• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Brain Res. Author manuscript; available in PMC Oct 27, 2009.
Published in final edited form as:
PMCID: PMC2634773
NIHMSID: NIHMS75810

Prenatal choline supplementation increases sensitivity to contextual processing of temporal information

Abstract

The effects of prenatal choline availability on contextual processing in a 30-s peak-interval (PI) procedure with gaps (1, 5, 10, and 15 s) were assessed in adult male rats. Neither supplementation nor deprivation of prenatal choline affected baseline timing performance in the PI procedure. However, prenatal choline availability significantly altered the contextual processing of gaps inserted into the to-be-timed signal (light on). Choline-supplemented rats displayed a high degree of context sensitivity as indicated by clock resetting when presented with a gap in the signal (light off). In contrast, choline-deficient rats showed no such effect and stopped their clocks during the gap. Control rats exhibited an intermediate level of contextual processing in between stop and full reset. When switched to a reversed gap condition in which rats timed the absence of the light and the presence of the light served as a gap, all groups reset their clocks following a gap. Furthermore, when filling the intertrial interval (ITI) with a distinctive stimulus (e.g., sound), both choline-supplemented and control rats rightward shifted their PI functions less on trials with gaps than choline-deficient rats, indicating greater contextual sensitivity and reduced clock resetting under these conditions. Overall, these data support the view that prenatal choline availability affects the sensitivity to the context in which gaps are inserted in the to-be-timed signal, thereby influencing whether rats run, stop, or reset their clocks.

Keywords: Interval timing, Time perception, Gaps, Attention, Time sharing, Context sensitivity, Prenatal nutrition, Neural development, Hippocampus

1. Introduction

A variety of behavioral and neurobiological evidence supports the view that adult rats given prenatal-choline supplementation have increased memory capacity and precision while being able to form more enduring memories (e.g., Cheng et al., 2008; Meck et al., 1988, 1989, 2008; Meck and Williams, 1997b, 1999; Mellott et al., 2004; Montoya et al, 2000; Williams et al., 1998 – see McCann et al., 2006 and Meck and Williams, 2003 for reviews). Recent studies have shown that prenatal choline supplementation causes long-term adaptations in hippocampal choline metabolism (Cermak et al., 1998, 1999) and it is well accepted that the cholinergic system has a central role in memory function (Bartus et al., 1982; Hasselmo and Giocomo, 2006). It has also been demonstrated that prenatal-choline supplementation protects against seizure-induced memory deficits (Wong-Goodrich et al., 2008; Yang, et al., 2000) while elevating the baseline level of hippocampal neurogenesis in adult rats (Aimone et al., 2006; Glenn et al., 2007). In terms of neuroplasticity, adult hippocampal slices from prenatally choline-supplemented rats exhibit a lower threshold for the induction of long-term potentiation compared with slices from control rats (Jones et al., 1999; Pyapali et al., 1998). Furthermore, perinatal choline supplementation can alter behavior and neurochemistry following a variety of developmental disorders, including the alleviation of behavioral abnormalities associated with fetal alcohol syndrome in Sprague-Dawley rats (Thomas et al., 2000, 2004, 2007; Wagner and Hunt, 2006), and the attenuation of some of the motor deficits observed in a Mecp21lox mouse model of Rhett syndrome (Nag and Berger-Sweeney, 2007). Recent reports have also demonstrated that prenatal choline supplementation improves attention and sensory gating in a DBA/2 mouse model of schizophrenia that exhibits reduced numbers of hippocampal α7 nicotinic receptors (Stevens et al., 2008) as well as the contextual sensitivity of Pavlovian conditioning (Lamoureux et al., 2008).

The cholinergic innervation of the hippocampus is a major target of prenatal choline manipulations. Changes in the size and shape of basal forebrain cholinergic neurons (e.g., McKeon-O’Malley et al., 2003; Williams et al., 1998) following prenatal choline manipulations are accompanied by modifications in acetylcholine turnover and choline transporter expression in the septum and hippocampus (Cermak et al., 1999; Mellott et al., 2007b), modulation of hippocampal neurogenesis, gene expression, NGF levels, and MAPK and CREB activation (e.g., Glenn et al., 2007; Mellott et al., 2004, 2007a; Sandstrom et al., 2002), changes in dendritic fields and spine density in CA1 and dentate gyrus (DG) regions of the hippocampus (Meck et al., 2008), as well as modification of the neuropathological response to status epilepticus (e.g., Holmes et al., 2002; Wong-Goodrich et al., 2008) and thresholds for eliciting long-term potentiation (LTP) in the hippocampus (Jones et al., 1999; Pyapali et al., 1998.) These findings suggest that alterations in choline availability during early development may have specific impact on the ontogeny and later functioning of basal forebrain cholinergic neurons as well as efferent neurons involved in hippocampal LTP. These findings also predict that this dietary manipulation will affect mostly behaviors that rely on the hippocampus.

Working memory for event durations is affected by lesions of the hippocampal system. For example, fimbria-fornix lesions produce a complete amnesia for the memory of the duration of the event prior to an unexpected, brief retention-interval (gap), while lesions in the frontal system had no effect on working memory for duration (Meck et al., 1984, 1987; Olton et al., 1987). Consequently, it was of interest in the present study to investigate the effects of prenatal choline supplementation on the short-term memory for event durations and the contextual processing of temporal information. These questions were addressed using the peak-interval (PI) timing procedure, in which subject’s responses are reinforced for responding at a specific criterion duration. In well-trained subjects, the mean response rate increases after the onset of the to-be-timed signal, reaches a peak about the target duration and then gradually declines afterwards during unreinforced probe trials (Catania, 1970; Church, 1978; Paule et al., 1999; Penney et al. 1996). When trained in a PI procedure using both auditory (e.g., Cheng et al., 2006; Meck and Williams, 1997c) and visual signals (e.g., Cheng and Meck, 2007; Meck and Williams 1997a, c) adult rats treated prenatally with supplemental choline exhibit enhanced precision in the temporal control of responding. These beneficial effects can be related to the reduction in non-scalar sources of variance attributable to the non-temporal aspects of the procedure, as well as an increase in rats’ sensitivity to the inhibitory effects of a signaled delay to reinforcement, and enhanced control over the resetting of an internal clock (e.g., Gibbon and Church, 1984; Gibbon et al., 1984; Matell and Meck 1999; Cheng et al. 2006; Cheng and Meck, 2007). Here we address two outstanding questions relative to the role of choline supplementation in processing temporal information.

First, whether the increased memory capacity and attention gating exhibited by choline supplemented rats extends to memory for timed events, which can be tested in the PI procedure by inserting unexpected, brief breaks or gaps in the signal (Church, 1978; Roberts and Church, 1978; Fortin, 2003; Fortin and Tremblay, 2005; Fortin et al., 2008). Observed changes in the distribution of responses in trials with gaps following behavioral (Buhusi and Meck, 2000, 2006a, b) and neurobiological (e.g., Buhusi and Meck, 2002; Buhusi and Meck, 2007; Meck, 1988; Meck et al., 1984) manipulations in the PI procedure with gaps are used to address the mechanisms involved in memory for timed events. For example, when rats time a visual signal in a (standard) PI procedure, the introduction of a (dark) gap prompts rats to delay their response function by an amount approximately equal to the duration of the gap, which is taken to suggest that rodents retain in working memory the pre-gap interval and resume timing after the gap where they left off before the gap, using a stop mode (Church, 1978; Roberts and Church, 1978). However, when rats time the absence of a visual signal in a so-called reversed PI procedure (Buhusi and Meck, 2000), the introduction of a reversed, illuminated gap prompts rats to delay their response function after the gap for a duration that is approximately the sum of the gap and pre-gap intervals. This has been taken to suggest that they restart the entire timing process after the gap, using a reset mode (reviewed by Buhusi 2003; Buhusi and Meck, 2008). Such a reset mode was observed after lesions of the hippocampal system (Meck et al., 1984, 1987; Olton et al., 1987). We therefore incorporated gaps into the standard and reversed PI procedure in a manner similar to Buhusi and Meck (2000) in order to evaluate the effects prenatal choline availability on memory for timed events.

The second outstanding question is whether the increased temporal sensitivity exhibited by adult rats given prenatal choline supplementation extends to issues dealing with attention and contextual sensitivity. This issue can be addressed in the PI procedure with gaps by manipulating the relative salience of the gap to the signal (Buhusi and Meck, 2000; Buhusi et al., 2002; Buhusi et al., 2005; Buhusi et al., 2006) and the content of the signals used in the procedure (Buhusi and Meck, 2002). For example, both rodents and birds run, stop, or reset their clocks depending on gap content (Buhusi and Meck, 2002; Buhusi et al., 2002), gap discriminability (Buhusi et al., 2005, 2006), and level of visual acuity (Buhusi et al., 2005). Such results provide evidence for the hypothesis that during gaps in the to-be-timed signal resources are re-allocated (diverted away from timing) in proportion to the salience of the gap to the context in which it is presented, which includes both the to-be-timed signal and the intertrial-interval (ITI) (Buhusi 2003, Buhusi and Meck, 2008). Indeed, manipulations of the ITI, such as filling the ITI with a distinctive cue, were shown to affect the stop/reset mode in the PI procedure with gaps (Buhusi and Meck, 2002). Therefore, we also manipulated the content of the ITI in the PI procedure with gaps in a manner similar to Buhusi and Meck (2002) in order to evaluate the effects prenatal choline availability on interval timing in rats as a function of the context in which these gaps were inserted.

2. Results

2.1. Standard PI-GAP procedure

Choline-supplemented (SUP, n=7), choline-defficient (DEF, n=8), and control rats (CON, n=7) were trained to time the presence of a 30-s visual stimulus. All rats acquired the timing task at similar levels of performance as measured by the accuracy, precision, and peak rate of the response functions in PI trials. Three one-way ANOVAs failed to reveal differences among the treatment groups in PI trials with respect to timing accuracy (peak time of response function), F(2,19) = 3.18, timing precision (width of response function), F(2,19) = 0.01, and peak response rate (maximum height of response function), F(2,19) = 0.35, p’s > 0.05. The estimated mean peak time (± SEM) in the standard PI trials, 30.97 ± 0.72 s, was not significantly different from the 30-s criterion, t(21) = 1.35, p = 0.19.

During testing, rats were presented with unexpected, brief (5, 10, or 15 s) dark gaps in the 30-s to-be-timed visual signal (standard PI-GAP procedure, Buhusi and Meck, 2000). The left panel of Fig. 1 shows the effect of 5-s gaps in the standard condition. The graph shows the estimated peak time in trials with gaps (y axis) and without gaps (x axis) for individual rats in each treatment group. A 5-s gap prompts the DEF rats to delay their response functions approximately 5 s (the duration of the gap) relative to PI trials, suggesting that they maintained the pre-gap time in working memory during the gap, and resumed timing after the gap (stop mode). In contrast, the SUP rats delayed their response functions approximately 20 s (the duration of the gap, 5 s, plus the duration of the pre-gap interval, 15 s), suggesting that they failed to maintain the pre-gap duration in working memory, and instead re-started timing anew after the gap (reset mode). Finally, CON rats delayed their response function in-between the stop and reset modes.

Fig. 1
Standard peak-interval testing with gaps

To quantify these results, a shift in peak time in gap trials relative to PI trials was computed for each rat by subtracting from the estimated peak time in gap trials, the estimated peak time in PI trials and the duration of the gap. A null shift is indicative of the stop mode, and a shift equal to the pre-gap interval (15 s) is indicative of the reset mode. The right panel of Fig. 1 shows the shift in peak time after 5, 10, or 15-s gaps in CON, DEF, and SUP treatment groups. A mixed ANOVA with factors Group and Gap duration, revealed a significant main effect of Group, F(2,19) = 5.31, p < 0.05, but no significant effect of Gap duration, F(2,38) = 1.95, or Group × Gap duration interaction, F(4,38) = 1.48, p’s > 0.05. Post-hoc analyses indicated reliable differences between DEF and SUP rats (Scheffe test, p < 0.02), but not between CON and SUP, or between CON and DEF rats, p’s > 0.05. Further analyses indicated that the shift in peak time in SUP rats is not reliably different from 15 s (i.e., they reset timing) for all gap durations, t(6) ≤ 1.25, p’s > 0.05, while the shift in peak time in DEF rats was significantly less than 15 s (i.e., they did not reset timing), t(7) = 4.12, p < 0.01. CON rats reliably reset for the longer 10-s and 15-s gaps, t(6) ≤ 2.48, p’s > 0.05, but not for the shorter 5-s gap, t(6) = 3.60, p < 0.05. Together these data indicate that rats in the SUP treatment group were more sensitive to the interruption than rats in either the CON or the DEF groups, suggesting that they displayed a high degree of context sensitivity as indicated by clock resetting after a gap.

2.2. Reversed PI-GAP procedure

The effect of a gap has been shown to be highly sensitive to the features of the context of the timing procedure (reviewed by Buhusi, 2003; Buhusi and Meck, 2008). For example, when timing the presence of a stimulus, rats tend to stop timing after a dark (standard) gap, but when timing the absence of a stimulus, they tend to reset after an illuminated gap of the same duration (Buhusi and Meck, 2000). Therefore, we evaluated the sensitivity of the rats in the CON, DEF, and SUP treatment groups to non-temporal features of the gap procedure, by reversing the content of the stimuli while maintaining the temporal parameters of the protocol.

Rats were trained to time the absence of a 30-s visual stimulus in a reversed PI-GAP procedure (Buhusi and Meck, 2000), and then tested with brief (1, 5, and 10-s) illuminated gaps. Three one-way ANOVAs failed to reveal differences among the CON, DEF, and SUP treatment groups in reversed PI trials with respect to timing accuracy, F(2,19) = 0.14, timing precision, F(2,19) = 0.93, and peak response rate, F(2,19) = 0.94, p’s > 0.05. The estimated mean peak time (± SEM) in the standard PI trials, 32.41 ± 1.35 s, was not significantly different from the 30-s criterion, t(21) = 1.79, p > 0.05, suggesting that rats in all treatment groups acquired the timing task at similar levels of performance.

When the rats were tested with reversed 1, 5, and 10-s gaps all treatment groups reset their timing as illustrated in Fig. 2. Indeed, a mixed ANOVA with factors Group and Gap duration failed to reveal any main effects of Group, F(2,19) = 0.36, and Gap duration, F(2,38) = 0.03, or Group × Gap duration interaction, F(4,38) = 0.35, p’s > 0.05. The shift in peak time in gap trials relative to PI trials was not reliably different from 15 s (reset mode), for either the CON, t(6) = 2.37, DEF, t(7) = 0.67, or SUP, t(6) = 0.4 groups, p’s > 0.05. Together these data indicate that all treatment groups were sensitive to reversing the content of the timed signals and gaps.

Fig. 2
Reversed peak-interval testing with gaps

2.3. Standard PI-GAP procedure with filled intertrial intervals

While reversing the signals prompts rats to switch their response mode from stop to reset after a gap in the visual signal (Buhusi and Meck, 2000), a switch in mode from reset to stop was observed in rats when the inter-trial interval (ITI) was filled with an auditory stimulus (Buhusi and Meck, 2002), suggesting that rats are highly sensitive to contextual manipulations of the PI-GAP procedure. Therefore, we tested the sensitivity of the rats in the CON, DEF, and SUP treatment groups to contextual manipulations features of the standard PI-GAP procedure by filling the ITI with white noise.

Rats were trained to time the presence of a 30-s visual stimulus in a standard PI-GAP procedure in which the ITI was dark and noisy (Buhusi and Meck, 2000), and were subsequently tested with brief (5, 10, and 15-s) dark, silent gaps. Three one-way ANOVAs failed to reveal differences among the CON, DEF, or SUP treatment groups in reversed PI trials in respect to timing accuracy, F(2,19) = 0.87, timing precision, F(2,19) = 1.01, and peak response rate, F(2,19) = 0.95, p’s > 0.05. This finding suggests that rats in all treatment groups acquired the timing task at similar levels of performance. The estimated mean peak time (± SEM) in the standard PI trials, 32.99 ± 1.03 s, was significantly larger than the 30-s criterion, t(21) = 2.90, p < 0.05.

The effect of filling the ITI when testing with standard 5, 10, and 15-s gaps is shown in Fig. 3. A mixed ANOVA with factors Group and Gap duration failed to reveal any main effects of Group, F(2,19) = 0.63, and Gap duration, F(2,38) = 0.72, or the Group × Gap duration interaction, F(4,38) = 0.18. p’s > 0.05. Further analyses indicated that in the CON and SUP treatment groups the shift in peak time in gap trials relative to PI trials was reliably smaller than 15 s (reset mode) for rats in the CON and SUP treatment groups, but not for rats in the DEF group, which reliably reset after 10-s and 15-s gaps, but not after a 5-s gap. Together these data indicate that rats in the SUP group are as sensitive as CON rats to the stopping effect of filling the ITI, but that rats in the DEF group are significantly less sensitive to this manipulation.

Fig. 3
Peak-interval testing with gaps with filled intertrial intervals (ITI)

2.4. Summary of PI-GAP results

The overall PI-GAP results as a function of treatment group, condition (standard, reversed, and filled ITI) and gap duration (1, 5, 10, and 15 s) are illustrated in Fig. 4. The graph indicates that relative to the standard condition, rats in both the CON and SUP treatment groups reset their timing in the reversed condition, but stop their clocks in the filled-ITI condition. In contrast, rats in the DEF treatment group reset their timing in the reversed condition, but are less sensitive to contextual effects in the filled-ITI condition. This latter suggestion was further supported by a joint analysis of data in the standard and filled-ITI conditions. A mixed ANOVA with factors Group, Gap duration, and Condition reveal a reliable main effect of condition (standard vs. filled ITI), F(1,19) = 5.22, and Group × Condition interaction, F(2,19) = 4.11 (p’s < 0.05), but no other significant main effects or interactions. Planned comparisons indicated a significant stopping effect of filling the ITI in the CON, F(1,19) = 4.42 and SUP rats, F(1,19) = 7.28 (p’s < 0.05), but not in the DEF rats, F(1,19) = 0.98, p > 0.05. Together these data indicate that rats in the CON and SUP treatment groups, but not rats in the DEF group, use contextual information about the ITI to flexibly modulate their behavior in the PI-GAP procedure. In conjunction with the finding that SUP rats are more sensitive to the gap in the standard PI condition, as demonstrated by their propensity to reset timing, these results suggest that prenatal choline availability affects the sensitivity to the context in which gaps are inserted in the to-be-timed signal, thereby influencing whether rats run, stop, or reset their clocks.

Fig. 4
Summary of the standard gap, reversed gap, and filled intertrial interval (ITI) conditions

3. Discussion

Previous research indicates that the effect of a gap in a to-be-timed signal is highly sensitive to the features of the context of the procedure (reviewed by Buhusi, 2003; Buhusi and Meck, 2008). For example, increasing the salience (Buhusi and Meck, 2000; Buhusi et al., 2005; Buhusi et al., 2006) of the to-be-timed signal prompts rats to switch from stopping their clocks to resetting their clocks after a gap in the signal. On the other hand, a switch from the reset mode to the stop mode was observed when increasing the duration of the ITI (Buhusi and Meck, 2008) or filling the ITI with a highly distinctive signal (Buhusi and Meck, 2002.) Therefore, we evaluated memory for time and contextual sensitivity as a function of prenatal choline availability using the PI procedure with gaps by (a) manipulating the duration of the gap (standard condition), (b) reversing the content of the stimuli (reversed condition), and (c) filling the ITI with an auditory stimulus (filled ITI condition), while maintaining all other temporal parameters of the procedure. We found that rats in the SUP treatment group were more sensitive to the gap than rats in the CON and DEF groups, in both resetting in the standard condition and stopping when filling the ITI, thus demonstrating a superior control over the resetting of an internal clock. In contrast, DEF rats showed reliably less sensitivity to contextual manipulations; they did not reset in the standard condition, and were not able to further stop their clocks in the filled ITI condition, thus demonstrating limited attentional control over the starting and resetting of an internal clock (Buhusi and Meck, 2008; Cheng et al., 2006; Meck, 1984).

Previous work has also shown that both the frontal and temporal systems are involved in memory for timed events, but in complementary ways. A double dissociation resulted from lesions of the frontal cortex and the nucleus basalis magnocellularis, on the one hand, and the hippocampus, fimbria-fornix, and the medial septal area, on the other. Lesions in the frontal system produce a rightward shift (overestimation) of the expected time of reinforcement, while lesions in the hippocampal system produce a leftward shift (for review see Buhusi and Meck, 2005; Gibbon et al., 1997; Meck, 1996, 2002; Meck et al., 1986, 1987). Dissociation was also found in the effects of these lesions on working memory for the duration of a stimulus prior to a gap or retention interval interpolated during that stimulus. Fimbria-fornix lesions produce a complete amnesia for the memory of the duration of the event prior to the gap, while lesions in the frontal system had no effect (Meck et al., 1984, 1987; Olton et al., 1987). In turn, modifications in acetylcholine turnover and choline transporter expression in the septum and hippocampus (Cermak et al., 1999; Mellott et al., 2007b), modulation of hippocampal neurogenesis, gene expression, NGF levels, and MAPK and CREB activation (e.g., Glenn et al., 2007; Mellott et al., 2004, 2007a; Sandstrom et al., 2002), changes in dendritic fields and spine density in CA1 and dentate gyrus (DG) regions of the hippocampus (Meck et al., 2008), as well as modification of the neuropathological response to status epilepticus (e.g., Holmes et al., 2002; Wong-Goodrich et al., 2008) and thresholds for eliciting long-term potentiation (LTP) in the hippocampus (Jones et al., 1999; Pyapali et al., 1998) accompany changes in the size and shape of basal forebrain cholinergic neurons (e.g., McKeon-O’Malley et al., 2003; Williams et al., 1998) following prenatal choline manipulations. These findings suggest that alterations in choline availability during early development may have specific impact on the ontogeny and later functioning of basal forebrain cholinergic neurons as well as efferent neurons involved in hippocampal LTP. Together, these results suggest that prenatal choline availability affects contextual processing of temporal information by means of changes in hippocampal function (Lamoureux et al., 2008), or hippocampal interaction with the other brain areas involved in time perception, notably cortico-striatal circuits (Buhusi and Meck, 2005; Cheng et al., 2007a, b; Meck, 1988, 2006a, b, c, 2007).

A description of the neurobiological mechanisms involved in interval timing is provided by the striatal beat-frequency (SBF) model, which ascribes a role for detecting event durations to medium spiny neurons within the dorsal striatum (e.g., Buhusi and Meck, 2005; Lustig et al., 2005; MacDonald and Meck, 2004; Matell and Meck, 2000, 2004). These striatal neurons have a set of functional properties that place them in an ideal position to detect behaviorally relevant patterns of afferent cortical input and reflect alteration in clock speed (e.g., Beiser and Houk, 1998; Lustig and Meck, 2005; Matell et al., 2003, 2004, 2006). Briefly, the SBF model posits that medium spiny neurons in the dorsal striatum become entrained to fire in response to oscillating, coincident cortical inputs that become active at previously trained event durations. This timing model is particularly useful insofar as the striatal neurons modeled using the SBF framework behave as they do when assessed using multiunit electrical recordings during interval-timing procedures (Matell et al., 2003 – see also Hinton and Meck, 2004). However, the exact nature of the horizontal shifts in timing functions as a result of attentional and/or clock speed manipulations and prenatal choline availability is as yet unresolved within the context of the SBF model (see Cheng et al., 2006). One proposal is that tonic dopamine levels within the striatum modulate the oscillatory frequency within the cortex through cortico-striato-thalamo-cortical feedback mechanisms (e.g., Bamford et al., 2004a, b; Buhusi and Meck, 2005; Lustig et al., 2005; Matell and Meck, 2004; Meck, 2006a, b). The observation that timing and attention to time are sensitive to prenatal choline availability further supports the view that differential activation of cortical, hippocampal, and striatal systems is critical for contextual processing and the control of the resetting of an internal clock (e.g., Buhusi and Meck, 2005; Cheng et al., 2006; Lamoureux et al., 2008; Lustig and Meck, 2001; Matell and Meck, 1999; Meck, 2005; Meck and Benson, 2002; Meck and Williams, 2003).

4. Experimental procedures

4.1. Animals and housing

Subjects

Twenty-two naive male Sprague-Dawley CD strain rats, the offspring of timed-pregnant dams obtained from Charles River Laboratories (Kingston, NY), served as subjects. All dams were obtained on embryonic day (ED) 9 and fed AIN-76A purified synthetic diet containing 1.1 g/kg choline chloride (Dyets, Bethlehem, PA) and water ad libitum. The manipulation of dietary choline took place from the evening of ED 11 through the morning of ED 18, after which all dams were fed standard purified diet. During the treatment period, all dams received drinking water containing 50 mM saccharin. Choline was supplemented (SUP) for one group of dams (n=4) with the addition of 25 mM choline chloride in the saccharin drinking water. A second group of dams (n=4) received drinking water without choline and was switched to a purified diet completely deficient (DEF) of choline. The third group of dams (n=4) served as a control (CON) and was maintained on the standard purified diet (1.1 g/kg choline chloride) and drinking water without added choline. Dams were housed individually in clear polycarbonate cages (27.9 × 27.9 × 17.8 cm) in a colony room maintained on a 12–12 h, light-dark cycle.

Litters of 10 male pups, each containing rats from all dietary choline treatments (SUP, DEF, and CON), were cross-fostered at birth to untreated control dams. Pups were weaned at 24 days postnatal (PD 24), housed five/cage at PD 30, and then two/cage on PD 45. These offspring received the standard AIN-76A diet described above and tap water ad libitum from weaning until PD 90. Throughout the remainder of the study, the rats were maintained at 85% of their ad libitum weights by limiting their access to food; water was still available continuously in the home cages. Twenty-two male rats: DEF = 8, CON = 7, and SUP = 7 were selected for study. Experiments were conducted during the light portion of the L/D cycle in accordance with standard procedures approved by the Institutional Animal Care and Use Committee of Duke University.

4.2. Apparatus

All experimental data were obtained in identical lever boxes (MED Associates, Model ENV-007) housed in light and sound attenuating cubicles (MED Associates, ModelENV-019). Each lever box had inside dimensions of approximately 24 cm × 31 cm × 31 cm. The top, sidewalls, and door were constructed of clear acrylic plastic. The front and back walls were constructed of aluminum, and the floor was comprised of 19 parallel stainless steel bars. Each lever box was equipped with two retractable response levers (MED Associates, Model ENV-112) situated on the front wall of the lever box. Precision food pellets (45 mg; Research Diets, New Brunswick, NJ) could be delivered by a pellet dispenser (MED Associates, Model ENV-203) to a food cup on the front wall 1 cm above the floor. A 28-V, 170-mA, 2,500-lx house-light was mounted at the center-top of the front wall. A white noise amplifier/speaker system (MED Associates, Model ENV-225) was mounted on the opposite wall from the levers. Each lever box was housed inside a sound and light attenuated chamber that was equipped with an eyepiece viewer for observation and a ventilation fan that produced a 60-dB background noise. An IBM-PC compatible computer attached to an electronic interface (MED Associates, Model DIG-700 and SG-215) was used to control the experimental equipment and record the data.

4.3. Magazine and lever training

Each rat received 5 sessions of combined magazine and lever training during which a food pellet was delivered once each minute for 60 min (magazine training), and in addition, each lever press produced food. The left retractable lever was extended into the chamber and 10 lever presses were reinforced; then the left lever was retracted and the right retractable lever was extended into the chamber and 10 lever presses were reinforced; then the right lever was retracted and the left lever was again extended. This alternation between levers continued until the rat had pressed each lever 30 times or 60 min had passed, whichever came first. The house light illuminated the chamber during these sessions.

4.4. Standard fixed-interval training (Sessions 1–10)

For each daily session all rats received 64 fixed-interval (FI) trials during which the house light was turned on for the to-be-timed interval; the first lever press 30 s after the onset of the visual signal was reinforced by the delivery of a food pellet and turned off the house light for the duration of the random intertrial interval (ITI). Trials were separated by a 60 ± 30 s random ITI, which was silent and dark.

4.5. Standard peak-interval testing with gaps (Sessions 11–31)

During each session the rats received 32 FI trials randomly intermixed with 32 non-reinforced peak0interval (PI) trials in which the visual signal was presented for a duration three times longer than the FI, before being terminated irrespective of responding. Trials were separated by a 60 ± 30 s random ITI (silent, dark). During the last two (test) sessions, rats received 32 FI trials randomly intermixed with 32 non-reinforced test trials (8 trials for each of the four types of test conditions). Eight test trials were standard PI trials during which the visual to-be-timed stimulus was not interrupted. During the remaining 24 test trials, half-way into the to-be-timed interval, i.e., 15 s after the beginning of the visual signal, the timed visual signal was interrupted by either a 5-s, 10-s, or 15-s dark gap (8 test trials each). At the offset of the gap, the to-be-timed visual signal was reinstated for a duration matching that of the PI trials, and then terminated independently of responding for the 60 ± 30 s random duration of the ITI (silent, dark). The sum of the pre-gap, gap, and post-gap durations was equal to the duration of the to-be-timed visual signal in PI trials.

4.6. Reversed peak-interval testing with gaps (Sessions 32–56)

These sessions were identical in terms of temporal parameters with those described above except the stimuli were reversed: the to-be-timed signal was 30-s of the absence of the visual signal (dark) and the ITI was illuminated. During the last three (test) sessions, rats received 32 reversed FI trials randomly intermixed with 32 non-reinforced test trials (8 trials for each of the four types of test conditions). Eight test trials were reversed PI trials during which the visual to-be-timed stimulus (dark) was not interrupted. During the remaining 24 test trials, half-way into the to-be-timed interval, i.e., 15 s after the beginning of the visual signal, the timed visual signal was interrupted by either a 1-s, 5-s, or 10-s illuminted gap (8 test trials each). At the offset of the gap, the to-be-timed visual signal was reinstated for a duration matching that of the PI trials, and then terminated independently of responding for the 60 ± 30 s random duration of the ITI (silent, illuminated). The sum of the pre-gap, gap, and post-gap durations was equal to the duration of the to-be-timed visual signal in PI trials.

4.7. Standard peak-interval testing with filled intertrial intervals (Sessions 57–80)

These sessions were otherwise identical with the standard PI testing except an auditory stimulus (white noise) was presented throughout the inter-trial interval. During the last three (gap) sessions, rats received 32 FI trials randomly intermixed with 32 non-reinforced test trials (8 PI trials, and 8 dark gap trials as described above). Trials were separated by a 60 ± 30 s random ITI, which was dark and noisy. Please see Table 1 for an outline of the experimental conditions.

TABLE 1
EXPERIMENTAL CONDITIONS

4.8. Data analysis

The experimental procedures were controlled through a MED Associates interface connected to an IBM-PC compatible computer running a MED-PC software system (MED Associates, 1999). Lever presses were recorded in real time. Lever presses recorded during test (gap) trials were used to estimate the peak time, peak rate, and precision of timing (width of the response functions) for each rat. The number of responses (in 5-s bins) was averaged daily over trials, to obtain a mean response rate function for each rat. Analyses were conducted on the data from an interval twice as large as the FI (i.e., 60 s), starting at the onset of the to-be-timed signal (for data in standard PI trials) or at the offset of the gap/distracter (for gap, distracter, and gap+distracter trials). The mean absolute response rate in the interval of interest was fit using the Marquardt-Levenberg iterative algorithm (Marquardt, 1963) to find the coefficients (parameters) of a Gaussian+linear equation that gave the “best fit” (least squares minimization) between the equation and the data (Buhusi and Meck, 2000). This algorithm provides the following parameters of the response curve: the accuracy of timing (response peak time, parameter t0), precision of timing (width of response function, parameter b), and peak rate of response (parameter a+d, for details see Buhusi and Meck, 2000). A shift in gap trials relative to PI trials was computed by subtracting from the estimated peak time t0 in gap trials the estimated peak time t0 in PI trials and the duration of the gap. These parameters were submitted to statistical analyses. All statistical tests were evaluated at a significance level of 0.05.

Acknowledgments

This work was supported by grants to CVB from the National Institute of Mental Health (MH065561 and MH073057), and by a grant to WHM from the National Institute of Aging (AG09525).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

REFERENCES

  • Aimone JB, Wiles J, Gage FH. Potential role for adult neurogenesis in the encoding of time in new memories. Nature Neurosci. 2006;9:723–727. [PubMed]
  • Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK. Dopamine modulates release from corticostriatal terminals. J. Neurosci. 2004a;24:9541–9552. [PubMed]
  • Bamford NS, Zhang H, Schmitz Y, Wu N-P, Cepeda C, Levine MS, Schmauss C, Zakharenko SS, Zablow L, Sulzer D. Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron. 2004b;42:653–663. [PubMed]
  • Bartus RT, Dean RL, 3rd, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408–414. [PubMed]
  • Beiser DG, Houk JC. Model of cortical-basal ganglionic processing: encoding the serial order of sensory events. J. Neurophysiol. 1998;79:3168–3188. [PubMed]
  • Buhusi CV. Dopaminergic mechanisms of interval timing and attention. In: Meck WH, editor. Functional and neural mechanisms of interval timing. Boca Raton, FL: CRC Press; 2003. pp. 317–338.
  • Buhusi CV, Meck WH. Timing for the absence of a stimulus: The gap paradigm reversed. J. Exp. Psych. Anim. Behav. Process. 2000;26:305–322. [PubMed]
  • Buhusi CV, Meck WH. Differential effects of methamphetamine and haloperidol on the control of an internal clock. Behav. Neurosci. 2002;116:291–297. [PubMed]
  • Buhusi CV, Meck WH. What makes us tick? Functional and neural mechanisms of interval timing. Nat. Rev. Neurosci. 2005;6:755–765. [PubMed]
  • Buhusi CV, Meck WH. Interval timing with gaps and distracters: evaluation of the ambiguity, switch, and time-sharing hypotheses. J. Exp. Psychol. Anim. Behav. Process. 2006a;32:329–338. [PubMed]
  • Buhusi CV, Meck WH. Time sharing in rats: a peak-interval procedure with gaps and distracters. Behav. Process. 2006b;71:107–115. [PubMed]
  • Buhusi CV, Meck WH. Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps. Behav. Process. 2007;74:159–167. [PMC free article] [PubMed]
  • Buhusi CV, Meck WH. Relative time sharing: new findings and an extension of the resource allocation model of temporal processing. Phil. Trans. R. Soc. Lond. B. 2008 in press. [PMC free article] [PubMed]
  • Buhusi CV, Paskalis J-PG, Cerutti DT. Time-sharing in pigeons: Independent effects of gap duration, position and discriminability from the timed signal. Behav. Process. 2006;71:116–125. [PubMed]
  • Buhusi CV, Perera D, Meck WH. Memory for timing visual and auditory signal in albino and pigmented rats. J. Exp. Psych. Anim. Behav. Process. 2005;31:18–30. [PubMed]
  • Buhusi CV, Sasaki A, Meck WH. Temporal integration as a function of signal/gap intensity in rats (Rattus norvegicus) and pigeons (Columba livia) J. Comp. Psych. 2002;116:381–390. [PubMed]
  • Catania AC. Reinforcement schedules and psychophysical judgments: a study of some temporal properties of behavior. In: Schoenfeld WN, editor. The theory of reinforcement schedules. New York: Appleton-Century-Crofts; 1970. pp. 1–42.
  • Cermak JM, Blusztajn JK, Meck WH, Williams CL, Fitzgerald C, Rosene DL, Loy R. Prenatal availability of choline alters the development of acetylcholinesterase in rat hippocampus. Dev. Neurosci. 1999;21:94–104. [PubMed]
  • Cermak JM, Holler T, Jackson DA, Blusztajn JK. Prenatal availability of choline modifies development of the hippocampal cholinergic system. FASEB J. 1998;12:349–357. [PubMed]
  • Cheng RK, Meck WH, Williams CL. α7 nicotinic acetylcholine receptors and temporal memory: synergistic effects of combining prenatal choline and nicotine on reinforcement-induced resetting of an interval clock. Learn. Mem. 2006;13:127–134. [PMC free article] [PubMed]
  • Cheng RK, Etchegaray M, Meck WH. Impairments in timing, temporal memory, and reversal learning linked to neurotoxic regimens of methamphetamine intoxication. Brain Res. 2007a;1186:255–266. [PubMed]
  • Cheng RK, Hakak OL, Meck WH. Habit formation and the loss of control of an internal clock: inverse relationship between the level of baseline training and the clock-speed enhancing effects of methamphetamine. Psychopharmacology. 2007b;193:351–362. [PubMed]
  • Cheng RK, MacDonald CJ, Williams CL, Meck WH. Prenatal choline supplementation alters the timing, emotion, and memory performance (TEMP) of adult male and female rats as indexed by differential reinforcement of low-rate schedule behavior. Learn. Mem. 2008;15:153–162. [PMC free article] [PubMed]
  • Cheng RK, Meck WH. Prenatal choline supplementation increases sensitivity to time by reducing non-scalar sources of variance in adult temporal processing. Brain Res. 2007;1186:242–254. [PMC free article] [PubMed]
  • Church RM. The internal clock. In: Hulse SH, Fowler H, Honig WK, editors. Cognitive processes in animal behavior. Vol. Hillsdale, NY: Erlbaum; 1978. pp. 277–310.
  • Droit-Volet S, Meck WH. How emotions colour our perception of time. Trends Cogn. Sci. 2007;11:504–513. [PubMed]
  • Fortin C. Attentional time-sharing in interval timing. In: Meck WH, editor. Functional and neural mechanisms of interval timing. Boca Raton, FL: CRC Press; 2003. pp. 235–260.
  • Fortin C, Fairhurst S, Malapani C, Morin C, Towey J, Meck WH. Expectancy in multisecond peak-interval timing with gaps in humans. Percep. Psychophys. 2008 in press. [PubMed]
  • Fortin C, Tremblay S. Interrupting timing in interval production and discrimination: similarities and differences. Behav. Process. 2005;71:336–343. [PubMed]
  • Gibbon J, Church RM. Sources of variance in an information processing theory of timing. In: Roitblat HL, Bever TG, Terracce HS, editors. Animal cognition. Hillsdale, NJ: Lawrence Erlbaum Associates; 1984. pp. 465–488.
  • Gibbon J, Church RM, Meck WH. Scalar timing in memory. Ann. NY Acad. Sci. 1984;423:52–77. [PubMed]
  • Gibbon J, Malapani C, Dale CL, Gallistel CR. Toward a neurobiology of temporal cognition: advances and challenges. Cur. Opin. Neurobiol. 1997;7:170–184. [PubMed]
  • Glenn MJ, Gibson EM, Kirby ED, Mellott TJ, Blusztajn JK, Williams CL. Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats. Eur. J. Neurosci. 2007;25:2473–2482. [PMC free article] [PubMed]
  • Hasselmo ME, Giocomo LM. Cholinergic modulation of cortical function. J. Mol.Neurosci. 2006;30:133–135. [PubMed]
  • Hinton SC, Meck WH. Frontal-striatal circuitry activated by human peak-interval timing in the supra-seconds range. Cogn. Brain Res. 2004;21:171–182. [PubMed]
  • Holmes GL, Yang Y, Liu Z, Cermak JM, Sarkisian MR, Stafstrom CE, Neill JC, Blusztajn JK. Seizure-induced memory impairment is reduced by choline supplementation before or after status epilepticus. Epilepsy. Res. 2002;48:3–13. [PubMed]
  • Jones JP, Meck WH, Williams CL, Wilson WA, Swartzwelder HS. Choline availability to the developing rat fetus alters adult hippocampal long-term potentiation. Dev. Brain. Res. 1999;118:159–167. [PubMed]
  • Lamoureux JA, Williams CL, Meck WH. Availability of prenatal dietary choline alters the context sensitivity of Pavlovian conditioning in adult rats, Learn. Mem. 2008 in press. [PMC free article] [PubMed]
  • Lustig C, Meck WH. Paying attention to time as one gets older. Psych. Sci. 2001;12:478–484. [PubMed]
  • Lustig C, Meck WH. Chronic treatment with haloperidol induces working memory deficits in feedback effects of interval timing. Brain Cogn. 2005;58:9–16. [PubMed]
  • Lustig C, Matell MS, Meck WH. Not “just” a coincidence: frontal-striatal synchronization in working memory and interval timing. Memory. 2005;13:441–448. [PubMed]
  • MacDonald CJ, Meck WH. Systems-level integration of interval timing and reaction time. Neurosci. Biobehav. Rev. 2004;28:747–769. [PubMed]
  • Marquardt DW. An algorithm for least squares estimation of parameters. J. Soc.Indust. App. Math. 1963;11:431–441.
  • Matell MS, Bateson M, Meck WH. Single-trials analyses demonstrate that increases in clock speed contribute to the methamphetamine-induced horizontal shifts in peak-interval timing functions. Psychopharmacology. 2006;188:201–212. [PubMed]
  • Matell MS, King GR, Meck WH. Differential adjustment of interval timing by the chronic administation of intermittent or continuous cocaine. Behav. Neurosci. 2004;118:150–156. [PubMed]
  • Matell MS, Meck WH. Reinforcement-induced within-trial resetting of an internal clock. Behav. Processes. 1999;45:159–171.
  • Matell MS, Meck WH. Neuropsychological mechanisms of interval timing behaviour. Bioessays. 2000;22:94–103. [PubMed]
  • Matell MS, Meck WH. Cortico-striatal circuits and interval timing: Coincidence-detection of oscillatory processes. Cog. Brain Res. 2004;21:139–170. [PubMed]
  • Matell MS, Meck WH, Nicolelis MAL. Interval timing and the encoding of signal duration by ensembles of cortical and striatal neurons. Behav. Neurosc. 2003;117:760–773. [PubMed]
  • McCann JC, Hudes M, Ames BN. An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosci. Biobehav. Rev. 2006;30:696–712. [PubMed]
  • McKeon-O’Malley C, Siwek D, Lamoureux JA, Williams CL, Kowall NW. Prenatal choline deficiency decrease the cross-sectional area of cholinergic neurons in the medial septal nucleus. Brain Res. 2003;977:278–283. [PubMed]
  • Meck WH. Attentional bias between modalities: effect on the internal clock, memory, and decision stages used in animal time discrimination. Ann. NY Acad. Sci. 1984;423:528–541. [PubMed]
  • Meck WH. Hippocampal function is required for feedback control of an internal clock's criterion. Behav. Neurosci. 1988;102:54–60. [PubMed]
  • Meck WH. Neuropharmacology of timing and time perception. Cogn. Brain Res. 1996;3:227–242. [PubMed]
  • Meck WH. Choline uptake in the frontal cortex is proportional to the absolute error of a temporal memory translation constant in mature and aged rats. Learn. Motiv. 2002;33:88–104.
  • Meck WH. Neuropsychology of timing and time perception. Brain Cogn. 2005;58:1–8. [PubMed]
  • Meck WH. Frontal cortex lesions eliminate the clock speed effect of dopaminergic drugs on interval timing. Brain Res. 2006a;1108:157–167. [PubMed]
  • Meck WH. Neuroanatomical localization of an internal clock: a functional link between mesolimbic, nigrostriatal, and mesocortical dopaminergic systems. Brain Res. 2006b;1109:93–107. [PubMed]
  • Meck WH. Temporal memory in mature and aged rats is sensitive to choline acetyltransferase inhibition. Brain Res. 2006c;1108:168–175. [PubMed]
  • Meck WH. Acute ethanol potentiates the clock-speed enhancing effects of nicotine on timing and temporal memory. Alcohol. Clin. Exp. Res. 2007;31:2106–2113. [PubMed]
  • Meck WH, Benson AM. Dissecting the brain's internal clock: how frontal-striatal circuitry keeps time and shifts attention. Brain Cogn. 2002;48:195–211. [PubMed]
  • Meck WH, Church RM, Olton DS. Hippocampus, time, and memory. Behav. Neurosci. 1984;98:3–22. [PubMed]
  • Meck WH, Church RM, Wenk GL. Arginine vasopressin inoculates against age-related increases in sodium-dependent high affinity choline uptake and discrepancies in the content of temporal memory. Eur. J. Pharm. 1986;130:327–331. [PubMed]
  • Meck WH, Church RM, Wenk GL, Olton DS. Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory. J. Neurosci. 1987;7:3505–3511. [PubMed]
  • Meck WH, Smith RA, Williams CL. Pre- and postnatal choline supplementation produces long-term facilitation of spatial memory. Dev. Psychobio. 1988;21:339–353. [PubMed]
  • Meck WH, Smith RA, Williams CL. Organizational changes in cholinergic activity and enhanced visuospatial memory as a function of choline administered prenatally or postnatally or both. Behav. Neurosci. 1989;103:1234–1241. [PubMed]
  • Meck WH, Williams CL. Characterization of the facilitative effects of perinatal choline supplementation on timing and temporal memory. NeuroReport. 1997a;8:2831–2835. [PubMed]
  • Meck WH, Williams CL. Perinatal choline supplementation increases the threshold for chunking in spatial memory. Neuroreport. 1997b;8:3053–3059. [PubMed]
  • Meck WH, Williams CL. Simultaneous temporal processing is sensitive to prenatal choline availability in mature and aged rats. Neuroreport. 1997c;8:3045–3051. [PubMed]
  • Meck WH, Williams CL. Choline supplementation during prenatal development reduces proactive interference in spatial memory. Dev. Brain. Res. 1999;118:51–59. [PubMed]
  • Meck WH, Williams CL. Metabolic imprinting of choline by its availability during gestation: Implications for memory and attentional processing across the lifespan. Neurosci. Biobehav. Rev. 2003;27:385–399. [PubMed]
  • Meck WH, Williams CL, Cermak JM, Blusztajn JK. Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia, Front. Integr. Neurosci. 2008;1:7. [PMC free article] [PubMed]
  • MED-Associates. version 1.15 [Computer software] Vol. St. Albans, VT: 1999. WMPC software.
  • Mellott TJ, Follettie MT, Diesl V, Hill AA, Lopez-Coviella I, Blusztajn JK. Prental choline availability modulates hippocampal and cerebral gene expression. FASEB J. 2007a;21:1311–1323. [PubMed]
  • Mellott TJ, Kowall NW, Lopez-Coviella I, Blusztajn JK. Prenatal choline deficiency increases choline transporter expression in the septum and hippocampus during postnatal development and in adulthood in rats. Brain Res. 2007b;1151:1–11. [PMC free article] [PubMed]
  • Mellott TJ, Williams CL, Meck WH, Blusztajn JK. Prenatal choline supplementation advances hippocampal development and enhances MAPK and CREB activation. FASEB J. 2004;18:545–547. [PubMed]
  • Montoya DAC, White AM, Williams CL, Blusztajn JK, Meck WH, Swartzwelder HS. Prenatal choline exposure alters hippocampal responsiveness to cholinergic stimulation in adulthood. Dev. Brain Res. 2000;123:25–32. [PubMed]
  • Nag N, Berger-Sweeney JE. Postnatal dietary choline supplementation alters behavior in a mouse model of Rhett syndrome. Neurobiol. Dis. 2007;26:473–480. [PubMed]
  • Nag N, Mellott TJ, Berger-Sweeney JE. Effects of postnatal dietary choline supplemenation on motor regional brain volume and growth factor expression in a mouse model of Rett syndrome. Brain Res. 2008 in press. [PubMed]
  • Olton DS, Meck WH, Church RM. Separation of hippocampal and amygdaloid involvement in temporal memory dysfunctions. Brain Res. 1987;404:180–188. [PubMed]
  • Paule MG, Meck WH, McMillan DE, Bateson M, Popke EJ, Chelonis JJ, Hinton SC. The use of timing behaviors in animals and humans to detect drug and/or toxicant effects. Neurotoxicol. Teratol. 1999;21:491–502. [PubMed]
  • Penney TB, Holder MD, Meck WH. Clonidine-induced antagonism of norepinephrine modulates the attentional processes involved in peak-interval timing. Exp. Clin. Psychopharm. 1996;4:82–92.
  • Pyapali GK, Turner DA, Williams CL, Meck WH, Swartzwelder HS. Prenatal dietary choline supplementation decreases the threshold for induction of long-term potentiation in young adult rats. J. Neurophysiol. 1998;79:1790–1796. [PubMed]
  • Roberts S, Church RM. Control of an internal clock. J. Exp. Psych. Anim. Behav. Process. 1978;4:318–337.
  • Sandstrom NJ, Loy R, Williams CL. Prenatal choline supplementation increases NGF levels in the hippocampus and frontal cortex of young and adult rats. Brain Res. 2002;947:9–16. [PubMed]
  • Stevens KE, Adams CE, Yonchek J, Hickel C, Danielson J, Kisley MA. Permanent improvement in deficient sensory inhibition in DBA/2 mice with increased perinatal choline. Psychopharmacology. 2008;198:413–420. [PubMed]
  • Talsma D, Kok A, Slagter HA, Cipriani G. Attentional orienting across the sensory modalities. Brain Cogn. 2008;66:1–10. [PubMed]
  • Thomas JD, Biane JS, O’yan KA, O’Neill TM, Dominguez HD. Choline supplementation following third-trimester-equivalent alcohol exposure attenuates behavioral alterations in rats. Behav. Neurosci. 2007;121:120–130. [PubMed]
  • Thomas JD, Garrison M, O’Neill TM. Perinatal choline supplementation attenuates behavioral alterations associated with neonatal alcohol exposure in rats. Neurotoxicol. Teratol. 2004;26:35–45. [PubMed]
  • Thomas JD, La Fiette MH, Quinn VR, Riley EP. Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats. Neurotoxicol. Teratol. 2000;22:703–711. [PubMed]
  • Wagner AF, Hunt PS. Impaired trace fear conditioning following neonatal ethanol: reversal by choline. Behav. Neurosci. 2006;120:482–487. [PubMed]
  • Williams CL, Meck WH, Heyer D, Loy R. Hypertrophy of basal forebrain neurons and enhanced visouspatial memory in perinatally choline-supplemented rats. Brain Res. 1998;794:225–238. [PubMed]
  • Wong-Goodrich SJE, Mellott TJ, Glenn MJ, Blusztajn JK, Williams CL. Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus. Neurobiol. Dis. 2008;30:255–269. [PMC free article] [PubMed]
  • Yang Y, Liu Z, Cermak JM, Tandon P, Sarkisian MR, Stafstrom CE, Neill JC, Blusztajn JK, Holmes GL. Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J. Neurosci. 2000;20:RC109. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...