Lawrence A. Rothblat

Object recognition memory in the rat : the role of the hippocampus

Object recognition memory of rats with fimbria-fornix or ventral temporal lesions was evaluated with a behavioral protocol (delayed non-matching-to-sample task with trial-unique stimuli) similar to that used to test recognition functions in primates. Animals with damage to the hippocampal system showed no evidence of lasting impairment on the object recognition task with retention intervals up to 30 s. In contrast, rats with fimbria-fornix lesions displayed severe and enduring deficits on a test of spatial memory, i.e. rewarded alternation, with but 5 s delays. These results provide further evidence that a dissociation exists between the types of memory that are and are not lost following damage to the hippocampus. Whereas the hippocampus is necessary for some types of mnemonic processes, other types of recognition functions (e.g. perceptual recognition) may be fully mediated in regions of sensory and/or association neocortex without the involvement of the hippocampus.

Executive functions in the heterozygous reeler mouse model of schizophrenia

Deficits in working memory and executive functions are now considered among the most reliable endophenotypes for schizophrenia. To determine whether cognitive deficits exist in mouse models of the disease, the authors trained heterozygous reeler (+/rl) mice on a series of visual discriminations similar to those used to test executive abilities in primates. These mice resemble schizophrenia patients in that both have reduced levels of reelin protein and altered gamma aminobutyric acid neurotransmission in the prefrontal cortex. The +/rl mice showed a selective deficit in reversal learning, with a pattern of errors that suggested impaired visual attention rather than a deficiency in perseveration and inhibitory control. These results show that cognitive dysfunction may serve as a useful biomarker in mouse models of neuropsychiatric disease.

Discrimination of multidimensional visual stimuli by mice: intra- and extradimensional shifts.

A visual discrimination protocol similar to that used with monkeys was adapted to measure attentional set-shifting in mice. An automated touchscreen procedure with compound visual stimuli was used to train mice to attend to 1 of 2 stimulus dimensions (lines or shapes). On a 2nd problem with new stimuli, the mice were required to attend to the same dimension (intradimensional [ID] shift) or switch to the previously irrelevant dimension (extradimensional [ED] shift). Mice readily learned the initial compound discrimination and following shift problem, but there was no ID-ED difference. The fact that mice can be tested with stimuli and task sequences similar to those used with primates suggests that this method can be used to directly compare higher cognitive functions in diverse species.

Discrimination of computer-graphic stimuli by mice: a method for the behavioral characterization of transgenic and gene-knockout models.

An automated method is described for the behavioral testing of mice in an apparatus that allows computer-graphic stimulus material to be presented. Mice responded to these stimuli by making a nose-poke toward a computer monitor that was equipped with a touchscreen attachment for detecting responses. It was found that C57BL/6 mice were able to solve single-pair visual discriminations as well as 3-pair concurrent visual discriminations. The finding that mice are capable of complex visual discriminations introduces the possibility of testing mice on nonspatial tasks that are similar to those used with rats, monkeys, and humans. Furthermore, the method seems particularly well suited to the comprehensive behavioral assessment of transgenic and gene-knockout models.

The hippocampus and long-term object memory in the rat

Animal models of amnesia have yielded many insights into the neural substrates of different types of memories. Some very important aspects of memory, however, have been ignored in research using experimental animals. For example, to examine long-term memory investigators traditionally have relied on measures of information acquisition, which stand in contrast to the measures of retention commonly used in work with humans. We have recently developed a behavioral paradigm that measures both the acquisition and long-term retention of object discriminations, and found a selective retention impairment in rats with entorhinal-hippocampal disconnection (Vnek et al., 1995). The present study was designed to determine whether direct damage to the hippocampus likewise would lead to a selective deficit in the retention of visual discriminations. Rats with aspiration lesions of the dorsal hippocampus, rats with neocortical control lesions, and normal controls were trained on three object discrimination problems and then retrained 3 weeks later to measure retention. All animals showed the same level of performance during the training (acquisition) phase of testing, but the performance of animals with dorsal hippocampal injury fell below that of controls during retraining (retention). Taken together, these and our earlier results suggest that the hippocampus and anatomically related structures are particularly important for retaining visual discriminations over long delay intervals. These findings may clarify the role of the hippocampus in nonspatial memory.

Age-related changes in the distribution of visual callosal neurons following monocular enucleation in the rat

Abstract The distribution of visual callosal neurons was identified in tangential sections from flattened hemispheres of normal rats and animals unilaterally enucleated at various postnatal ages with the retrogradely transported fluorescent label, Fast Blue. Following enucleation on or after postnatal day 10, callosal neurons along the 17/18a border appear adult-like in their configuration. Enucleation prior to this age stabilizes callosal development in the hemisphere contralateral to the enucleated eye.

Role of the parahippocampal region in spatial and non-spatial memory : effects of parahippocampal lesions on rewarded alternation and concurrent object discrimination learning in the rat

Rats with aspiration or excitotoxic (NMDA) lesions of the parahippocampal region were trained on a series of behavioral tasks which consisted of: (1) a test of spatial memory (discrete trial rewarded alternation), (2) a black-white discrimination, and (3) a test of non-spatial memory commonly used in primate models of amnesia (visual concurrent object discrimination). Rats in both lesion groups were severely impaired on the concurrent discrimination, even though they were able to learn the black-white discrimination normally. Animals with aspiration lesions were also impaired on the spatial memory task, whereas those with NMDA lesions did not differ from controls. The results indicate that concurrent object discrimination is a particularly sensitive measure of hippocampal/parahippocampal functions and suggest that these structures in the rat may serve mnemonic functions which are qualitatively similar to those of human and non-human primates.

Stimulus specific deficit on visual reversal learning after lesions of medial prefrontal cortex in the mouse

Tests of executive abilities, such as discrimination reversal and attentional set shifting, are sensitive to prefrontal cortex (PFC) damage in primates. The purpose of the present study was to use a primate reversal task to determine if PFC in the mouse is involved in similar cognitive functions. Mice with lesions of medial PFC and Sham operated control animals were trained on a series of visual problems in a computer-automated touchscreen apparatus using stimuli that varied in either pattern (lines) or luminance (black-white). PFC-lesioned mice learned to discriminate both sets of stimuli as readily as controls, but displayed a stimulus specific (pattern only) deficit on the reversal task. Analysis of error patterns on the line reversal suggests the deficit exhibited by PFC-lesioned mice was related to stimulus specific aspects of visual attention, rather than perseveration. These results demonstrate that medial PFC may play a role in control of directed attention and provide further evidence that the touchscreen procedure can be a useful tool for examining functional similarities in brain regions of very diverse species.

The basal forebrain cholinergic system and object memory in the rat

Rats with near complete destruction of basal forebrain cholinergic neurons from intracerebroventricular injections of 192 IgG-saporin were trained on object discrimination problems and then retrained two weeks later to measure retention. Despite dramatic reductions of acetylcholinesterase-positive fibers in hippocampus and neocortex, these animals did not differ from controls on an analysis of savings scores. Thus, the basal forebrain cholinergic system may serve functions that support non-spatial memory but are not specifically mnemonic in nature.

Intact and impaired executive abilities in the BTBR mouse model of autism.

BTBR T+tf/J (BTBR) inbred mice are frequently used as a model of autism spectrum disorders (ASD) as they display social deficits and repetitive behaviors that resemble the symptoms of the human syndrome. Since deficits on tasks that measure cognitive (executive) control are also reliable phenotypes in ASD, we wanted to determine whether executive abilities were compromised in the mouse model. BTBR mice were trained on two visual discrimination paradigms requiring differing degrees of cognitive control. BTBR mice performed normally on a visual discrimination reversal where rule switching was relatively automatic, but were severely impaired on a task-switch paradigm that required the active use of contextual information to switch between rules in a flexible manner. The present findings further characterize the behavior of BTBR mice as a model of ASD. Moreover, the demonstration of both intact and impaired executive functions in BTBR mice illustrates the importance of developing new cognitive assays for comprehensive behavioral assessment of mouse models of human brain disorders.