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Aged male rats at 10, 20, and 30 mo of age were trained on a 2.0 vs. 8.0-s duration bisection procedure using both auditory and visual signals and were then tested with visual signal durations in which the spacing of the intermediate signal durations was held constant as the short (S) and long (L) anchor durations were moved progressively closer to each other across blocks of sessions. Auditory clicks also preceded some trials in order to determine the potential effects of arousal and/or distraction on the timing of visual signals. The consequences of aging, reducing the S:L ratio, and auditory clicks were to increase the likelihood of observing reversals in response classifications around the geometric mean of the anchor durations. Taken together, these results suggest that the bisection "reversal effect" is dependent upon the calculation of the subjective mid-point between the two anchor durations and the differential setting of response thresholds around this category boundary as a function of temporal context.

Choline supplementation of the maternal diet has long-term facilitative effects on spatial and temporal memory processes in the offspring. To further delineate the impact of early nutritional status on brain and behavior, we examined effects of prenatal-choline availability on hippocampal oscillatory frequency bands in 12 month-old male and female rats. Adult offspring of time-pregnant dams that were given a deficient level of choline (DEF=0.0 g/kg), sufficient choline (CON=1.1 g/kg) or supplemental choline (SUP=3.5 g/kg) in their chow during embryonic days (ED) 12-17 were implanted with an electroencephalograph (EEG) electrode in the hippocampal dentate gyrus in combination with an electromyograph (EMG) electrode patch implanted in the nuchal muscle. Five consecutive 8-h recording sessions revealed differential patterns of EEG activity as a function of awake, slow-wave sleep (SWS) and rapid-eye movement (REM) sleep states and prenatal choline status. The main finding was that SUP rats displayed increased power levels of gamma (30-100 Hz) band oscillations during all phases of the sleep/wake cycle. These findings are discussed within the context of a general review of neuronal oscillations (e.g., delta, theta, and gamma bands) and synchronization across multiple brain regions in relation to sleep-dependent memory consolidation in the hippocampus.

Altered dietary choline availability early in life leads to persistent changes in spatial memory and hippocampal plasticity in adulthood. Developmental programming by early choline nutrition may determine the range of adult choline intake that is optimal for the types of neural plasticity involved in cognitive function. To test this, male Sprague-Dawley rats were exposed to a choline chloride deficient (DEF), sufficient (CON), or supplemented (SUP) diet during embryonic days 12-17 and then returned to a control diet (1.1 g choline chloride/kg). At 70 days of age, we found that DEF and SUP rats required fewer choices to locate 8 baited arms of a 12-arm radial maze than CON rats. When switched to a choline-deficient diet (0 g/kg), SUP rats showed impaired performance while CON and DEF rats were unaffected. In contrast, when switched to a choline-supplemented diet (5.0 g/kg), DEF rats' performance was significantly impaired while CON and SUP rats were less affected. These changes in performance were reversible when the rats were switched back to a control diet. In a second experiment, DEF, CON, and SUP rats were either maintained on a control diet, or the choline-supplemented diet. After 12 weeks, DEF rats were significantly impaired by choline supplementation on a matching-to-place water-maze task, which was also accompanied by a decrease in dentate cell proliferation in DEF rats only. IGF-1 levels were elevated by both prenatal and adult choline supplementation. Taken together, these findings suggest that the in utero availability of an essential nutrient, choline, causes differential behavioral and neuroplastic sensitivity to the adult choline supply.

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.

Choline supplementation of the maternal diet has a long-term facilitative effect on timing and temporal memory of the offspring. To further delineate the impact of early nutritional status on interval timing, we examined effects of prenatal choline supplementation on the temporal sensitivity of adult (6 months) male rats. Rats that were given sufficient choline in their chow (CON: 1.1 g/kg) or supplemental choline added to their drinking water (SUP: 3.5 g/kg) during embryonic days (ED) 12-17 were trained with a peak-interval procedure that was shifted among 75%, 50%, and 25% probabilities of reinforcement with transitions from 18 s-->36 s-->72 s temporal criteria. Prenatal choline supplementation systematically sharpened interval timing functions by reducing the associative/non-temporal response enhancing effects of reinforcement probability on the Start response threshold, thereby reducing non-scalar sources of variance in the left-hand portion of the Gaussian-shaped response functions. No effect was observed for the Stop response threshold as a function of any of these manipulations. In addition, independence of peak time and peak rate was demonstrated as a function of reinforcement probability for both prenatal choline-supplemented and control rats. Overall, these results suggest that prenatal choline supplementation facilitates timing by reducing impulsive responding early in the interval, thereby improving the superimposition of peak functions for different temporal criteria.

Methamphetamine intoxication has long-term consequences on dopaminergic function and corticostriatal-mediated behaviors in humans and other animals. In order to determine the potential impact on timing and temporal memory, we examined methamphetamine dose regimens that have been linked to neurotoxicity in adult (8 months) male rats. Rats that were given repetitive, high-dose methamphetamine (3.0 mg/kg ip × 4 injections/2 h) or saline injections were trained on a 2-s vs 8-s bisection procedure using auditory and visual signal durations. Following the high-dose regimen, baseline timing performance was reestablished prior to the rats' receiving reversal training in which the spatial/temporal mapping of the anchor durations (2 s and 8 s) to response options (left or right lever) was reversed. Low-dose methamphetamine (0.5 mg/kg ip) or saline injections were subsequently used to evaluate the effectiveness of the neurotoxic doses in terms of modifying the horizontal leftward shifts associated with increases in clock speed. Overall, the results indicate that MAP intoxication leads to reduced auditory/visual differences in clock speed, deficits in reversal learning, distortions in temporal memory, and lowered dopaminergic regulation of clock speed consistent with damage to prefrontal cortex and corticostriatal circuitry.

Behavioral and pharmacological challenges using methamphetamine (MAP-0.5 and 1.0 mg/kg, i.p.), haloperidol (HAL-0.12 mg/kg, i.p.), and sulfated cholecystokinin octapeptide (CCK-0.05 and 0.1 mg/kg, i.p.) were used to evaluate the effects of excitotoxic lesions of cholinergic cell bodies in the medial septal area and the nucleus basalis magnocellularis, radiofrequency lesions of the fimbria-fornix, and aspiration lesions of the frontal cortex on interval timing in rats trained on a 40-s peak-interval procedure. Results demonstrated that lesions of the nucleus basalis magnocellularis and frontal cortex selectively reduced the modulatory control of clock speed which is likely mediated by dopamine D(2) receptors located on cortico-striatal neurons.

Choline supplementation of the maternal diet has a long-term facilitative effect on the interval-timing ability and temporal memory of the offspring. Here, we examined whether prenatal-choline supplementation has modality-specific effects on duration discrimination in aged (20 mo) male rats. Adult offspring of rats that were given sufficient choline in their chow (CON: 1.1 g/kg) or supplemental choline added to their drinking water (SUP: 3.5 g/kg) during embryonic days (ED) 12-17 were trained and tested on a two-modality (auditory and visual signals) duration bisection procedure (2 s vs. 8 s). Intensity (high vs. low) of the auditory and visual timing signals was systematically manipulated across test sessions such that all combinations of signal intensity by modality were tested. Psychometric response functions indicated that prenatal-choline supplementation systematically increased sensitivity to auditory signals relative to visual signals, thereby magnifying the modality effect that sounds are judged to be longer than lights of equivalent duration. In addition, sensitivity to signal duration was greater in rats given prenatal-choline supplementation, particularly at low intensities of both the auditory and visual signals. Overall, these results suggest that prenatal-choline supplementation impacts interval timing by enhancing the differences in temporal integration between auditory and visual stimuli in aged subjects.

The effects of a potent inhibitor of choline acetyltransferase (ChAT), BW813U, on timing behavior in mature (6–10 months) and aged (26–30 months) male rats were assessed. Twenty rats were trained on a discrete trial 20-s peak-interval (PI) procedure. During baseline (non-drug) training, the time of the maximum response rate (peak time) for mature rats was approximately at the time of scheduled reinforcement, but peak time for aged rats was reliably later. A single administration of BW813U (100 mg/kg, ip) produced a long-lasting increase in peak time for both mature and aged rats that occurred gradually and was synergistic with age. These horizontal shifts in peak time indicate a change in the content of reference memory for the remembered time of reinforcement that is similar for both aging processes and BW813U administration. When a 5-s gap was imposed in the signal, PI-GAP procedure, control rats of both ages summed the signal durations before and after the gap, whereas rats given BW813U showed no retention of the signal duration prior to the gap. This loss of trial-specific temporal information suggests a drug-induced working memory dysfunction. Taken together, these results demonstrate that both working and reference memory for temporal information are sensitive to choline acetyltransferase inhibition in rats.

The effects of selective dopamine (DA) depleting lesions with 6-hydroxydopamine microinjection into the SN, CPu, and NAS, as well as radiofrequency lesions of the CPu on the performance characteristics of rats trained on a single-valued 20-s peak-interval (PI) timing procedure or a double-valued 10-s and 60-s PI procedure were evaluated. A double dissociation in the performance of duration discriminations was found. Rats with CPu lesions were unable to exhibit temporal control of their behavior suggesting complete insensitivity to signal duration but were able to show discrimination of the relative reward value of a signal by differentially modifying their response rates appropriately. In contrast, rats with NAS lesions were able to exhibit temporal control of their behavior by differentially modifying their response rates as a function of signal duration(s), suggesting no impairment of sensitivity to signal duration, but were unable to show discrimination of the relative reward value of a signal.

The effects of choline supplementation during two time-frames of early development on radial-arm maze performance and the morphology of basal forebrain neurons immunoreactive for the P75 neurotrophin receptor (NTR) in male and female Sprague-Dawley rats were examined. In the first experiment, rats were supplemented with choline chloride from conception until weaning. At 80 days of age, subjects were trained once a day on a 12-arm radial maze for 30 days. Compared to control littermates, supplemented rats made fewer working and reference memory errors; however, the memory enhancing effects of choline supplementation were greater in males than females. A morphometric analysis of NTR-immunoreactive cell bodies at three levels through the medial septum/diagonal band (MS/DBv) of these rats revealed that perinatal choline supplementation caused the somata of cells in the MS/DBv to be larger by 8-15%. In a second experiment, choline supplementation was restricted to embryonic days 12-17. A developmental profile of NTR immunoreactive cell bodies in the MS/DBv of 0-, 8-, 16-, 30- and 90-day old male and female rats again revealed that cell bodies were larger in choline-supplemented rats than controls. As in the behavioral studies, the effect of choline supplementation was greater in male than female rats. These data are consistent with the hypothesis that supplementation with choline chloride during early development leads to an increase in the size of cell bodies of NTR-immunoreactive cells in the basal forebrain and that this change may contribute to long-term improvement in spatial memory.

The role of the hippocampus and the amygdala in timing and in the memory of previously timed events was investigated in rats. Two testing procedures used the peak time (the time at which the maximum response rate occurred) to identify the time at which the rat expected reinforcement. Amygdala (AMG) lesions had no effect on the remembered time of reinforcement or on the ability to remember the duration of a previous stimulus. Fimbria-fornix (FF) lesions had two effects: these rats remembered the time of reinforcement as occurring earlier than it really did, and could not remember the duration of a previous stimulus even after a gap of only 0.5 s. This behavior pattern endured throughout testing in spite of reinforcement contingencies designed to eliminate it. Atropine, 0.45 mg/kg, caused control rats to forget the duration of a previous stimulus, while haloperidol, 0.15 mg/kg, did not. Taken together, these data indicate that the hippocampus, but not the amygdala, has an important role in the memory for time. They suggest that alterations in temporal processes may be intimately involved in the amnesic syndrome seen following damage to temporal lobe structures.