Effects Of Bilateral Excitotoxic Lesions Research Articles

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse.

The anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex as in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a state-dependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects. We investigated in outbred rats the effects of bilateral excitotoxic lesions of AIC induced both prior to or after long-term exposure to extended access heroin self-administration, on the development and maintenance of escalated heroin intake and the subsequent vulnerability to relapse following abstinence. Compared to sham surgeries, pre-exposure AIC lesions had no effect on the development of loss of control over heroin intake, but lesions made after a history of escalated heroin intake potentiated escalation and also enhanced responding at relapse. These data show that the AIC inhibits or limits the loss of control over heroin intake and propensity to relapse, in marked contrast to its influence on the loss of control over cocaine intake.

The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning: Performance and extinction of Pavlovian fear-conditioned responses and instrumental avoidance responses

This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component of CARs depends on the DLS, NAc and DMS; (iii) although the NAc-co is also needed for learning the instrumental component, it is not clear whether it plays a role in learning the instrumental component per se or if it simply allows learning of the Pavlovian component which is a pre-condition for learning the instrumental component; (iv) we did not find evidence that the DMS and DLS play the same roles in habit and goal-directed aspects of the instrumental component of CARs as observed in appetitive motivated instrumental responding.

Hippocampal lesions impair performance on a conditional delayed matching and non-matching to position task in the rat

The hippocampus is thought to be involved in a range of cognitive processes, from the ability to acquire new memories, to the ability to learn about spatial relationships. Humans and monkeys with damage to the hippocampus are typically impaired on delayed matching to sample tasks, of which the operant delayed matching to position task (DMTP) is a rat analogue. The reported effects of hippocampal damage on DMTP vary, ranging from delay-dependent deficits to no deficit whatsoever. The present study investigates a novel memory task; the conditional delayed matching/non-matching to position task (CDM/NMTP) in the Skinner box. CDM/NMTP uses the presence of specific stimulus cues to signify whether a particular trial is matching or non-matching in nature. Thus, it incorporates both the task contingencies within one session, and supplements the requirement for remembering the side of the lever in the sample phase with attending to the stimulus and remembering the conditional discrimination for the rule. Rats were trained preoperatively and the effects of bilateral excitotoxic lesions of the hippocampus were examined on postoperative retention of the task. Rats with lesions of the hippocampus incurred a significant impairment on the task that was manifest at all delays intervals. Despite a bias towards matching during training, trials of either type were performed with equivalent accuracy and neither rule was affected differentially by the lesion. This task may prove useful in determining the cognitive roles of a range of brain areas.

Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity

It is becoming increasingly apparent that multiple functions of the frontal cortex such as inhibitory control and executive attention are likely sustained by its functionally distinct and interacting sub-regions but the precise localization of dissociable executive processes has proved difficult and controversial. In the present series of studies, we investigated the behavioural effects of bilateral excitotoxic lesions of different regions of the rat neocortex in the 5-choice serial reaction time task. Whereas lesions of the dorsal anterior cingulate cortex (ACC) impaired performance of the task as revealed by a reduction in discriminative accuracy, lesions made to distinct ventral regions of the frontal cortex showed selective deficits in inhibitory measures of control. Specifically, the infralimbic lesion produced increases in premature responding that was accompanied by fast response latencies. By comparison, the orbitofrontal lesion showed perseverative tendencies particularly when the inter-trial interval was made long and unpredictable, a challenge that would normally promote premature responding instead. These different behavioural effects following dorsal and ventral lesions of the rodent frontal cortex signifies the integrity of the frontal cortex in multiple executive mechanisms that work independently and complementarily by which performance is optimized. Furthermore, these data provide new insights into the functional organization of the rodent frontal cortex with a particular emphasis on localization of function.

An examination of the effects of bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on responding to sucrose reward

The effects of bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus (PPTg) on sucrose intake were examined in three experiments. First, in tests of conditioned place preference using 20% sucrose as the reinforcer, it was shown that lesioned rats, regardless of whether they were food deprived or non-deprived, formed normal place preferences and showed normal amounts of locomotion. However, consumption of 20% sucrose in the pairing trials was increased in the deprived PPTg lesioned rats compared to their matched controls. A second experiment showed that sucrose consumption in the home cage was increased in both deprived and non-deprived PPTg lesioned rats, but only when the concentration of sucrose was greater than 12%: below this there were no differences in intake between the lesioned and control rats. In a third home cage experiment, it was again shown that non-deprived PPTg lesioned rats increased their consumption of 20% sucrose compared to controls. PPTg lesioned rats concomitantly reduced their intake of lab chow such that overall energy intake remained the same as that of control rats. These data are taken to suggest (i) that bilateral excitotoxic lesions of the PPTg increase consumption of sucrose selectively in conditions of high motivational excitement; (ii) that the perception of the rewarding value of 20% sucrose, as judged by place preference, is not affected by these lesions; and (iii) that PPTg lesioned rats are able to adjust their energy intake to accommodate increased sucrose loads. These data are consistent with the hypothesis that bilateral excitotoxic lesions of the PPTg do not affect energy balance regulation or judgment of the hedonic value of sucrose, but that they do affect the control of responding in the face of high levels of motivational excitement.

The cerebellum and cognition: cerebellar lesions impair sequence learning but not conditional visuomotor learning in monkeys

Claims that the cerebellum contributes to cognitive processing in humans have arisen from both functional neuroimaging and patient studies. These claims challenge traditional theories of cerebellar function that ascribe motor functions to this structure. We trained monkeys to perform both a visuomotor conditional associative learning task and a visually guided sequence task, and studied the effects of bilateral excitotoxic lesions in the lateral cerebellar nuclei. In the first experiment three operated monkeys showed a small impairment in post-operative retention of a visuomotor associative task (A) but were then not impaired in learning a new task (B). However, the impairment on A could have been due to a problem in making the movements themselves. In a second experiment we therefore gave the three control animals a further pre-operative retest on both A and B and then tested after surgery on retention of both tasks. Though again the animals showed motor problems on task A, they reached criterion, and at this stage could clearly make both movements satisfactorily. The critical test was then retention of task B, and they were not impaired. In the final experiment (serial reaction time task) the monkeys response times on a repeating visuomotor sequence were compared with those for a pseudo-random control sequence. After bilateral nuclei lesions they were slow to execute the pre-operatively learned sequence but were still faster on this than on the control task. However, when they were then given a new repeating sequence to learn, they never performed the sequence as quickly as they had on retention of the first sequence. We conclude that the cerebellum is not essential for the learning or recall of stimulus-response associations but that it is crucially involved in the process by which motor sequences become automatic with extended practice.

Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats.

Lesioning the subthalamic nucleus (STN) has been suggested as possible therapy for the treatment of parkinsonism. Previous experiments investigating this hypothesis in rats confirmed that excitotoxic STN lesions alleviate the motor impairment induced by striatal dopamine depletion, which reproduced the degeneration observed in parkinsonism, but elicited presumed non-motor deficits such as premature responding, suggesting that the STN could be involved in other aspects of response control. The aim of the present study was to extend this analysis to choice paradigms. We thus investigated the behavioural effects of bilateral excitotoxic lesions of the STN in rats performing a five-choice test of divided and sustained visual attention, modelled on the human continuous performance task. This task required the animals to detect a brief visual stimulus presented in one of five possible locations and respond by a nose-poke in this illuminated hole within a fixed delay, for food reinforcement. Bilateral lesions of the STN severely impaired several aspects of performance, including discriminative accuracy, but also increased premature, anticipatory responding as well as perseverative panel pushes and nose-poke responses. While increasing the stimulus duration and reducing the waiting period for the stimulus partially alleviated the accuracy deficit and the premature responding deficit respectively, other deficits, such as perseverative panel pushes and nose-poke responses, were sustained under these conditions. Systemic injection of the mixed dopaminergic D1/D2 receptor antagonist, alpha-flupenthixol (0.03-0.18 mg/kg), reduced premature responses and perseverative panel pushing without affecting the perseverative nose-poke responses, suggesting that some of the deficits were independent of striatal dopaminergic transmission. These results suggest that STN lesions have multiple, dissociable effects on attentional performance, including discriminative deficits, impulsivity and perseverative behaviour. They are consistent in part with a hypothesized role of the STN in recent models of basal ganglia function in action selection and inhibition. The results also show that other aspects of behaviour should be monitored when examining the capacity of STN lesions to reverse the parkinsonian deficit induced by striatal dopamine depletion.

Effects of subthalamic nucleus lesions in a putative model of tardive dyskinesia in the rat.

The effects of bilateral excitotoxic lesions of the subthalamic nucleus on vacuous chewing movements induced by chronic neuroleptic therapy were examined in the rat. Fluphenazine decanoate (25 mg/kg i.m.q 3 weeks x 24 weeks) induced vacuous chewing movements, as previously described. This response was suppressed to control levels in animals tested 1-3 weeks following bilateral infusion of quinolinic acid (100 nmol/1 microliter per side) into the subthalamic nucleus. Subthalamic nucleus lesions resulted in increased locomotion and sniffing in neuroleptic-naive animals, but these responses were suppressed by concomitant neuroleptic treatment. As vacuous chewing movements induced by chronic neuroleptics are considered to be analogous to tardive dyskinesia in humans, our findings lend further support to the importance of the subthalamic nucleus in the regulation of orofacial movements and suggest that tardive dyskinesia may, in part, be related to altered activity in this structure. This, in turn, suggests that current models of basal ganglia function are inadequate to account for certain pathological states and require re-examination.

The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task.

Dissociable effects of bilateral excitotoxic lesions of different regions of the rat neocortex, including medial prefrontal and anterior cingulate cortices, were investigated in a five-choice serial reaction time task that provides several indices of the accuracy and speed of attentional function. Whereas medial prefrontal cortical lesions impaired performance of the task as revealed by a reduction in choice accuracy, an increase in the latency to respond correctly to the visual target and enhanced perseverative responding, lesions of the anterior cingulate cortex specifically increased premature responding. By contrast, lateral frontal cortical lesions did not significantly disrupt baseline performance of the task, but rather increased the latency to respond correctly to the visual target during various behavioral manipulations, for example, when the length of the intertrial interval was varied unpredictably and during interpolation of distracting bursts of white noise. Lesions of the parietal cortex failed to disrupt any aspect of task performance investigated. These behavioral effects in the five-choice task were compared with the effect of these same lesions on acquisition and retention of a one-trial passive avoidance task. The main finding from this paradigm was that lesions of the lateral frontal cortex produced a significant disruption to the retention of passive avoidance, which stands in marked contrast to the successful retention observed by animals of the other lesion groups. In addition, this pattern of results reveals that the 'disinhibitory' effect of cingulate cortex lesions are relatively specific to the five-choice attentional task. Finally, the results of the present study are compared with the findings of previous experiments using the five-choice task, which have examined the effect of selective manipulations of the ascending noradrenergic, cholinergic, dopaminergic, and serotonergic projections. In particular, the deficits in attentional function observed following cholinergic lesions of the nucleus basalis magnocellularis appear to be attributable to cholinergic denervation of the medial frontal cortex. These results are discussed in terms of the role of parallel distributed neural systems within the neocortex that mediate continuous attentional performance in the rat.

Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: implication for limbic-striatal interactions.

The effects of bilateral excitotoxic lesions of 3 major sources of afferents to the ventral striatum (nucleus accumbens) were compared on an open field test of food neophobia allowing the choice between familiar and novel food. Whereas lesions of the basolateral amygdala and ventral subiculum had qualitatively similar effects to reduce food neophobia (although not affecting the latency to eat), amygdala lesions increased and the ventral subiculum decreased locomotor activity. In contrast, damage to the ventromedial prelimbic prefrontal cortex only affected initial food choice and latency measures. By comparison, excitotoxic lesions of the nucleus accumbens itself and intra-accumbens infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 increased activity and attenuated food neophobia. Results are discussed in terms of the role of limbic and prefrontal neuronal networks converging in the nucleus accumbens to control different aspects of the behavioral response to novelty.

Pharmacological alleviation of cholinergic lesion induced memory deficits in rats

The cholinergic cells of the nucleus basalis of Meynert (nbM) have recently been found to degenerate in Alzheimer's disease and are thought to be at least partly responsible for the cognitive deficits which are characteristic of this disease. These experiments explored the behavioral effects of bilateral excitotoxic lesions of the nbM in adult rats. The first experiment showed that nbM lesions lead to a substantial deficit in the 24 hour retention of the habituation to a novel environment without affecting general exploratory behavior. The second experiment showed that this retention deficit is a general phenomenon reflected in the 72 hour retention of a one trial passive avoidance task. These retention deficits could be reversed by the postacquisition administration of the acetylcholinesterase inhibitor, physostigmine. These results support the hypothesis that central cholinergic systems are involved in the retention of learned responses, and suggest that cholinergic lesion induced retention deficits can be reversed by pharmacological means.