Accuracy Of Rats Research Articles

Turning the body into a clock: Accurate timing is facilitated by simple stereotyped interactions with the environment

How animals adapt their behavior according to regular time intervals between events is not well understood, especially when intervals last several seconds. One possibility is that animals use disembodied internal neuronal representations of time to decide when to initiate a given action at the end of an interval. However, animals rarely remain immobile during time intervals but tend to perform stereotyped behaviors, raising the possibility that motor routines improve timing accuracy. To test this possibility, we used a task in which rats, freely moving on a motorized treadmill, could obtain a reward if they approached it after a fixed interval. Most animals took advantage of the treadmill length and its moving direction to develop, by trial-and-error, the same motor routine whose execution resulted in the precise timing of their reward approaches. Noticeably, when proficient animals did not follow this routine, their temporal accuracy decreased. Then, naïve animals were trained in modified versions of the task designed to prevent the development of this routine. Compared to rats trained in the first protocol, these animals didn't reach a comparable level of timing accuracy. Altogether, our results indicate that timing accuracy in rats is improved when the environment affords cues that animals can incorporate into motor routines.

Application of Physiologically Based Pharmacokinetic Modeling to Predict the Effects of FcRn Inhibitors in Mice, Rats, and Monkeys

There is a growing interest in developing inhibitors of the neonatal Fc-receptor, FcRn, for use in the treatment for humoral autoimmune conditions. We have developed a new physiologically based pharmacokinetic model that is capable of characterizing the pharmacokinetics and pharmacodynamics of anti-FcRn monoclonal antibodies (mAb) in mice, rats, and monkeys. The model includes incorporation of FcRn recycling of immune gamma globulin (IgG) in hematopoietic cells in addition to FcRn recycling of IgG in vascular endothelial cells and considers FcRn turnover and intracellular cycling. The model captured antibody disposition in wild-type and FcRn-knockout mice and rats, and also predicted the effects of intravenous immune globulin and anti-FcRn mAb on IgG disposition. Simulations predicted the change in IgG clearance in response to intravenous immune globulin with good accuracy in rats (mean prediction error of 7.15% ± 7.67%). In monkeys, prediction windows for simulated IgG concentration versus time data, as generated through Monte Carlo simulation, were able to capture the effects of anti-FcRn mAb on endogenous IgG. The model may have utility in guiding preclinical evaluations of anti-FcRn therapies in development, potentially assisting in the identification of optimal dosing strategies for this emerging class of immunosuppressive drugs.

Accuracy of Rats in Discriminating Visual Objects Is Explained by the Complexity of Their Perceptual Strategy

SummaryDespite their growing popularity as models of visual functions, it remains unclear whether rodents are capable of deploying advanced shape-processing strategies when engaged in visual object recognition. In rats, for instance, pattern vision has been reported to range from mere detection of overall object luminance to view-invariant processing of discriminative shape features. Here we sought to clarify how refined object vision is in rodents, and how variable the complexity of their visual processing strategy is across individuals. To this aim, we measured how well rats could discriminate a reference object from 11 distractors, which spanned a spectrum of image-level similarity to the reference. We also presented the animals with random variations of the reference, and processed their responses to these stimuli to derive subject-specific models of rat perceptual choices. Our models successfully captured the highly variable discrimination performance observed across subjects and object conditions. In particular, they revealed that the animals that succeeded with the most challenging distractors were those that integrated the wider variety of discriminative features into their perceptual strategies. Critically, these strategies were largely preserved when the rats were required to discriminate outlined and scaled versions of the stimuli, thus showing that rat object vision can be characterized as a transformation-tolerant, feature-based filtering process. Overall, these findings indicate that rats are capable of advanced processing of shape information, and point to the rodents as powerful models for investigating the neuronal underpinnings of visual object recognition and other high-level visual functions.

Improvement of attention with amphetamine in low- and high-performing rats.

Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. Acute low dose amphetamine (0.1 and 0.25mg/kg) improved accuracy, while the highest dose (1.25mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents.

Donepezil reverses a mnemonic deficit produced by scopolamine but not by perforant path lesion or transient cerebral ischaemia.

The purpose of these studies were threefold. Firstly, to further characterize the effect of perforant path transection on a test of short-term memory: delayed matching (or nonmatching)-to-position [D(N)MTP]. Secondly, to evaluate the effect of a transient cerebral ischaemia in the same task. Both surgical procedures were chosen as they produce a CNS lesion similar to that described in Alzheimer's Disease (AD). Thirdly, the effect of the acetylcholinesterase inhibitor, donepezil (Aricept(R), E2020), on the resulting cognitive impairment was studied. Perforant path transection produced a robust, delay-dependent impairment of choice accuracy in rats performing either a delayed matching- or nonmatching-to-position task. Sample latency was also reduced following lesion, yet the lesion-induced impairment was not affected by increasing the response requirement at the sample stage. An 11-min period of transient ischaemia (two-vessel occlusion model) resulted in almost complete loss of hippocampal CA1 pyramidal cells and a delay-dependent impairment in DMTP performance. However, unlike perforant path lesions, this deficit was unstable and declined in magnitude over the experimental period. Increasing the delay interval restored this deficit. Donepezil, at doses that robustly attenuated a scopolamine (0.06 mg/kg s.c.)-induced DMTP accuracy impairment in naïve, unoperated rats, had no effect against either lesion-induced impairment. The results are considered in terms of the effectiveness of acetylcholinesterase inhibitors in noncholinergic-based preclinical cognitive models.

Coadministration of Galanin Antagonist M40 with a Muscarinic M1Agonist Improves Delayed Nonmatching to Position Choice Accuracy in Rats with Cholinergic Lesions

The neuropeptide galanin is overexpressed in the basal forebrain in Alzheimer's disease (AD). In rats, galanin inhibits evoked hippocampal acetylcholine release and impairs performance on several memory tasks, including delayed nonmatching to position (DNMTP). Galanin(1-13)-Pro2-(Ala-Leu)2-Ala-NH2 (M40), a peptidergic galanin receptor ligand, has been shown to block galanin-induced impairment on DNMTP in rats. M40 injected alone, however, does not improve DNMTP choice accuracy deficits in rats with selective cholinergic immunotoxic lesions of the basal forebrain. The present experiments used a strategy of combining M40 with an M1 cholinergic agonist in rats lesioned with the cholinergic immunotoxin 192IgG-saporin. Coadministration of intraventricular M40 with intraperitoneal 3-(3-S-n-pentyl-1,2,5-thiadiazol-4-yl)-1,2,5, 6-tetrahydro-1-methylpyridine (TZTP), an M1 agonist, improved choice accuracy significantly more than a threshold dose of TZTP alone. These results suggest that a galanin antagonist may enhance the efficacy of cholinergic treatments for the cognitive deficits of AD.

Cholinergic channel activator, ABT-418, enhances delayed-response accuracy in rats

The purpose of this study was to evaluate ABT-418, a recently developed isoxasole bioisostere of nicotine and cholinergic channel activator (ChCA), in rats trained to perform a delayed-response task, the Delayed Stimulus Discrimination Task (DSDT). In dose-effect studies, ABT-418 improved DSDT performance, while mecamylamine decreased accuracy of the task. The improvements afforded by optimal doses of ABT-418 were further substantiated by repeated administration on a separate occasion. Surprisingly, mecamylamine (1.0 mg/kg), when combined with optimal doses of ABT-418, failed to prevent improvements in accuracy of the task, as it had in a previous study with nicotine. The basis for this effect is unclear but may be related to the purported subtype selectivity of ABT-418. None of the drug-induced changes in DSDT accuracy was modality specific (i.e., whether the stimulus was the presented light or tone), and none of the drug manipulations produced significant changes in response latencies. Overall, the data confirm findings of previous rodent and nonhuman primate studies, which indicate that the nicotinic ligand has the potential to improve memory. Drug Dev. Res. 40:304–312, 1997. © 1997 Wiley-Liss, Inc.

Cholinergic channel activator, ABT‐418, enhances delayed‐response accuracy in rats

Cholinergic channel activator, ABT‐418, enhances delayed‐response accuracy in rats

Differential effects of MK-801, NMDA and scopolamine on rats learning a four-member repeated acquisition paradigm

The glutamatergic (NMDA) and cholinergic neurotransmitter systems have been extensively implicated as neurochemical mediators of learning processes. These two systems may differentially affect learning; for example, although both the cholinergic antagonist scopolamine and the NMDA antagonist MK-801 reduced overall accuracy of rats in a 3-member repeated acquisition paradigm, the nature of the underlying error patterns produced by the two drugs differed significantly: rats administered scopolamine produced a pattern of skipping errors, while administration of MK-801 predominantly increased perseverative errors (Cohn et al., 1992). The present experiment extended that study to examine whether a more complex task, i.e. a 4-member repeated acquisition paradigm, would alter the nature of the error patterns resulting from administration of each drug, and whether NMDA itself would increase accuracy on the repeated acquisition paradigm. MK-801 (0.05-0.3mg/kg i.p.) significantly decreased overall accuracy in a dose-dependent manner, and the rats produced a pattern of errors similar, although not identical to, that noted in the 3-member paradigm, including perseverative errors early in the sequence, but additional skipping errors at later points in the sequence. MK-801 dramatically decreased correct initiation of a sequence following an error at any point in the sequence. NMDA (10.0-30.0mg/kg) itself did not facilitate sequence acquisition, i.e. it did not affect overall accuracy. However, it was the only drug to increase the frequency of correctly reinitiating a sequence following an incorrect first or an incorrect second sequence member. Like MK-801, scopolamine (0.5-3.0mg/kg i.p.) also produced a decline in overall accuracy which was again achieved primarily through increased skipping errors. Scopolamine did not, however, interfere with correctly reinitiating a sequence either after successful completion of a sequence, or after an error. These findings suggest that cholinergic and glutamatergic compounds exert their effects on learning through different behavioral mechanisms.

Pharmacological correction of ketamine-impaired spatial memory of rats

Ketamine in dose 10 mg/kg increased the number of erroneous choices of rats with spatial strategy and didn't effect searching accuracy of rats with non-spatial strategy in 8-arm radial maze. Ketamine in doses 1 and 5 mg/kg disrupted rat short-term memory in delayed response reaction. Physostigmine and aspartic acid, but not haloperidol, diminished ketamine amnesia, therefore ketamine impaired the interaction of cholinergic and glutamate/aspartatergic neurons of hippocampal areas.

Polydipsia's Contribution to Temporal Discrimination of Rats on a Fixed Interval Schedule

This experiment concerned the contribution of polydipsia on the temporal discrimination of rats during a fixed-interval 60-sec. schedule. In this study, the timing accuracy of 12 rats which had access to water during training was compared to that of 12 rats which had no water during training. The rats were trained for 25 sessions on an FI 60-sec. schedule. In early sessions before polydipsia was fully developed, no differences existed between the timing accuracy of the water group and no-water group. As the amount of water drunk by the water group increased as the number of sessions increased, a parallel increase was noted in the timing accuracy of the water group. In the final sessions, a significant difference was found between the timing accuracy of rats in the water group and that of those in the no-water group. It was concluded that polydipsia facilitated the development of the temporal discrimination which is characteristic of a fixed-interval 60-sec. schedule.

ROC Analysis of Choice Accuracy in Rats

Rats’ running latencies were recorded prior to and following decisions in a conditional discrimination in a modified T maze. Postdecisional latencies, by Signal Detection Theory analysis, failed to discriminate correct from incorrect choices (d’ = −.09). Decision latencies, however, yielded d’ =.57, which is significantly greater than zero. Fast choice times were associated with correct responses. The data were interpreted as support for a non-feedback view of postdecision behavior.