-old mice exhibited a significant bias toward the selection of a cue strategy. There was no relationship between strategy preference in the probe test and spatial learning ability, but the 23-mo-old mice did exhibit a strong trend toward shorter latencies during visible platform training, possibly reflecting the enhanced function of striatal-based neural systems in aging. These data demonstrate that 23-mo-old C57B6 × SJL F1 mice are capable of effective place learning, but if a place strategy is pitted against the use of a cue strategy, the use of a cue strategy predominates in the aged mice. The strategy preference observed here may reflect an emergence of differential processing in underlying brain circuitry with age in the B6 × SJL F1 mouse strain.     

Visual speech contributes to phonetic learning in 6-month-old infants

Previous research has shown that infants match vowel sounds to facial displays of vowel articulation [Kuhl, P. K., & Meltzoff, A. N. (1982). The bimodal perception of speech in infancy. Science, 218, 1138–1141; Patterson, M. L., & Werker, J. F. (1999). Matching phonetic information in lips and voice is robust in 4.5-month-old infants. Infant Behaviour & Development, 22, 237–247], and integrate seen and heard speech sounds [Rosenblum, L. D., Schmuckler, M. A., & Johnson, J. A. (1997). The McGurk effect in infants. Perception & Psychophysics, 59, 347–357; Burnham, D., & Dodd, B. (2004). Auditory-visual speech integration by prelinguistic infants: Perception of an emergent consonant in the McGurk effect. Developmental Psychobiology, 45, 204–220]. However, the role of visual speech in language development remains unknown. Our aim was to determine whether seen articulations enhance phoneme discrimination, thereby playing a role in phonetic category learning. We exposed 6-month-old infants to speech sounds from a restricted range of a continuum between /ba/ and /da/, following a unimodal frequency distribution. Synchronously with these speech sounds, one group of infants (the two-category group) saw a visual articulation of a canonical /ba/ or /da/, with the two alternative visual articulations, /ba/ and /da/, being presented according to whether the auditory token was on the /ba/ or /da/ side of the midpoint of the continuum. Infants in a second (one-category) group were presented with the same unimodal distribution of speech sounds, but every token for any particular infant was always paired with the same syllable, either a visual /ba/ or a visual /da/. A stimulus-alternation preference procedure following the exposure revealed that infants in the former, and not in the latter, group discriminated the /ba/–/da/ contrast. These results not only show that visual information about speech articulation enhances phoneme discrimination, but also that it may contribute to the learning of phoneme boundaries in infancy.