Frontal-striatal disconnection disrupts cognitive performance of the frontal-type in the rat.

The prefrontal cortex is considered to provide executive control of response selection and planning in diverse cognitive tasks, translated into action via descending subcortical projections (or 'loops') through the basal ganglia. We have used a disconnection strategy to demonstrate first that bilateral fronto-striatal disconnection disrupts rats' abilities to perform delayed alternation, the classic test of prefrontal function in rats and monkeys, and second that crossed unilateral cortical and striatal lesions on opposite sides similarly disrupt rats' abilities to perform the same cognitive task. We found that effective disconnection requires interruption of interhemispheric transfer, achieved by transection of the anterior corpus callosum. This produces a moderate deficit in its own right, which is not exacerbated by additional prefrontal and striatal lesions in one hemisphere. Conversely, the animals are significantly more impaired after crossed prefrontal and striatal lesions of similar total magnitude. The results demonstrate than an intact cortico-striatal pathway is necessary to sustain performance on a classical prefrontal task, and provide a model within which to assess circuit reconstruction with novel cell therapies for brain repair.

On the transience of egocentric working memory: evidence from testing the contribution of limbic brain regions.

Rats trained on a nonmatching-to-turn rule revealed that egocentric working memory is readily disrupted, hard to use, and transient. In Experiment 1, rats failed to acquire the rule in a plus-maze. Experiment 2 used 2 different plus-mazes to remove any intramaze cues. Task acquisition occurred only when rats could use direction cues (i.e., nonegocentric cues). In Experiments 3 and 4, a J maze was used to minimize the retention interval and eliminate handling rats within a trial. All rats acquired the nonmatching rule, although a 3-s retention delay severely impaired performance. Fornix lesions transiently disrupted performance of the J-maze task (Experiments 3 and 4), but neither fornix (Experiment 1) nor retrosplenial (Experiment 2) lesions impaired the plus-maze tasks.

Sensory preconditioning in rats with lesions of the anterior thalamic nuclei: evidence for intact nonspatial 'relational' processing.

Rats with neurotoxic lesions centered in the anterior thalamic nuclei were trained in two versions of a nonspatial, sensory preconditioning procedure. In both versions, two stimulus compounds (AX and BY) were first presented and then X, but not Y, was paired with an aversive unconditioned stimulus. This procedure resulted in greater conditioned responding to A than B. Anterior thalamic lesions had no apparent effect on these two examples of sensory preconditioning, nor did they affect fear conditioning or conditioned taste aversion. In contrast, the same lesions led to a severe deficit on a test of spatial memory. These results help to refine our understanding of the contribution of the anterior thalamic nuclei to spatial memory.

Neurotoxic lesions of the rat perirhinal cortex fail to disrupt the acquisition or performance of tests of allocentric spatial memory.

Rats with neurotoxic lesions of the perirhinal cortex (n = 9) were compared with sham controls (n = 14) on a working memory task in the radial arm maze. Rats were trained under varying levels of proactive interference and with different retention intervals. Finally, performance was assessed when the maze was switched to a novel room. None of these manipulations differentially impaired rats with perirhinal lesions. Rats were next trained on delayed matching-to-place in the water maze. Even with retention delays of 30 min, there was no evidence of a deficit. Although interactions between the perirhinal cortex and hippocampus may be important for integrating object-place information, the perirhinal cortex is often not necessary for tasks that selectively tax allocentric spatial memory.

Visuospatial attention: the role of target contrast and task difficulty when assessing the effects of cues.

Cueing paradigms have become popular in assessing the processes of attention. In two experiments we manipulated (i) the contrast of the target, and (ii) the similarity between the targets discriminated. We used a cue that would isolate the exogenous component of attention. Both a reduction in target contrast and an increase in target similarity raised overall reaction times by a similar amount; however, the target contrast manipulation produced a much greater cueing effect compared with the target similarity manipulation. The results suggest that manipulation of target contrast changes the attention cueing effect at a stage of attracting attention to a location of the target (the 'move' stage), rather than at a later processing stage.

Effects of selective thalamic and prelimbic cortex lesions on two types of visual discrimination and reversal learning.

The effects of excitotoxic lesions of the mediodorsal nucleus of the thalamus, the anterior thalamic nuclei and of the prelimbic cortex were examined on two tests of discrimination and reversal learning. In experiment 1A (visual discrimination and reversal), rats were required to discriminate two stimuli, and respond to the stimulus associated with reward (the S+ stimulus). There was no effect of lesion on acquisition of this task. However, when stimulus-reward contingencies were reversed, animals with lesions of the mediodorsal nucleus of the thalamus made significantly more errors than control animals or animals of other lesion groups. In experiment 1B (conditional discrimination), animals were required to learn a rule of the type 'If stimulus A then go left, if stimulus B then go right'. No main effect of lesion on acquisition was observed in this experiment. To test the generality of the reversal effect obtained in experiment 1A, a second cohort of animals with the same lesions was tested on acquisition of the visuospatial conditional task immediately postsurgery, followed by the reversal of the conditional rule (experiment 2). As in experiment 1B, no main effect of lesion group was observed during acquisition of the task. However, lesions of the mediodorsal nucleus of the thalamus resulted in a mild impairment according to number of sessions required to attain criterion performance of the task when the response rule was reversed. The results of the present study provide evidence for a role for the mediodorsal nucleus of the thalamus in new learning, particularly when stimulus-reward contingencies are reversed. Furthermore, they show that the functions of this thalamic nucleus can be dissociated from those of the anterior thalamus and the prelimbic cortex.

The conjoint importance of the hippocampus and anterior thalamic nuclei for allocentric spatial learning: evidence from a disconnection study in the rat.

A disconnection procedure was used to test whether the hippocampus and anterior thalamic nuclei form functional components of the same spatial memory system. Unilateral excitotoxic lesions were placed in the anterior thalamic (AT) nuclei and hippocampus (HPC) in either the same (AT-HPC Ipsi group) or contralateral (AT-HPC Contra group) hemispheres of rats. The behavioral effects of these combined lesions were compared in several spatial memory tasks sensitive to bilateral hippocampal lesions. In all of the tasks tested, T-maze alternation, radial arm maze, and Morris water maze, those animals with lesions placed in the contralateral hemispheres were more impaired than those animals with lesions in the same hemisphere. These results provide direct support for the notion that the performance of tasks that require spatial memory rely on the operation of the anterior thalamus and hippocampus within an integrated neural network.

Perirhinal cortex and place-object conditional learning in the rat.

The present study examined whether excitotoxic lesions of the perirhinal cortex can affect acquisition of a place-object conditional task in which object and spatial information must be integrated. Testing was carried out in a double Y-maze apparatus, in which rats learned a conditional rule of the type, "In Place X, choose Object A, not Object B (A+ vs. B-); in Place Y, choose Object B, not Object A (A- vs. B+)." Perirhinal cortex lesions significantly impaired acquisition of this task while sparing performance of an allocentric spatial memory task performed in a radial arm maze. Perirhinal cortex lesions also had no apparent effect on a 1-pair object discrimination task performed in the double Y maze or on retention and acquisition of 4-pair concurrent discrimination problems performed in a computer-automated touch screen testing apparatus. The results suggest that, although the perirhinal cortex and hippocampus can be functionally dissociated, their normal mode of operation includes the integration of object and spatial information.

Loss of the thalamic nuclei for "head direction" impairs performance on spatial memory tasks in rats.

This study sought to characterize the effects of removing the nuclei of primary importance in relaying the thalamic head direction signal to the hippocampal formation (the anterior dorsal [AD] and lateral dorsal [LD] nuclei) on the performance of a variety of spatial and nonspatial tasks. The results indicate that combined excitotoxic lesions of the AD and LD nuclei produce marked deficits on a variety of spatial tasks. These tasks included T-maze alternation and the ability to locate a hidden platform set at a fixed distance and fixed direction from a beacon in a Morris water maze. Although object recognition appeared unaffected, marked impairments were found in the ability to detect when an object was placed in a novel position (object-in-place memory).

Visual attention in the rat: a role for the prelimbic cortex and thalamic nuclei?

The behavioral effects of lesions of the prelimbic cortex (PL), mediodorsal nucleus of the thalamus (MD), and anterior thalamic nuclei (ANT) were investigated in 2 attentional tasks in rats: the 5-choice serial reaction time task and a vigilance task. Although there was no lesion effect on accuracy in the 5-choice task, PL lesions enhanced perseverative responding during baseline performance and when stimulus duration was reduced. In contrast, MD lesions increased premature responding during baseline performance and when the intertrial interval was varied unpredictably. In the vigilance paradigm, PL lesions also impaired rats' ability to detect the light signal at baseline and at the reduced stimulus duration. ANT lesions did not substantially disrupt performance. The results suggest that different aspects of attention may be attributable to the PL and the MD and that the mechanisms underlying inhibitory control of behavior may be attributable to functionally different thalamocortical circuits.

The role of the nucleus accumbens in instrumental conditioning: Evidence of a functional dissociation between accumbens core and shell.

In three experiments we examined the effect of bilateral excitotoxic lesions of the nucleus accumbens core or shell subregions on instrumental performance, outcome devaluation, degradation of the instrumental contingency, Pavlovian conditioning, and Pavlovian-instrumental transfer. Rats were food deprived and trained to press two levers, one delivering food pellets and the other a sucrose solution. All animals acquired the lever-press response although the rate of acquisition and overall response rates in core-lesioned animals were depressed relative to that in the shell- or sham-lesioned animals. Furthermore, in shell- and sham-lesioned rats, post-training devaluation of one of the two outcomes using a specific satiety procedure produced a selective reduction in performance on the lever that, in training, delivered the prefed outcome. In contrast, the core-lesioned rats failed to show a selective devaluation effect and reduced responding on both levers. Subsequent tests revealed that these effects of core lesions were not caused by an impairment in their ability to recall the devalued outcome, to discriminate the two outcomes, or to encode the instrumental action-outcome contingencies to which they were exposed. Additionally, the core lesions did not have any marked effect on Pavlovian conditioning or on Pavlovian-instrumental transfer. Importantly, although shell-lesioned rats showed no deficit in any test of instrumental conditioning or in Pavlovian conditioning, they failed to show any positive transfer in the Pavlovian-instrumental transfer test. This double dissociation suggests that nucleus accumbens core and shell differentially mediate the impact of instrumental and Pavlovian incentive processes, respectively, on instrumental performance.

Excitotoxic lesions of the rostral thalamic reticular nucleus do not affect the performance of spatial learning and memory tasks in the rat.

Rats with cytotoxic lesions of the rostral pole of the thalamic reticular nucleus were compared with surgical control animals on a series of spatial learning and memory tests. While evidence was found for an initial, transient impairment on forced-choice alternation in a T-maze, this rapidly disappeared, and overall performance was unaffected. Subsequent experiments found no evidence that lesions of the rostral reticular nucleus affected the acquisition or performance of tests in the radial arm maze and the Morris water maze. Thus, it appears that the rostral pole of the thalamic reticular nucleus often does not play a necessary role in the performance of tests of spatial learning and memory, in spite of its interconnections with other regions that are required for normal spatial memory.

Intact negative patterning in rats with fornix or combined perirhinal and postrhinal cortex lesions.

It has been proposed that the hippocampal formation is necessary for the acquisition of tasks that require the use of configural representations for their solution, including spatial learning and negative patterning. Tests of this influential view have, however, yielded conflicting results. For example fornix or hippocampal lesions, which reliably impair spatial learning, do not reliably impair negative patterning. A problem in interpreting these results has been the lack of controls for factors such as over-responding, excitatory effects of reward, and the possibility of non-configural solutions. At the same time, other studies have pointed to a role in configural learning for parahippocampal regions such as the perirhinal cortex. The present experiments controlled for the above factors and revealed that neither lesions of the fornix nor of the perirhinal/postrhinal cortex in the rat had any effect on negative patterning, although subsequent tests of object and spatial memory demonstrated the functional efficacy of the lesions.

Distinct patterns of behavioural impairments resulting from fornix transection or neurotoxic lesions of the perirhinal and postrhinal cortices in the rat.

The present study provides evidence that lesions of the fornix (FNX) and of the perirhinal/postrhinal cortex (PPRH), which both disconnect the hippocampus from other brain regions, can lead to distinct patterns of behavioural impairments on tests of spatial memory and spontaneous object recognition. For example, whereas FNX lesions impaired allocentric spatial delayed alternation in a T-maze but generally spared a test of spontaneous object recognition, PPRH lesions produced the opposite pattern of results. Indeed, on the T-maze task PPRH animals significantly outperformed controls when the retention delay was increased to 60 s. In addition, some evidence was found that contributions from both the fornix and perirhinal/postrhinal cortex may be required when object and spatial information must be integrated. In an object-in-place test, for example, PPRH animals failed according to two measures, and FNX animals failed according to one measure, to discriminate objects that had remained in fixed locations from those that had exchanged locations with other objects. Neither lesion, however, affected performance of a visuospatial conditional task, a Pavlovian autoshaping task, or a one-pair pattern discrimination task. It is suggested that the perirhinal/postrhinal cortex, rather than being specialised for a particular type of associative learning, is important for processing complex visual stimuli.

Disconnecting hippocampal projections to the anterior thalamus produces deficits on tests of spatial memory in rats.

A disconnection procedure was used to test whether projections from the hippocampus to the anterior thalamic nuclei (AT), via the fimbria-fornix (FX), form functional components of a spatial memory system. The behavioural effects of combined unilateral lesions in the AT and FX were compared when they were either in contralateral hemispheres (AT-FX Contra) or the same hemisphere (AT-FX Ipsi). Other groups received bilateral FX lesions and Sham surgeries. Expt 1 demonstrated that none of these lesions affected performance of an object recognition task, while performance of an object location task, which tests the subjects' preference for an object that has changed location, was impaired in the AT-FX Contra and FX groups. In a T-maze alternation task, however, the FX group was severely impaired while both the AT-FX Ipsi and AT-FX Contra lesion groups showed only a mild impairment. In order to test whether spared crossed projections might support spatial performance in the AT-FX Contra group we then examined the effects of a combined AT-FX Contra lesion coupled with transection of the hippocampal commissure. This combination of lesions produced a severe disruption in spatial memory performance in the water maze, radial arm maze and T-maze, which was significantly greater than that produced by ipsilateral and contralateral AT-FX lesions alone. These results support the notion that disconnection of the AT from their hippocampal inputs produces impairments on a range of spatial memory tasks, but indicate that there are an array of different routes that can subserve this function.

Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region.

The present study investigated the effects of naturally fluctuating endogenous levels of oestrogen on the induction and maintenance of long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. Using an anaesthetized in vivo preparation, the results showed that the induction of LTP was augmented during the pro-oestrous stage of the oestrous cycle. In contrast to LTP, however, the induction of paired-pulse LTD was severely attenuated during pro-oestrous, but was clearly manifested by rats during met/dioestrous and oestrous stages of the cycle. These findings are discussed with reference to: (i) the modulatory effects of oestrogen on N-methyl-D-aspartate (NMDA) receptor function and gamma-aminobutyric acid (GABA) neurotransmission in the hippocampus; and (ii) the functional implications that such cyclical changes in synaptic plasticity have for learning and memory processes supported by the hippocampus.

Does pretraining spare the spatial deficit associated with anterior thalamic damage in rats?

Rats that had been pretrained on 2 tests of allocentric memory (water maze and T maze) received bilateral cytotoxic lesions in the anterior thalamic nuclei (ATN) or transection of the fimbria-fornix (FF). After surgery, both groups of rats were impaired on both tasks, although the preoperative training resulted in a rapid initial reacquisition of the water maze task. Those rats with lesions largely restricted to the ATN were impaired at a level comparable to that produced by FF lesions. This finding is consistent with a close functional relationship between the hippocampus and the ATN, necessary for the acquisition and on-line processing of allocentric spatial information but not for the maintenance/retrieval of procedural information. The rats with more extensive thalamic lesions were more impaired in both tasks and did show a loss of procedural information.

Decline in visual attention and spatial memory in aged rats.

The present study was a longitudinal study of age-related changes in performance of the 5-choice serial reaction time task, a test of visual attention. Following acquisition of the task, animals were tested on two occasions on their ability to perform the 5-choice task. In Test 1 (Young: 7 months; Aged: 13-14 months) no age-related effects on baseline performance were revealed. However, increasing the attentional load of the task revealed an impairment in choice accuracy by animals of the Aged group. In Test 2 (Young: 10-11 months; Aged 23-24 months), animals of the Aged group were significantly impaired on the baseline schedule of the task compared to the Young group. The deficit in accuracy on the task could be improved in the Aged animals by decreasing the attentional load. The results of the present study suggest a deficit in attentional function as a result of the aging process, markedly similar to that observed following lesions of the basalo-cortical cholinergic system.

Functionally dissociating aspects of event memory: the effects of combined perirhinal and postrhinal cortex lesions on object and place memory in the rat.

Reciprocal interactions between the hippocampus and the perirhinal and parahippocampal cortices form core components of a proposed temporal lobe memory system. For this reason, the involvement of the hippocampus in event memory is thought to depend on its connections with these cortical areas. Contrary to these predictions, we found that NMDA-induced lesions of the putative rat homologs of these cortical areas (perirhinal plus postrhinal cortices) did not impair performance on two allocentric spatial tasks highly sensitive to hippocampal dysfunction. Remarkably, for one of the tasks there was evidence of a facilitation of performance. The same cortical lesions did, however, disrupt spontaneous object recognition and object discrimination reversal learning but spared initial acquisition of the discrimination. This pattern of results reveals important dissociations between different aspects of memory within the temporal lobe. Furthermore, it shows that the perirhinal-postrhinal cortex is not a necessary route for spatial information reaching the hippocampus and that object familiarity-novelty detection depends on different neural substrates than do other aspects of event memory.

Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist.

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling [3H]histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with [125I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by approximately 100% histamine turnover rate and steady state level of tele-methylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H3-receptor agonist induced enhancement of water consumption in rats with and ID50 of 0.09 +/- 0.04 mg/kg, i.p. In cats, ciproxifan (0.15-2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.