Role of the hippocampal system in associative learning beyond the spatial domain.

Expert opinion remains divided on the issue of whether the hippocampal system functions exclusively in spatial information processing, e.g. in navigation or in understanding spatial relations, or whether it plays a more general role in higher brain function. Previous work on monkeys and rats has tended to support the former view, whereas observations in the clinic point to the latter, including functions as diverse as declarative knowledge, episodic memory, word learning, and understanding relations among objects. One influential theory posits a general role for the hippocampal system in associative learning, with emphasis on associations learned rapidly and recently. The results presented here are consistent with this theory, along with previous clinical and theoretical studies indicating that the hippocampal system is necessary for associative learning even if no component of the association relies on spatial information. In the study reported here, rhesus monkeys learned a series of conditional stimulus-response associations involving complex visual stimuli presented on a video monitor. Each stimulus instructed one of three responses: tapping the stimulus with the hand, steady hand contact with the stimulus for a brief period of time, or steady contact for a longer time. Fornix transection impaired the learning of these associations, even though both the stimuli and the responses were nonspatially differentiated, and this deficit persisted for at least 2 years. This finding indicates that the hippocampal system plays an important role in associative learning regardless of the relevance of spatial information to any aspect of the association. Fornix-transected monkeys were impaired in learning new stimulus-response associations even when the stimuli were highly familiar. Thus, the deficit was one of associating each stimulus with a response, as opposed to problems in distinguishing the stimuli from each other. In contrast to these effects, fornix transection did not impair performance when familiar stimuli instructed a response according to an already-learned association, which shows that the deficit was one of learning new associations rather than one of retention or retrieval of previously learned ones. Taken together, these results show that fornix transection causes a long-lasting impairment in associative learning outside of the spatial domain, in a manner consistent with theories of hippocampal-system function that stress a general role in the rapid acquisition of associative knowledge.

The effect of excitotoxic lesions of the pedunculopontine tegmental nucleus on performance of a progressive ratio schedule of reinforcement.

The pedunculopontine tegmental nucleus has connections with sites in both dorsal and ventral striatum, and a number of studies have suggested that it has a role in reward-related behaviour. The present experiment aimed to investigate the perception of reward in pedunculopontine tegmental nucleus-lesioned rats responding for food under a progressive ratio schedule, which measures willingness to work for a given reward. Rats were trained on a progressive ratio-5 schedule for food reward, then given ibotenic acid or sham lesions of the pedunculopontine tegmental nucleus. Their performance under this schedule was examined again following recovery from surgery. Compared with sham-lesioned rats, those with lesions of the pedunculopontine tegmental nucleus showed significantly reduced breaking points and significantly longer post-reinforcement pauses. However, there was no difference between the groups in their latency to collect food pellets once earned, suggesting that pedunculopontine tegmental nucleus excitotoxin and sham-lesioned rats were equally motivated by the presence of food. Excitotoxin-lesioned rats made significantly more responses on the control lever and more entries to the food hopper as progressive ratio increment increased, but did not differ from controls when the schedule requirement was low. These results are interpreted as indicating no global loss of motivation, since lesioned rats performed normally at low schedule requirements, and were as fast as controls to collect pellets. But as the schedule requirement increased, excitotoxin-lesioned rats showed reductions in responding on the active lever (that is, a reduction in breaking point) and an increase in inappropriate responses towards the food hopper and the control lever.We consider these data to indicate that the behavioural deficits in pedunculopontine-lesioned rats arise not from a sensory or hedonic change, but from alteration in the control of motor output.

The morphology, integration, and functional efficacy of striatal grafts differ between cell suspensions and tissue pieces.

In order to develop a surgical protocol for use in clinical trials of striatal transplantation in Huntington's disease (HD), the issues involved in the preparation and implantation of the embryonic striatal tissue must be addressed. Rodent models of HD offer the best experimental paradigm with which to study various aspects of striatal transplantation. In this article we present the results of an investigation of the role of trypsin and the process of trituration in the preparation of cell suspensions compared to the use of solid pieces of tissue. The embryonic material was derived from the lateral ganglionic eminence (LGE) and implanted into the excitotoxically lesioned striatum of the host rats. Twelve weeks following implantation, retrograde tracing of projections from the graft to the globus pallidus was performed. Grafts derived from cell suspensions triturated in the presence of trypsin contained larger quantities of striatal tissue within the graft and more DARPP-32-positive medium spiny neurons than grafts implanted as fragments of tissue. Afferent and efferent connectivity was also better in the trypsinized suspension graft group. Modest recovery in paw reaching was observed contralateral to the grafted side in animals implanted with solid fragments of embryonic striatal tissue. No relationship was observed between functional effect and the graft anatomy. These results suggest that local graft host interaction may also be involved in graft-mediated functional recovery.

Behavioral recovery after transplantation into a rat model of Huntington's disease: dependence on anatomical connectivity and extensive postoperative training.

Rats were trained to perform a conditioned stimulus-response task known to be sensitive to striatal damage, after which they received unilateral excitotoxic striatal lesions. The subsequent implantation of graft tissue into the lesioned striatum was either immediate (9 days) or substantially delayed (70 days). When retested 14 weeks later, all graft and lesion rats were equally impaired initially and biased their responding toward the ipsilateral side. Graft-associated recovery was evident with repeated postoperative testing, but only in rats that had received transplants 9 days postlesion. It is suggested that this training-dependent, graft-associated recovery is mediated specifically by the restored host-graft connections.

Unilateral lesions of the medial agranular cortex impair responding on a lateralised reaction time task.

The present study assessed the behavioural sequalae of unilateral excitotoxic cortical lesions made either in the medial agranular cortex (AGm) or in the medial prefrontal cortex (mPFC) using a visual reaction time task. The task required animals to sustain a nose-poke in a central hole, until a brief light stimulus was presented in either of two holes which were located on the same side of the box: this enabled performance on each side of the rat's body to be assessed independently. Lesions of the AGm impaired performance on the contralateral side, with rats biasing their responding to the nearer of the two response locations. Analysis of the deficit revealed that rats were able to discriminate between the two stimuli and suggested that AGm lesions disrupted the control of contralateral responding. Lesions of the mPFC produced similar response-related deficits, but these were more transient in nature. Neither AGm lesions nor mPFC lesions impaired performance on the ipsilateral side, consistent with the concept of an egocentrically coded deficit.

Embryonic donor age and dissection influences striatal graft development and functional integration in a rodent model of Huntington's disease.

The method of embryonic dissection and the age of the donor material remain areas of controversy in the preparation of striatal tissue for intrastriatal implantation. This study explores the relationship between these two parameters with respect to the morphology, function, and physiological integration of the resultant grafts. Tissue derived from embryos of 14 and 16 days of gestation (CRL 10-11 and 14-15 mm, respectively) was prepared as whole, lateral, and medial ganglionic eminence suspensions (WGE, LGE, and MGE, respectively). The embryonic material was implanted into the excitotoxically lesioned striatum of host rats. Grafts derived from E14 LGE attenuated drug-induced rotational bias whereas grafts from E14 MGE ameliorated contralateral deficits in paw reaching. Six months after grafting retrograde tracing of graft projections to the globus pallidus was performed followed by electrical excitation of cortical afferent fibers. Grafts derived from E14 WGE had the largest volume of striatum-like tissue and more striatal neurons compared to LGE from the same donor age. These results suggest that MGE tissue as well as LGE plays a role in the structural and functional integration of striatal grafts.

Medial prefrontal and neostriatal lesions disrupt performance in an operant delayed alternation task in rats.

An operant version of the classical delayed alternation task is presented and applied to evaluate the effects of bilateral prefrontal and striatal lesions in rats. Retractable levers in a conventional operant chamber control discrete trial opportunities for making sequential choice responses to the two sides, and the rats are required to maintain repeated nose poke responses to a central panel during the delay interval, which is randomly varied. The operant task provides measures of the speed and accuracy of response alternation and side bias; analysis at different delay intervals provides an index of the memory demands of accurate performance; and analysis of accuracy depending on the response on preceding trials provides measures of proactive interference and perseveration. Following pretraining in the task contingencies, both striatal and prefrontal lesions induced profound deficits in task accuracy, with no change in side bias and only small changes in movement times. The deficit in the prefrontal lesion group recovered more rapidly, neither group showed any change in sensitivity to proactive interference, while the rats with striatal lesions alone exhibited an increased tendency to perseverate incorrect responses on either side. We conclude that the operant delayed alternation task should assist analysis of fronto-striatal function in rats as well as be useful for the analysis of strategies for fronto-striatal repair.

Behavioural recovery following striatal transplantation: effects of postoperative training and P-zone volume.

Rats were trained on an operant task and then received striatal lesions and grafts. Grafts were derived either from whole-ganglionic eminences or restricted to the lateral eminence. When retested 4 months later; graft-associated behavioural recovery was only apparent with extensive retesting. There was no difference in performance between rats that received whole-dissection or lateral-dissection grafts, and no correlation between performance and the amount of striatal-like (P-zone) tissue within the graft. It is suggested that P-zone reconstruction may be necessary, but not sufficient for behavioural recovery, which may additionally depend upon rehabilitative training.

Associative plasticity in striatal transplants.

Striatal lesions disrupt both motor and cognitive performance in rats, many aspects of which can be restored by striatal transplants. Because the normal striatum is involved in the formation and maintenance of motor habits, it has been hypothesized that grafted animals may require explicit retraining to relearn previously established habits that have been disrupted by the lesions. We have used a lateralized-discrimination task to reproduce this "learning to use the transplant" effect, combined with a transfer-of-training paradigm to demonstrate that recovery requires relearning specific lateralized stimulus-response associations and cannot be explained simply by a generalized training-dependent improvement in motor skill. These results have clear implications for developing appropriate strategies for the rehabilitation of Huntington's disease patients participating in clinical transplantation programs.

Distinct roles for striatal subregions in mediating response processing revealed by focal excitotoxic lesions.

This study examined the relative roles of distinct striatal areas in response processing. Rats were trained on a reaction time task that enabled performance on each side of the rat's body to be assessed independently. Rats then received unilateral lesions of the whole dorsal striatum or restricted medial or lateral lesions. Both medial and lateral lesions induced a response bias in contralateral space, but this bias was less severe in rats with medial lesions. Medial striatal lesions led to an increase in premature responses. Lateral striatal lesions produced an increase in late responses. It is suggested that the lateral striatum mediates the selection of responses, and the medial striatum acts to influence inhibitory control over responding. Discrete striatal areas are thus functionally dissociable, but both have a crucial role in the organization of responding in space.

Striatal lesions produce distinctive impairments in reaction time performance in two different operant chambers.

The dorsal striatum plays a crucial role in mediating voluntary movement. Excitotoxic striatal lesions in rats have previously been shown to impair the initiation but not the execution of movement in a choice reaction time task in an automated lateralised nose-poke apparatus (the "nine-hole box"). Conversely, when a conceptually similar reaction time task has been applied in a conventional operant chamber (or "Skinner box"), striatal lesions have been seen to impair the execution rather than the initiation of the lateralised movement. The present study was undertaken to compare directly these two results by training the same group of rats to perform a choice reaction time task in the two chambers and then comparing the effects of a unilateral excitotoxic striatal lesion in both chambers in parallel. Particular attention was paid to adopting similar parameters and contingencies in the control of the task in the two test chambers. After striatal lesions, the rats showed predominantly contralateral impairments in both tasks. However, they showed a deficit in reaction time in the nine-hole box but an apparent deficit in response execution in the Skinner box. This finding confirms the previous studies and indicates that differences in outcome are not simply attributable to procedural differences in the lesions, training conditions or tasks parameters. Rather, the pattern of reaction time deficit after striatal lesions depends critically on the apparatus used and the precise response requirements for each task.

Unilateral lesions of the dorsal striatum in rats disrupt responding in egocentric space.

Rats were trained in a specially designed, multichoice operant chamber on a visual choice reaction time task designed to assess performance on each side of the rat's body. The task required animals to sustain a nose poke in a central hole, until a brief light stimulus was presented in either of two holes that were located on the same side of the box. Once the rats were trained to perform the task to both sides independently they received unilateral injections of quinolinic acid into the dorsal striatum. Postoperatively, lesioned animals were impaired when performing the task on the side contralateral to the lesion. The time taken to initiate contralateral responses was increased. Contralateral responses were also exclusively biased toward the nearer of the two response locations, regardless of the location of the stimulus. This was interpreted as a specific impairment in generating responses in contralateral space. In contrast, no comparable deficit was seen when the animals performed the task on the side ipsilateral to the lesion. Additional postoperative challenges, in which response options were presented bilaterally, showed this response deficit to be defined in egocentric coordinates, with the severest response deficits for the most contralateral locations.

The effect of systemic d-amphetamine on motor versus motivational processes in the rat.

This study examined the effects of systemic amphetamine in rats performing a reaction time task in which motivation and motor readiness were independently varied. Visual cues indicated the number of trials (one, two or three) needed before reinforcement was made available (i.e., reward cost). Lower reward cost was reflected in both a greater proportion of correctly completed trials and faster reaction times. Reaction times were also shorter as a function of increasing time from start of trial to the onset of the imperative stimulus (foreperiod), reflecting motor readiness or temporal probability summation. It was found that increasing dose of amphetamine resulted in faster reaction times, but the manner in which reaction time was speeded more closely resembled that of motor readiness than it did the speeding due to increasing motivation. Furthermore, the effects on performance of amphetamine and motivational condition were found to be entirely independent: there was no evidence to suggest that amphetamine enhanced, or disrupted, the expectation of forthcoming work or the response vigor which this engenders. It is concluded that systemic amphetamine does not act simply to amplify a natural reward signal. By contrast, amphetamine was found to enhance the effect of foreperiod, suggestive of a mechanism for the psychomotor stimulating effects of amphetamine.