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Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions.

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Experience-produced deficits in trace conditioning and context conditioning have been useful tools for examining the role of the hippocampus in learning. It has also been suggested that learning in these tasks is especially vulnerable to neurotoxic effects of alcohol during key developmental periods such as adolescence. In five experiments we systematically examined the presence and source of age-dependent vulnerability to the memory-disrupting effects of acute ethanol in trace conditioning and contextual fear conditioning. In Experiment 1a pre-training ethanol disrupted trace conditioning more strongly in adolescent (postnatal day, PD30-35) than adult rats (PD65-75). In Experiment 1b when pre-training ethanol was accompanied by pre-test ethanol no deficit in trace conditioning was observed in adolescents, suggesting that state-dependent retrieval failure mediated ethanol's disruption of trace conditioning at this age. Experiment 2a and b examined the effect of ethanol pretreatment on context conditioning. Here, adult but not adolescent rats were impaired in conditioned freezing to context cues. Experiment 2c explored state-dependency of this effect. Pre-training ethanol continued to disrupt context conditioning in adults even when ethanol was also administered prior to test. Collectively these findings reveal clear age-dependent and task-dependent vulnerabilities in ethanol's disruptive effects on hippocampus-dependent memory. Adolescents were more disrupted by ethanol in trace conditioning than adults, and adults were more disrupted by ethanol in context conditioning than adolescents. We suggest that adolescents may be more susceptible to changes in internal state (state-dependent retrieval failure) than adults and that ethanol disrupted performance in trace and context conditioning through different mechanisms. Relevance of these findings to theories of hippocampus function is discussed.

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Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5g/kg/day ethanol on postnatal days (PD) 4-9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as 'gap filling' completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions.

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Several studies using rodent subjects have now shown that extra dietary choline may prevent or even reverse the deleterious effects of pre- and early post-natal ethanol administration. Choline supplementation has been shown to attenuate many, although not all, of ethanol's effects on brain development and behavior. Our laboratory has consistently reported impaired habituation of the heart rate orienting response to a novel olfactory stimulus in animals exposed to ethanol on postnatal days (PD) 4-9. Here we examine whether supplemental choline given both during and after ethanol administration could alleviate these ethanol-induced deficits. Subjects were given 5g/kg/day ethanol or sham intubations on PD 4-9. Half of the subjects in each group were given a single daily s.c. injection of choline chloride on PD 4-20, while the other half were injected daily with saline. Pups were tested for heart rate orienting and response habituation in a single test session on PD 23. Results replicated the ethanol-induced impairment in response habituation. However, choline supplementation had no effect on orienting or habituation in either neonatal treatment group. These findings indicate that habituation deficits induced by ethanol are not alleviated by extra dietary choline using these parameters. Choline holds great promise as a treatment for some fetal alcohol effects, but is not an effective treatment for all ethanol-related deficits.

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The developing hippocampus is particularly vulnerable to the toxic effects of alcohol, and behavioral deficits on hippocampus-dependent tasks have been reported following neonatal alcohol exposure in rodents. Previously, we have found that trace fear conditioning (a hippocampus-dependent learning task) is disrupted in rats exposed to alcohol during postnatal days (PD) 4-9, although delay fear conditioning is not. The present study indicates that this impairment in trace fear conditioning, previously only measured during adolescence, persists into adulthood but only in females. Animals were exposed to 5.0 g/kg/day alcohol on PD 4-9 and were trained on either PD 30 or 65. Alcohol exposure significantly impaired trace conditioning in both sexes at PD 30. In animals trained as adults, the deficit in trace was only observed in female subjects, suggesting that although males exhibit an age-related recovery of function, alcohol-induced trace conditioning deficits are more persistent in female Sprague-Dawley rats.

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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.

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Despite the prevalence of smoking among adolescents, few studies have assessed the effects of adolescent nicotine exposure on learning in adulthood. In particular, it remains unclear whether adolescent nicotine exposure has effects on hippocampus-dependent learning that persist into adulthood. The present experiment examined whether there were effects of adolescent nicotine exposure on context conditioning, a form of learning dependent on the integrity of the hippocampus, when tested during adulthood. Rats were exposed to nicotine during adolescence (postnatal days [PD] 28-42) via osmotic minipump (0, 3.0 or 6.0mg/kg/day). Context conditioning occurred in early adulthood (PD 65-70). Animals were exposed to an experimental context and were given 10 unsignaled footshocks or no shock. Additional groups were included to test the effects of adolescent nicotine on delay conditioning, a form of learning that is not dependent upon the hippocampus. Conditioning was assessed using a lick suppression paradigm. For animals in the context conditioning groups, adolescent nicotine resulted in significantly less suppression of drinking in the presence of context cues compared with vehicle-pretreated animals. For animals in the delay conditioning groups, there was a trend for adolescent nicotine (3.0mg/kg/day) to suppress drinking compared to vehicle-pretreated animals. There were no differences in extinction of contextual fear or cued fear between rats previously exposed to vehicle or nicotine. The data indicate that adolescent nicotine administration impairs context conditioning when animals are trained and tested as adults. The present data suggest that adolescent nicotine exposure may disrupt hippocampus-dependent learning when animals are tested during adulthood.

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In humans, prenatal alcohol exposure can result in significant impairments in several types of learning and memory, including declarative and spatial memory. Animal models have been useful for confirming that many of the observed effects are the result of alcohol exposure, and not secondary to poor maternal nutrition or adverse home environments. Wagner and Hunt (2006) reported that rats exposed to ethanol during the neonatal period (postnatal days [PDs] 4-9) exhibited impaired trace fear conditioning when trained as adolescents, but were unaffected in delay fear conditioning. The present series of three experiments represent a more detailed analysis of ethanol-induced deficits in trace conditioning. In Experiment 1, the dose of ethanol given to neonates was varied (3.0, 4.0, or 5.0g/kg/day). There was a dose-dependent reduction in trace conditioning, with the poorest performance observed in animals treated with the highest dose. In Experiment 2, it was found that the impairment in trace conditioning resulting from neonatal ethanol exposure was dependent on the duration of the trace interval used for training; less learning was evident in ethanol-exposed animals trained with longer trace interval durations. These results confirm other reports of delay-dependent memory deficits. Finally, Experiment 3 determined that ethanol exposure limited to the first half of the neonatal period (PDs 4-6) was more detrimental to later trace conditioning than exposure during the second half (PDs 7-9). These results support the hypothesis that trace-conditioning impairments resulting from early ethanol exposure are due to the drug's teratogenic effects on the developing hippocampus, as the findings parallel those observed in animals with discrete hippocampal lesions. Comparisons between delay and trace fear-conditioning performance in animals exposed to ethanol during the brain growth spurt provide a model system to study both selective learning impairments and possible treatment approaches for humans with fetal alcohol spectrum disorders.

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BACKGROUND: We have previously shown that the rate of habituation of the heart rate orienting response to a novel odor in rats is negatively affected by neonatal ethanol exposure. Thus far, however, only young rats (16 days of age) have been tested. Given the persistence of attention and memory problems evident in humans exposed to ethanol in utero, the purpose of this experiment was to examine the longer-term consequences of ethanol exposure on response habituation. METHODS: Ethanol (5.25 g/kg/d) was administered intragastrically to male and female Sprague-Dawley rats on postnatal days (PD) 4 to 9, and controls were given sham intubations. Animals were tested for heart rate orienting and response habituation to a novel olfactory stimulus (amyl acetate) on PD 16, 23, or 30. RESULTS: Animals tested on PD 16 or 23 showed normal heart rate deceleration to the novel odor, a measure of the orienting response. However, ethanol-treated subjects showed impaired response habituation compared with sham controls. While controls exhibited complete habituation within 4 to 5 trials, ethanol-treated animals continued to respond throughout the testing session, with little decrement in heart rate response magnitude across 10 stimulus presentations. A different pattern of responding was observed in animals tested during adolescence (PD 30). Control animals failed to show the typical heart rate decrease indicative of orienting, and instead showed a tendency toward tachycardia. In contrast, ethanol-treated animals tested on PD 30 showed orienting bradycardia that persisted for several trials. CONCLUSIONS: These data suggest that there are relatively long-term consequences of neonatal ethanol exposure on nonassociative memory. This impairment in habituation may be relevant to the distractibility and poor focused attention that is pervasive among humans diagnosed with fetal alcohol spectrum disorders.

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Ethanol has complex effects on memory performance, although hippocampus-dependent memory may be especially vulnerable to disruption by acute ethanol intoxication occurring during or shortly after a training episode. In the present experiments, the effects of post-training ethanol on delay and trace fear conditioning were examined in adolescent rats. In Experiment 1, 30-day-old Sprague-Dawley rats were given delay or trace conditioning trials in which a 10s flashing light CS was paired with a 0.5 mA shock US. For trace groups, the trace interval was 10 s. On days 31-33, animals were administered ethanol once daily (0.0 or 2.5 g/kg via intragastric intubation), and on day 34 animals were tested for CS-elicited freezing. Results showed that post-training ethanol affected the expression of trace, but had no effect on delay conditioned fear. Experiment 2 revealed that this effect was dose-dependent; doses lower than 2.5 g/kg were without effect. Experiment 3 evaluated whether proximity of ethanol to the time of training or testing was critical. Results show that ethanol administration beginning 24h after training was more detrimental to trace conditioned freezing than administration that was delayed by 48 h. Finally, in Experiment 4 animals were trained with one of three different trace intervals: 1, 3 or 10s. Results indicate that post-training administration of 2.5 g/kg ethanol disrupted trace conditioned fear in subjects trained with a 10s, but not with a 1 or 3s, trace interval. Collectively the results suggest that ethanol administration impairs post-acquisition memory processing of hippocampus-dependent trace fear conditioning.

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This article summarizes the proceedings of a symposium organized by Mark Stanton and Pamela Hunt and presented at the annual meeting of the International Society for Developmental Psychobiology. The purpose of the symposium was to review recent advances in neurobiological and developmental studies of fear and eyeblink conditioning with the hope of discovering how neural circuitry might inform the ontogenetic analyses of learning and memory, and vice versa. The presentations were: (1) Multiple Brain Regions Contribute to the Acquisition of Pavlovian Fear by Michael S. Fanselow; (2) Expression of Learned Fear: Appropriate to Age of Training or Age of Testing by Rick Richardson; (3) Trying to Understand the Cerebellum Well Enough to Build One by Michael D. Mauk; and (4) The Ontogeny of Eyeblink Conditioning: Neural Mechanisms by John H. Freeman. Taken together, these presentations converge on the conclusions that (1) seemingly simple forms of associative learning are governed by multiple "engrams" and by temporally dynamic interactions among these engrams and other circuit elements and (2) developmental changes in these interactions determine when and how learning emerges during ontogeny.

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In most studies comparing trace and delay conditioning, CS duration is kept constant across training conditions but the interstimulus interval (ISI), the time from CS onset to US onset, is confounded. In the infrequently used long-delay condition, however, ISI is kept constant across the trace and delay conditions but CS duration varies. A recent study reported that trace and long-delay fear conditioning have the same developmental trajectory, with both emerging later in development than standard-delay conditioning (). Past studies have shown that trace conditioning is mediated by the cholinergic system; given the parallel developmental emergence of trace and long-delay conditioning, the present study examined whether the cholinergic system also mediates long-delay conditioning. Two experiments, both involving Sprague-Dawley-derived rats and using freezing as a measure of learned fear, showed that the cholinergic system is critically involved in trace conditioning but is not involved in long-delay conditioning. Specifically, pre-training injections of the muscarinic receptor antagonist scopolamine impaired acquisition of a CS-US association in 32-day-old rats trained with a trace procedure but had no effect on rats this age trained with a long-delay procedure (Experiment 1). Similarly, pre-training injections of physostigmine, a cholinesterase inhibitor, enhanced acquisition of trace conditioning in 25-day-old rats but had no effect on long-delay conditioning in rats this age (Experiment 2). Taken together, the results indicate that despite the similarities between trace and long-delay conditioning in terms of developmental emergence and level of conditioned responding, they are mediated by different physiological systems.

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Relative to freezing, fear-potentiated startle (FPS) is developmentally delayed. Rats trained on Postnatal Day (PD) 18 expressed conditioned stimulus learning on PD 19 in freezing but not in FPS, whereas rats trained on PD 24 and tested on PD 25 expressed both freezing and FPS (Experiment 1). According to a neural maturation hypothesis, this delay results from functional immaturity of pathways mediating FPS. When rats were trained on PD 18, neither delaying the FPS test, allowing FPS pathways to develop, nor administrating the "reminder" treatment, the expression of FPS was promoted (Experiments 1, 2, and 2A). PD 18 learning was expressed in FPS on PD 25 when nontarget conditioned stimulus-unconditioned stimulus training occurred prior to the test, and this effect was modality dependent (Experiments 3 and 4). The authors conclude that engaging mechanisms of associative encoding when FPS pathways are functional is a critical condition for integrating learning and FPS response systems in development.

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In four experiments the effects of serial compound conditioning on responding to a trace-conditioned CS were evaluated using a fear conditioning paradigm. The subjects were 18- and 25-day-old Sprague-Dawley rats, previously shown to exhibit little or no trace fear conditioning. Here, animals as young as 18 days of age were shown to be capable of trace conditioning between a visual CS1 and a shock US, provided the trace interval was filled with a non-target CS2 during serial conditioning trials (CS1-->CS2-->US). To explore cholinergic mechanisms involved in trace and serial conditioning, additional experiments assessed conditioned responding following pre-training administration of the muscarinic receptor antagonist scopolamine. Scopolamine produced a dose-dependent reduction in responding to the trace CS1, regardless of whether subjects were trained with standard trace (CS1-->trace interval-->US) or serial (CS1-->CS2-->US) trials. Responding to CS2 was unaffected by scopolamine. These data suggest that central cholinergic systems are functional in the young animals, but are not normally sufficiently activated by standard trace conditioning procedures. The results suggest that serial compound conditioning can promote trace conditioning in young rats, as it does in adults, perhaps by enhancing cholinergic activity during training. Implications for the late ontogenetic emergence of trace conditioning as it relates to maturation of neural pathways and their role in the potentiating effects of a gap filler are discussed.

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