Different roles for M1 and M2 receptors within perirhinal cortex in object recognition and discrimination.

Recognition and discrimination of objects and individuals are critical cognitive faculties in both humans and non-human animals, and cholinergic transmission has been shown to be essential for both of these functions. In the present study we focused on the role of M1 and M2 muscarinic receptors in perirhinal cortex (PRh)-dependent object recognition and discrimination. The selective M1 antagonists pirenzepine and the snake toxin MT-7, and a selective M2 antagonist, AF-DX 116, were infused directly into PRh. Pre-sample infusions of both pirenzepine and AF-DX 116 significantly impaired object recognition memory in a delay-dependent manner. However, pirenzepine and MT-7, but not AF-DX 116, impaired oddity discrimination performance in a perceptual difficulty-dependent manner. The findings indicate distinct functions for M1 and M2 receptors in object recognition and discrimination.

Muscimol, AP5, or scopolamine infused into perirhinal cortex impairs two-choice visual discrimination learning in rats.

The perirhinal cortex (PRh) has been strongly implicated in object recognition memory and visual stimulus representation. Studies of object recognition have revealed evidence for the involvement of several neurotransmitter subsystems, including those involving NMDA (N-methyl-d-aspartic acid) and muscarinic cholinergic receptors. In the present study, we assessed the possible involvement of PRh and related receptor subsystems in two-choice visual discrimination learning by Lister Hooded rats tested in touchscreen-equipped operant boxes. In Experiment 1, daily pre-training inactivation of PRh with the GABA(A) receptor agonist muscimol (0.5 microg/hemisphere) significantly impaired acquisition of the two-choice visual discrimination. In Experiment 2, daily pre-training blockade of either NMDA or muscarinic receptors in PRh with AP5 (5.9 microg/hemisphere) or scopolamine (10 microg/hemisphere), respectively, impaired task acquisition. These results parallel the findings from object recognition studies and suggest a generality of neurotransmitter receptor involvement underlying the role of PRh in both object recognition memory and visual discrimination learning. The involvement of PRh in both types of tasks may be related to its role in complex visual stimulus representation.

Perceptual functions of perirhinal cortex in rats: zero-delay object recognition and simultaneous oddity discriminations.

The perirhinal cortex (PRh) is widely accepted as having an important role in object recognition memory in humans and animals. Contrary to claims that PRh mediates declarative memory exclusively, previous evidence suggests that PRh has a role in the perceptual processing of complex objects. In the present study, we conducted an examination of the possible role of PRh in perceptual function in rats. We examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus postrhinal cortices) in the rat would cause deficits in a zero-delay object-recognition task and a simultaneous oddity discrimination task. Both of these tasks measured spontaneous (untrained, unrewarded) behavior, and the stimuli in these experiments were manipulated to produce varying levels of perceptual difficulty. As predicted by simulations using a computational model, rats with PPRh lesions were impaired in object recognition when the stimuli to be discriminated were manipulated to share many features in common. Furthermore, rats with PPRh and PRh lesions were impaired in a simultaneous oddity discrimination task when the stimuli to be discriminated were manipulated explicitly to be more perceptually similar. These findings provide support for the idea that PRh in the rat is important for the perceptual processing of complex objects, in addition to its well established role in memory.

Scopolamine infused into perirhinal cortex improves object recognition memory by blocking the acquisition of interfering object information.

In a previous study, we reported apparently paradoxical facilitation of object recognition memory following infusions of the cholinergic muscarinic receptor antagonist scopolamine into the perirhinal cortex (PRh) of rats. We attributed these effects to the blockade by scopolamine of the acquisition of interfering information. The present study tested this possibility directly by modifying the spontaneous object recognition memory task to allow the presentation of a potentially interfering object either before the sample phase or in the retention delay between the sample and choice phases. Presentation of an object between the sample and choice phases disrupted subsequent recognition of the sample object (retroactive interference), and intra-PRh infusions of scopolamine prior to the presentation of the irrelevant object prevented this retroactive interference effect. Moreover, presentation of an irrelevant object prior to the sample phase interfered proactively with sample object recognition, and intra-PRh infusions of scopolamine prior to the presentation of the pre-sample object prevented this proactive interference effect. These results suggest that blocking muscarinic cholinergic receptors in PRh can disrupt the acquisition of potentially interfering object information, thereby facilitating object recognition memory. This finding provides further, strong evidence that acetylcholine is important for the acquisition of object information in PRh.

Perirhinal cortex resolves feature ambiguity in configural object recognition and perceptual oddity tasks.

The perirhinal cortex (PRh) has a well-established role in object recognition memory. More recent studies suggest that PRh is also important for two-choice visual discrimination tasks. Specifically, it has been suggested that PRh contains conjunctive representations that help resolve feature ambiguity, which occurs when a task cannot easily be solved on the basis of features alone. However, no study has examined whether the ability of PRh to resolve configural feature ambiguity is related to its role in object recognition. Therefore, we examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus post-rhinal cortices) in the rat would cause deficits in a configural spontaneous object recognition task, and a configural simultaneous oddity discrimination task, in which the task could not be solved on the basis of features, but could only be solved using conjunctive representations. As predicted by simulations using a computational model, rats with PPRh lesions were impaired during a minimal-delay configural object recognition task. These same rats were impaired during a zero-delay configural object recognition task. Furthermore, rats with localized PRh lesions were impaired in a configural simultaneous oddity discrimination task. These findings support the idea that PRh contains conjunctive representations for the resolution of feature ambiguity and that these representations underlie a dual role for PRh in memory and perception.

Rats spontaneously discriminate purely visual, two-dimensional stimuli in tests of recognition memory and perceptual oddity.

Animal models have been central to advances made in understanding the neural basis of human cognition, but maximizing the use of animal models requires tasks that match those used to assess human subjects. Tasks used in humans frequently use visual 2-dimensional stimuli, assess 1-trial learning, and require little pretraining. This article describes novel versions of 2 tasks for the rat, spontaneous object recognition and spontaneous oddity preference, both of which use purely visual, 2-dimensional picture-card stimuli, test 1-trial learning, and require no pretraining. Rats showed robust memory for a variety of picture-card stimuli, demonstrating almost no loss of memory for some of the stimulus types even after a 2-hr delay period. Rats were able to show spontaneous oddity preference for all 3 visual stimulus types tested (photos, shapes, and patterns), as well as for 3-dimensional objects. These 2 tasks are quick to administer, involve no fearful learning associations, and require a simple apparatus. They may be particularly useful for high-throughput pharmacological or genetic screening using rodent models.

A computer-automated touchscreen paired-associates learning (PAL) task for mice: impairments following administration of scopolamine or dicyclomine and improvements following donepezil.

RATIONALE: Performance on the Cambridge Neuropsychological Test Automated Battery touchscreen paired-associates learning (PAL) test is predictive of Alzheimer's disease and impaired in schizophrenia and chronic drug users. An automated computer touchscreen PAL task for rats has been previously established. A pharmacologically validated PAL task for mice would be a highly valuable tool, which could be useful for a number of experimental aims including drug discovery. OBJECTIVES: This study sought to investigate the effects of systemic administration of cholinergic agents on task performance in C57Bl/6 mice. METHODS: Scopolamine hydrobromide (0.02, 0.2, and 2.0 mg/kg), dicyclomine hydrochloride (M(1) receptor antagonist; 2.0, 4.0, and 8.0 mg/kg), and donepezil hydrochloride (cholinesterase inhibitor; 0.03, 0.1, and 0.3 mg/kg) were administered post-acquisition in C57Bl/6 mice performing the PAL task. RESULTS: Scopolamine (0.2 and 2.0 mg/kg) and dicyclomine (at all administered doses) significantly impaired PAL performance. A significant facilitation in PAL was revealed in mice following donepezil administration (0.3 mg/kg). CONCLUSIONS: The present study shows that mice can acquire the rodent PAL task and that the cholinergic system is important for PAL task performance. M(1) receptors in particular are likely implicated in normal performance of PAL. The finding that mouse PAL can detect both impairments and improvements indicates that this task could prove to be a highly valuable tool for a number of experimental aims including drug discovery.

Intact attentional processing but abnormal responding in M1 muscarinic receptor-deficient mice using an automated touchscreen method.

Cholinergic receptors have been implicated in schizophrenia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, to better target therapeutically the appropriate receptor subsystems, we need to understand more about the functions of those subsystems. In the current series of experiments, we assessed the functional role of M(1) receptors in cognition by testing M(1) receptor-deficient mice (M1R(-/-)) on the five-choice serial reaction time test of attentional and response functions, carried out using a computer-automated touchscreen test system. In addition, we tested these mice on several tasks featuring learning, memory and perceptual challenges. An advantage of the touchscreen method is that each test in the battery is carried out in the same task setting, using the same types of stimuli, responses and feedback, thus providing a high level of control and task comparability. The surprising finding, given the predominance of the M(1) receptor in cortex, was the complete lack of effect of M(1) deletion on measures of attentional function per se. Moreover, M1R(-/-) mice performed relatively normally on tests of learning, memory and perception, although they were impaired in object recognition memory with, but not without an interposed delay interval. They did, however, show clear abnormalities on a variety of response measures: M1R(-/-) mice displayed fewer omissions, more premature responses, and increased perseverative responding compared to wild-types. These data suggest that M1R(-/-) mice display abnormal responding in the face of relatively preserved attention, learning and perception.

Heightened susceptibility to interference in an animal model of amnesia: impairment in encoding, storage, retrieval--or all three?

There has recently been a resurgence in the idea that amnesia may be characterized by an increased susceptibility to interference. In the present study we tested this idea using a well-controlled and well-established animal model of amnesia: impairment in object recognition following perirhinal and postrhinal cortical (PPRh) damage. We used this paradigm to test whether memory impairment was exacerbated by the interpolation of a potentially interfering item either before (proactive interference) or after (retroactive interference) the to-be-remembered item. Rats with PPRh damage were impaired in object recognition memory, with a minimal delay, when the interfering stimulus was perceptually similar to the test stimuli. When the interfering stimulus was less perceptually similar to the test stimuli, the PPRh-lesioned rats performed similarly to Controls. Both proactive and retroactive interference were observed, and both depended on the similarity of the interfering item to the test items. These findings provide support for the idea that amnesia can indeed be characterized by increased vulnerability to interference, and we illustrate, using simulations generated by a computational model of amnesia, how the mechanism for this vulnerability to interference can be understood, not in terms of an impairment in encoding, storage or retrieval, but in terms of an impairment in encoding, storage and retrieval.