Dissociable effects of frontal cortical lesions on measures of visuospatial attention and spatial working memory in the rat.

Frontal cortex controls voluntary movement through projections to striatum that continue as parallel pallido-thalamic loops. In previous studies we found evidence of a double dissociation in rat striatum between visuospatial response time (RT) and radial maze delayed non-matching (DNM) tasks. Here we compare the effects of frontal cortical lesions on these tasks. We found that lesions involving sensorimotor areas in dorsolateral cortex affect RT for responding to visuospatial stimuli without affecting other measures of response speed or producing signs of attentional or sensory impairment. These deficits were equivalent to impairments observed with lesions in sensorimotor areas of dorsolateral striatum. Dorsal prefrontal lesions produced RT deficits indicative of attentional impairment that have not been observed with striatal or thalamic lesions. This suggests contributions of prefrontal cortex to attention independent of striatum and thalamus. Prefrontal lesions had significant but circumscribed effects on DNM consistent with effects of lesions in anatomically related areas of striatum or thalamus observed in earlier studies. These results are consistent with evidence implicating prefrontal cortex in aspects of spatial memory mediated by anatomically related pathways in the basal ganglia and thalamus.

Effects of intralaminar thalamic lesions on sensory attention and motor intention in the rat: a comparison with lesions involving frontal cortex and hippocampus.

A self-paced serial reaction task was developed to differentiate between the effects of intralaminar thalamic lesions on sensory attention and intentional motor function. Results were compared for hippocampal and frontal cortical lesions to test for the possible involvement of pathways involving these parts of the brain in any impairments associated with the thalamic lesion. Lesions of the intralaminar thalamic nuclei affected response latency without affecting accuracy. This increase in latency was unaffected by variations in stimulus duration, even though this manipulation had a substantial effect on response accuracy. Intralaminar lesions did not affect the response to distracting stimuli or to manipulations of stimulus salience. Thus it seems unlikely that the effects of intralaminar lesions on motor function were related to sensory loss or attentional dysfunction. Hippocampal lesions had no significant effect on any measure of performance. Frontal cortical lesions were associated with an increase in latency comparable to the intralaminar group and also affected the accuracy of responding to brief stimuli or under conditions of reduced stimulus salience. These results are discussed in light of evidence that lesions of the intralaminar nuclei affect functions mediated by anatomically related areas of frontal cortex and striatum.

Effects of dorsal and ventral striatal lesions on delayed matching trained with retractable levers.

Recent evidence has suggested that thalamic amnesia results from damage to the intralaminar nuclei, an important source of input to striatum. To test the hypothesis that intralaminar damage disrupts functions mediated by striatum, we studied the effects of striatal lesions on a delayed matching task known to be affected by intralaminar lesions. Rats were trained to perform the task and given one of five treatments: sham surgery or a lesion of medial or lateral caudate/putamen, nucleus accumbens, or ventral striatum. Rats with ventral striatal lesions were impaired compared to all other groups. Rats with medial caudate/putamen or nucleus accumbens lesions were impaired compared to controls. The effects of ventral striatal lesions were sufficient to account for impairments in the accuracy and latency of delayed matching responses observed in previous studies of intralaminar and medial frontal cortical lesions. The ventral striatal lesions involved portions of ventral pallidum and thus it seems likely that they affected functions mediated by the nucleus accumbens as well as striatal areas of the tubercle. Serial reversal learning trained in the same apparatus with the same reinforcer was unaffected by all of the lesions. These results are discussed in terms of the roles of midline thalamic nuclei and of thalamo-cortico-striatal circuits in delayed conditional discrimination tasks.

Effects of reversible inactivation of thalamo-striatal circuitry on delayed matching trained with retractable levers.

The intralaminar thalamic nuclei are characterized by their prominent projections to striatum. Lesions of the intralaminar nuclei have been found to impair delayed matching trained with retractable levers. Comparable impairments have been observed for rats with lesions of the olfactory tubercle, involving ventral areas of striatum and pallidum. We conducted two experiments to test the functional dependence of thalamic and striatal lesions on the delayed matching task. In experiment 1, we determined the effects of inactivating the intralaminar nuclei with bilateral lidocaine infusions. In experiment 2, we compared the effects of unilateral thalamic inactivations in rats with unilateral olfactory tubercle lesions. We trained rats to perform the delayed matching task to criterion and then implanted dual cannulas aimed at the bilaterally symmetrical areas in the intralaminar nuclei. Rats in experiment 2 were also given a unilateral olfactory tubercle lesion. The results of experiment 1 showed dose-dependent impairments for bilateral infusions that were qualitatively similar, although of lesser severity than delayed matching impairments observed in previous studies for rats with lesions involving extensive areas of the intralaminar nuclei. A comparable impairment was observed in experiment 2 when thalamus was inactivated on the side opposite the olfactory tubercle lesion. Performances were significantly worse when thalamus was inactivated on the contra-lesion than on the ipsi-lesion side of the brain. These results are discussed in terms of the role of ventral striatum and related thalamic nuclei in memory.

A comparison of the effects of hippocampal or prefrontal cortical lesions on three versions of delayed non-matching-to-sample based on positional or spatial cues.

We trained rats to perform one of three versions of delayed non-matching-to-sample (DNMS): DNMS between two retractable levers in an enclosed operant chamber; varying-choice DNMS between two arms selected at random on every trial in an uncovered eight-arm radial arm maze; or recurring-choice DNMS between the same two arms on every trial in a covered radial maze (N=33/task). Rats with medial prefrontal cortical lesions showed delay-independent impairments on the retractable lever and recurring-choice tasks, but performed varying-choice DNMS normally. Rats with hippocampal lesions exhibited delay-independent impairments of the retractable lever task and delay-dependent impairments of both radial maze tasks. When rats trained initially to perform recurring choice DNMS were switched to varying choice DNMS, the impairments of both the prefrontal and hippocampal groups were reduced, although hippocampal animals remained significantly impaired. When rats trained initially to perform varying choice DNMS were switched to recurring choice DNMS, the impairment of the hippocampal group was exacerbated while the prefrontal group remained unimpaired. Thus training the prefrontal group to perform the varying choice task first seemed to protect from impairment when these rats were subsequently trained to perform recurring choice DNMS. This protection provides evidence against the possibility that factors related to proactive interference or to temporal discrimination can account for the effects of prefrontal lesions on delayed conditional discriminations involving two response alternatives in fixed locations.

Effects of chlordiazepoxide and FG 7142 on a rat model of diencephalic amnesia as measured by delayed-matching-to-sample performance.

The intralaminar thalamic nuclei (ILn) have been implicated as a critical site of pathology in amnesia. Lesions of the ILn have been found to produce behavioral effects comparable to benzodiazepine (BDZ) receptor agonists. We compared the effects of chlordiazepoxide (CDP), a BDZ agonist, and FG 7142, a partial inverse agonist at the BDZ receptor, in rats with thalamic lesions and in unlesioned controls. Delayed matching-to sample (DMS) performances were studied during treatment with ascending doses of CDP, counterbalanced trials with 2.5 mg/kg CDP and saline, ascending doses of FG 7142, and (for unlesioned controls only) counterbalanced trials with saline and higher doses of CDP. CDP had effects similar to the ILn lesion, decreasing response speed and percent correct responding in a delay-independent fashion. These effects were additive with the impairments associated with the ILn lesion. The effects of FG 7142 were more complex. At lower doses, it increased response speed without affecting response accuracy. At higher doses, it diminished both the speed and the accuracy of DMS responding. These results support the hypothesis that ILn lesions and BDZ agonists have similar effects on DMS performance. The biphasic effects observed for FG 7142 are consistent with other evidence that low doses of this drug enhance while higher doses impair memory performance. Although DMS accuracy was not improved, the enhancement observed for response speed provides evidence that partial inverse BDZ agonists have potential utility as treatments for cognitive impairments associated with amnesia.

Lesions of the frontal cortex, hippocampus, and intralaminar thalamic nuclei have distinct effects on remembering in rats.

Lesions of the intralaminar thalamic nuclei (ILn), the medial wall (MW) area of prefrontal cortex, and the hippocampus were compared and found to have distinct effects on delayed matching-to-sample (DMS) and delayed non-matching-to-sample (DNMS) tasks based on different types of stimulus cues. Hippocampal lesions impaired DNMS trained in a radial arm maze but had little effect on DMS trained with retractable levers or olfactory DNMS. MW lesions affected the DMS task but had limited effects on olfactory DNMS and radial arm maze DNMS. ILn lesions resulted in a more generalized pattern of impairment for radial maze tasks and (in previous studies) for the DMS and olfactory DNMS tasks. Only the hippocampal lesion was associated with a delay-dependent impairment. It is argued that ILn lesions disrupt remembering through their effects on the recurrent, feedback pathways that link functionally related areas of the basal ganglia and cortex.

Effects of thalamic and olfactory cortical lesions on continuous olfactory delayed nonmatching-to-sample and olfactory discrimination in rats (Rattus norvegicus).

We conducted 2 studies to determine the importance of several brain systems for remembering odorants in a go/no-go delayed nonmatching-to-sample (DNMTS) task. In Experiment 1, impairments were observed for lesions of pyriform cortex or (to a lesser extent) the lateral internal medullary lamina of thalamus. Lesions of the entorhinal cortex or the mediodorsal (MDn) or the paracentral and centrolateral (PC-CL) thalamic nuclei did not affect DNMTS. In Experiment 2, an impairment comparable to the pyriform lesion was observed for a lesion of the intralaminar nuclei (PC-CL plus the central medial nucleus) but not for a larger lesion of MDn. None of the lesions in either study affected the ability to learn a 2-choice odor discrimination using go/no-go procedures comparable with the DNMTS task.

Thalamic amnesia reconsidered: excitotoxic lesions of the intralaminar nuclei, but not the mediodorsal nucleus, disrupt place delayed matching-to-sample performance in rats (Rattus norvegicus).

Rats with large thalamic lesions affecting the mediodorsal (MDn) and intralaminar (ILn) nuclei are impaired performing delayed matching to sample tasks (DMTS). To determine the neurological basis of this deficit, we trained rats to perform a place DMTS task and then compared the effects of excitotoxic lesions of the MDn, the ILn, and the lateral internal medullary lamina (L-IML). The MDn lesion had little effect. The ILn group was significantly impaired throughout 8 months of training. The L-IML group exhibited an intermediate level of impairment. Varying the sample response requirement, retention intervals, and trial-to-trial congruence in the side reinforced, had predicted effects, as did variations in response latency. However, none of these factors interacted with the treatment effects. These findings indicate that DMTS performance is disrupted by lesions of the ILn but not the MDn.

The effects of frontal cortical lesions on remembering depend on the procedural demands of tasks performed in the radial arm maze.

We trained 24 rats to perform an eight-arm radial maze task and then assigned them with a matching procedure to one of three treatments: sham surgery or lesions of the projection areas of the mediodorsal thalamic nucleus (MDn) in the medial wall (MW) or in both the MW and rhinal sulcal (RS) areas of frontal cortex. After recovery we trained the rats to perform six tasks, beginning with the standard eight-arm task, followed by two versions of a four forced choice procedure, and then three versions of a two-choice delayed-nonmatching-to-sample (DNMTS) task. The two lesion groups performed comparably on all tasks, showing that impairments were not exacerbated by extension of the MW lesion to include all cortical areas innervated by MDn. As in previous studies, frontal animals performed the radial maze task poorly immediately after surgery but improved with subsequent training. Controlling the order of the arm entries by opening the first four gates in a random sequence had little effect on performance, although frontal animals were impaired when lengthy delays (5 or 15 min) were imposed after the last of the four forced entries. Frontal animals were not impaired on two-choice DNMTS when the arms used for training were selected at random from the eight alternatives on a trial by trial basis, even when visual cues were eliminated by darkening the room and covering the maze. Frontal animals were significantly impaired when the selection of sample and choice arms was limited to the same two alternatives on every trial. This finding may explain the reported sensitivity of DNMTS to the effects of frontal lesions when training is carried out in operant chambers.

A comparison of temporal decay in place memory tasks in rats (Rattus norvegicus) with lesions affecting thalamus, frontal cortex, or the hippocampal system.

Three experiments compared the effects of lesioning areas of thalamus, cortex, and the hippocampal system on delayed matching (DMTS) and nonmatching (DNMTS) to sample. Temporal decay was measured by comparing performances at different retention intervals (RIs) for rats trained to stability. Lesions of the lateral-internal medullary lamina site in thalamus and the medial wall area in frontal cortex produced impairments that were significantly greater than for lesions of the mediodorsal nucleus in thalamus, the fornix, or the dorsal hippocampus. The effects of lesions on temporal decay differed depending on how RIs were manipulated. When RIs were manipulated within training sessions, the DMTS and DNMTS impairments were delay independent (i.e., none of the lesions increased the rate of temporal decay). When RIs were manipulated between sessions, thalamic lesions were associated with an increase in the rate of temporal decay of DNMTS.

A comparison of the effects of frontal cortical and thalamic lesions on measures of spatial learning and memory in the rat.

Two experiments were conducted to compare the effects of radiofrequency lesions of thalamus and frontal cortex on three measures of spatial learning and memory: delayed non-matching to sample (DNMTS), radial arm maze with imposed delays, and serial reversal learning. Thalamic lesions were aimed at the lateral internal medullary lamina (L-IML) and cortical lesions at the projection areas of the mediodorsal nucleus along the medial wall (MW) and dorsal to the rhinal sulcus (RS) in frontal cortex. In Experiment 1 rats were trained on DNMTS prior to surgery. After recovery, rats with MW lesions showed persistent deficits on DNMTS that were significantly greater than for RS lesions. The deficits observed in MW lesioned animals were comparable to the effects of L-IML lesions on this task that have been described in previous studies. In Experiment 2 animals were trained to perform the radial arm maze task prior to treatment. After recovery, animals with L-IML lesions were impaired on the radial arm maze and on subsequent acquisition of the serial reversal task. Rats with RS and MW lesions showed transient impairments on the radial arm maze task, but otherwise performed as well as controls on both these tasks.

Comparison of the effects of frontal cortical and thalamic lesions on measures of olfactory learning and memory in the rat.

Rats were trained on an olfactory continuous delayed nonmatching-to-sample (DNMTS) task and then given 1 of 4 treatments: sham surgery or radio-frequency lesion of the lateral internal medullary lamina of the thalamus or of the frontal cortex along the medial wall or dorsal to the rhinal sulcus. Thalamic lesions produced persistent deficits on the continuous DNMTS task, and both the cortical lesions resulted in transient impairments that disappeared with continued training. Manipulations of stimulus set size and the delay between trials affected continuous DNMTS performance but did not exacerbate group differences. All 3 lesion groups performed normally when next trained on a discrimination task with odorants and go-no-go procedures comparable to continuous DNMTS. These results indicate that lesions did not affect ability to perform go-no-go procedures, to discriminate among odorants, or to use reference memory to respond on the basis of a fixed stimulus-response rule.

On the role of thalamic pathology in diencephalic amnesia.

Although it is now accepted that medial diencephalic lesions can produce severe amnesia in humans, the specific nuclei and neural pathways that must be damaged to impair memory have not yet been identified. Recent studies have shown that pyrithiamine-induced thiamine deficiency (PTD) in the rat can produce a consistent pattern of pathology in the thalamus and mammillary bodies and result in permanent impairments on behavioral measures of working memory. Behavioral deficits comparable to the PTD model have been observed in rats with thalamic lesions involving lateral portions of the internal medullary lamina (the L-IML site). Such impairments are not observed following lesions of limbic-related pathways associated with the fornix, mammillary bodies, or midline thalamus. The L-IML lesion affects the mediodorsal nucleus (MDn) and both the intralaminar and paralaminar non-specific thalamic nuclei. The relationship between the non-specific thalamic nuclei and working memory is underscored by the limited behavioral effects of MDn lesions, as compared to either L-IML or PTD-induced lesions, and by anatomical analyses of PTD-related pathology, which seems to destroy the non-specific nuclei while sparing large portions of the MDn. Recent physiological studies of thalamocortical processes suggest that there are several possible mechanisms by which the non-specific nuclei might participate in memory and by which lesions in these pathways might interfere with the consolidation of memories within the cortex.

MK-801 prevents brain lesions and delayed-nonmatching-to-sample deficits produced by pyrithiamine-induced encephalopathy in rats.

Rats were trained on a spatial delayed-nonmatching-to-sample (DNMTS) task and assigned by block randomization to one of four treatments: pyrithiamine-induced thiamine deficiency (PTD), PTD with administration of MK-801 after 12 days, control with MK-801 treatment, and control without MK-801. After 15 days of treatment followed by 21 days of recovery, the PTD rats showed significant deficits for DNMTS accuracy at retention intervals (RI) that ranged from 3.0 s to 15.0 s, the RIs that produced 75% accuracy on DNMTS in staircase training, and the rate at which a novel radial arm maze task was learned. The PTD-treated rats had consistent lesions in the thalamus and the mammillary bodies. MK-801 protected rats from both behavioral deficits and brain lesions (assessed quantitatively and qualitatively) that were produced by the PTD treatment.

Radio-frequency lesions of the thalamus produce delayed-nonmatching-to-sample impairments comparable to pyrithiamine-induced encephalopathy in rats.

Rats were trained and matched on a delayed-nonmatching-to-sample (DNMTS) task and randomly assigned to treatment. In Experiment 1, radio-frequency (RF) lesions were aimed at lateral portions of the internal medullary lamina (L-IML), midline thalamus (MT), mammillary bodies (MB), and the combination of MT and MB. In Experiment 2, RF lesions were aimed at the fornix. After recovery, DNMTS was retrained at retention intervals retention interval of 3.0-18.0 s, the critical retention interval for 75% DNMTS accuracy was determined by a staircase procedure, and spontaneous exploration was observed in an open field. L-IML lesions produced significant deficits on DNMTS and exploratory behavior that were comparable to deficits on the same tasks in rats recovered from pyrithiamine-induced thiamine deficiency. Fornix lesions produced significant DNMTS deficits that were substantially smaller than for the L-IML group. The MT, MB, and MT+MB treatments had no significant effect on DNMTS.

Depletion of cortical norepinephrine in rats by 6-hydroxydopamine does not impair performance of a delayed-nonmatching-to-sample task.

Rats were trained on a spatial delayed-nonmatching-to-sample (DNMTS) task, matched for performance, and randomly assigned to treatment with dorsal noradrenergic bundle injections of either 6-hydroxydopamine, to deplete cortical norepinephrine (NE), or vehicle, to control for the effects of surgery. After recovery, there were no significant differences between the groups when retrained on the DNMTS task at retention intervals (RI) from 0.1 to 15.0 s. Furthermore, no differences were observed when rats were trained at a 6.0-s RI filled with distracting stimuli or when dummy information runs were added to increase proactive interference. These results demonstrate that depletion of cortical NE cannot account for the DNMTS performance deficits observed in rats recovered from pyrithiamine-induced thiamine deficiency (Knoth & Mair, 1991; Robinson & Mair, 1992).

Diencephalic lesions, learning impairments, and intact retrograde memory following acute thiamine deficiency in the rat.

Previous studies have shown that following an acute bout of pyrithiamine-induced thiamine deficiency (PTD) rats are impaired in learning appetitively and aversively motivated T-maze tasks. The present study examined if PTD-treated rats exhibit both anterograde and retrograde memory loss of an aversively motivated spatial navigation task. Histological examination revealed two consistent lesions in the PTD treated rats: a bilateral, symmetrical destruction of medial thalamus centered on the internal medullary lamina (IML), and a lesion of the medial nucleus of the mammillary body. In Experiment 1, control and recovered PTD rats were trained to find a hidden platform in a Morris water maze. PTD rats with the IML lesion were impaired in learning the water maze task but were eventually able to perform as well as controls and PTD animals without the IML lesion. In Experiment 2, half of the pretrained CT animals underwent thiamine deficiency (PTD2), were recovered, and subsequently were tested for retention of the platform location. The remaining CT animals and the PTD1 group were also tested for retention. No significant group differences were observed on any of the four postretention trials. When compared to their performance on the last four preretention trials, the performance of PTD1 and PTD2 animals with IML lesions were similar to those of the controls. These results demonstrate that acute thiamine deficiency in rats produces damage of medial thalamic and mammillary body nuclei, a mild anterograde learning deficit, but no loss of retrograde memory of the Morris water maze task.

Analysis of aversively conditioned learning and memory in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were trained on tasks motivated by escape from mild footshock. On postmortem examination, the PTD model showed two consistent lesions: a bilaterally symmetrical lesion of the medial thalamus, which was centered on the internal medullary lamina (IML), and a lesion centered on the medial mammillary nuclei. PTD rats with IML lesions were impaired in learning a spatial nonmatching-to-sample (NMTS) task that was mastered without error by controls and PTD animals without IML lesions. These same animals were able to perform as well as controls on discrimination tasks based on either place or visual (light-dark) cues, although they made more errors than controls in reaching criterion in the initial place discrimination problem. These findings are consistent with findings from appetitively motivated tasks that PTD rats with IML lesions have an impaired capacity for working memory but not for reference memory.

Impairment of olfactory, auditory, and spatial serial reversal learning in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were compared with controls for spatial, auditory, and olfactory serial reversal learning (SRL); spatial matching to sample (MTS); auditory go-no-go discrimination; and open-field exploration. PTD rats made more errors reaching criterion for SRL in all modalities but showed normal transfer effects between problems. PTD rats were also impaired in learning the go-no-go and MTS tasks and showed consistent alterations in exploratory activity. It is argued that the PTD rat, like human Korsakoff patients, have impairments of learning and memory (but spared capacity for reference memory) that extend across sensory modalities. Postmortem analyses showed normal indices of cortical cholinergic, noradrenergic, dopaminergic, and serotonergic function and consistent bilateral lesions of the thalamus, which were centered on the internal medullary lamina, and the medial mammillary nucleus.