Cognitive ability is associated with altered medial frontal cortical circuits in the LgDel mouse model of 22q11.2DS.

We established a relationship between cognitive deficits and cortical circuits in the LgDel model of 22q11 Deletion Syndrome (22q11DS)-a genetic syndrome with one of the most significant risks for schizophrenia and autism. In the LgDel mouse, optimal acquisition, execution, and reversal of a visually guided discrimination task, comparable to executive function tasks in primates including humans, are compromised; however, there is significant individual variation in degree of impairment. The task relies critically on the integrity of circuits in medial anterior frontal cortical regions. Accordingly, we analyzed neuronal changes that reflect previously defined 22q11DS-related alterations of cortical development in the medial anterior frontal cortex of the behaviorally characterized LgDel mice. Interneuron placement, synapse distribution, and projection neuron frequency are altered in this region. The magnitude of one of these changes, layer 2/3 projection neuron frequency, is a robust predictor of behavioral performance: it is substantially and selectively lower in animals with the most significant behavioral deficits. These results parallel correlations of volume reduction and altered connectivity in comparable cortical regions with diminished executive function in 22q11DS patients. Apparently, 22q11 deletion alters behaviorally relevant circuits in a distinct cortical region that are essential for cognitive function.

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.

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.

Rhinal cortex removal produces amnesia for preoperatively learned discrimination problems but fails to disrupt postoperative acquisition and retention in rhesus monkeys.

To test whether the rhinal cortex (i.e., entorhinal and perirhinal cortex) plays a time-limited role in information storage, eight rhesus monkeys were trained to criterion on two sets of 60 object discrimination problems, one set at each of two different time periods separated by 15 weeks. After the monkeys had learned both sets, two groups balanced for preoperative acquisition rates were formed. One group received bilateral ablation of the rhinal cortex (n = 4), and the other was retained as an unoperated control group (n = 4). After a 2 week rest period, monkeys were assessed for retention of the object discrimination problems. Retention was significantly poorer in monkeys with removals of the rhinal cortex relative to the controls (68 vs 91%). Although both groups showed slightly better retention of problems from the more recently learned set, there was no evidence of a differential effect of the cortical removal across sets (i.e., no temporal gradient). In addition, the monkeys with rhinal cortex lesions subsequently learned three new sets of 10 object discrimination problems as quickly as the controls did, thus ruling out the possibility of a gross impairment in visual perception or discrimination abilities. Furthermore, they retained these postoperatively learned object discriminations as well as the controls did. The findings indicate that the rhinal cortex is critical for the storage and/or retrieval of object discrimination problems that were learned up to 16 weeks before rhinal cortex ablation; however, in the absence of the rhinal cortex, efficient learning and retention of new discrimination problems can still occur.

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.

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.

Entorhinal-hippocampal connections and object memory in the rat: acquisition versus retention.

Investigations of the neurobiology of memory using experimental animals have modeled many of the characteristic features of amnesia seen in human clinical populations. To examine long-term memory, however, animal models of amnesia often employ extended measures of acquisition, which stand in contrast to the retention measures used with humans. To determine the role of entorhinal-hippocampal circuitry on both information acquisition and long-term retention, rats with bilateral transections of the angular bundle were trained on three object discrimination problems and then retrained two weeks later to measure retention. Animals with discrete lesions of the angular bundle, which disrupted perforant path connections from the entorhinal cortex to the hippocampus and efferent hippocampal-cortical projections, acquired the object discrimination problems normally but showed a marked deficit in retention. These findings are important because they indicate that the role of entorhinal-hippocampal connections may be limited to maintaining some types of information (e.g., single object discriminations) for retention. This dissociation, moreover, suggests that behavioral paradigms that include a measure of retention may be particularly important for characterizing the mnemonic functions of the hippocampal/parahippocampal region.

Landmark discrimination in the rat: a measure of allocentric spatial ability.

A landmark discrimination task similar to that previously used with monkeys was adapted to measure allocentric spatial ability in rats. Rats were trained to approach one of two food wells, placed 36 cm apart, based on the proximity of the landmark. During initial training, the landmark was adjacent to the baited food well (0 cm). As training progressed, the distance of the landmark from the baited food well was increased in 1.25-cm increments. Results show that rats were able to successfully use a landmark as an external referent up to a distance of 11 cm (when the midpoint between food wells was 18 cm). Following the stepwise training phase, a 64-trial test of mixed distances was administered, and performance was above 80% up to and including 12.5 cm from the near landmark. The results suggest that this landmark discrimination task provides a means to assess allocentric spatial ability in rats and to explore underlying neural mechanisms across species.

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.

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.

Neurotrophic and behavioral effects of occipital cortex transplants in newborn rats.

Cell suspensions of embryonic occipital cortex were transplanted into newborn rats with large unilateral visual cortex lesions. When the animals were adults, they were tested on a difficult visual discrimination, and subsequently their brains were analyzed for possible neurotrophic effects of the transplants on nonvisual cortical areas which normally form connections with the occipital cortex. Behaviorally, animals with lesions and transplants learn to discriminate between columns and rows of squares at a rate which is identical to normal rats while animals with lesions and no transplants are impaired. Volume and cell-density measures show that the transplants also rescue neurons in cortical area 8 that would normally degenerate following the cortical lesion. No such neurotrophic effect of the transplants is found in cortical area 24 or area 17 contralateral to the lesion. In rats with lesions and no transplants, there is a significant correlation between the amount of area 8 remaining after the lesion and trials to criterion on the columns-rows discrimination, a relationship that does not exist in transplant animals because of their normal learning curve and the consistent sparing of area 8. Injections of HRP into the visual cortex contralateral to the lesion result in variable numbers of labeled cells within the transplant. However, there is no consistent relationship between the number of transplant cells which project to the opposite hemisphere and learning of the discrimination. It is suggested that the learning deficit following the lesion is largely attentional and that the sparing of cortical area 8 (which in rats may include the analog of the frontal eye fields present in the primate cortex) contributes to the sparing of function.

Short-term object recognition memory in the rat: nonmatching with trial-unique junk stimuli.

A delayed nonmatching-to-sample task with trial-unique stimuli (DNMS), similar to that used to test object recognition memory in primates, was adapted for use with rats. For each trial of the DNMS task, two stimuli were randomly selected from a pool of 250 small "junk" objects; one member of the pair was designated as the sample. On the first part of a trial, the rat traversed an elevated runway and displaced the sample for food reward. After a 10-s delay, the rat again traversed the runway to choose between the previously presented sample and the second member of the pair. Reward on the choice trial followed selection of the new object. Scores on the first day of DNMS were significantly above chance, and animals could consistently perform at approximately 75% accuracy. Extending the delay to 30 or 120 s lowered choice accuracy, but performance was still above chance. The DNMS taks for rats, unlike most other memory tests for rodents, does not require memory for spatial location. The similarity to tests used with primates should allow for more direct comparison of results of memory research across species.

Mediational factors underlying cognitive changes and laterality in affective illness.

Affective illness has been associated with lateralized right hemisphere deficits and global cognitive dysfunction. However, there has been very little exploration of information-processing strategies that may underlie cognitive changes in this population. Twenty euthymic, drug-free, bipolar patients and 20 controls were given a series of tasks to assess lateralized impairment of the cerebral hemispheres and sequential (analytic) versus simultaneous (gestalt) information-processing strategies. There were no differences between patients and controls in tests sensitive to right or left hemisphere impairment or in total errors on a face recognition task. However, patients tended to rely on individual facial features for recognition whereas controls were able to synthesize multiple elements of the faces. Moreover, on a task that required holistic synthesis of multiple stimulus elements (Street Gestalt Completion Test), patients made significantly more errors than controls. Implications for information-processing changes in bipolar affective illness are discussed.

Effect of certified artificial food coloring on learning and activity level in rats.

Chronic oral administration of a formula consisting of seven FD&C certified artificial food dyes, given in 0, 2.0, and 5.0 mg/kg doses, failed to produce changes in measures of physical or motor development in rat pups. Two learning tasks, one given during development and the other at maturity, also revealed no differences among groups. In addition, two activity level measures, time-sampled observations and the open field task, were taken on five occasions. These measures also failed to demonstrate any effects of food coloring. Although food dyes may have toxic effects at higher dose levels or under unusual dietary or environmental conditions, these results suggest that orally ingested low doses do not reliably elicit behavioral changes.

Experimental lead paint poisoning in nonhuman primates. II. Clinical pathologic findings and behavioral effects.

Oral administration of lead-containing paint to rhesus monkeys induced anemia, more profound in older primates. Erythrocytes were microcytic and hypochromic, but tended to become macrocytic terminally. Stippled erythrocytes were increased in all poisoned monkeys, especially in those with high blood lead levels and anemia. Proteinuria, glycosuria, casts and sloughed tubular cells containing acid-fast inclusion bodies were found on urinalysis. Terminal elevations of blood urea nitrogen were associated with profound anemia and renal tubular damage. Repeated blood lead values over 200 microgram/dl were associated with a moribund termination while monkeys which had levels under 100 microgram/dl remained apparently healthy. Behavioral studies in a small number of subclinically poisoned juveniles and neonates failed to reveal deficiencies of visual acuity or cognitive ability, nor was there evidence of alterations in levels of activity.