Biomedical subjects

T W Robbins

Publications and source records attributed to T W Robbins.

At least 271 records · Page 15Linked to original sources

PubMed1991

Simple and choice reaction time performance following unilateral striatal dopamine depletion in the rat. Impaired motor readiness but preserved response preparation.

Rats were trained to perform a visual spatial discrimination, where stimulus luminance provided information regarding the required direction of response. The visual stimuli were presented either in advance of a temporally unpredictable auditory imperative stimulus (simple reaction time condition) or simultaneously with the imperative stimulus (choice reaction time condition). Following unilateral striatal dopamine depletion, produced by intracerebral infusion of 6-hydroxydopamine, there was not only a marked spatial response bias towards the side of the dopamine depletion but also an abolition of the delay-dependent speeding of reaction time that reflects motor readiness, on the side contralateral to the lesion. Nevertheless, the rats continued to show a benefit in performance of the simple reaction time condition compared with the choice reaction time condition, indicating that they were able to use advance information to select and prepare responses. The results are discussed in the context of differential deficits shown by patients with Parkinson's disease in simple versus choice reaction time performance, and of the functions of parallel corticostriatal loops subserving the normal control of action.

Animals↗

PubMed1990

Damage to ceruleo-cortical noradrenergic projections impairs locally cued but enhances spatially cued water maze acquisition.

A series of 4 experiments tested the effects of central catecholamine depletion on acquisition of an escape response in a spatial water maze. In Expt. 1, local infusions of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DNAB) enhanced efficient acquisition of the spatial water maze in a stressful condition (cold water), but had no effect in warm water. In Expt. 2, lesions of the ventral noradrenergic bundle did not affect acquisition of the maze, indicating that the changes observed in Expt. 1 were unlikely to have been the result of incidental damage to the noradrenergic innervation of the hypothalamus. Measures of core body temperature and plasma corticosterone were taken in parallel with the behavioral experiments and revealed that central noradrenaline (NA) depletion did not alter these responses to cold or warm water swims. Expt. 3 revealed a contrasting pattern of effects following dopamine (DA) depletion from the caudate-putamen: swimming speed was reduced in warm, but not cold water and maze acquisition was impaired, to an equal extent in warm and cold water. Finally, in Expt. 4, rats with 6-OHDA lesions of the DNAB were impaired in discriminating local cues in a simultaneous visual discrimination water maze. These results support the hypothesis that ceruleo-cortical NA depletion broadens the span of attention, particularly under stressful circumstances. In contrast, the results also indicate that striatal DA depletion mainly affects vigour of responding, as measured by swim speed, and that this effect can be reversed by the stressful effects of cold water.

Amygdala↗

PubMed1990

Effects of dopamine depletion from the caudate-putamen and nucleus accumbens septi on the acquisition and performance of a conditional discrimination task.

Three experiments compared the effects of dopamine depletion from the caudate-putamen (CAUD; dorsal striatum) or nucleus accumbens septi (NAS; ventral striatum), or a systemically administered dopamine receptor antagonist (alpha-flupenthixol) on the acquisition and performance of a conditional discrimination task involving temporal frequency. In Expt. 1, rats receiving 6-hydroxydopamine (6-OHDA) lesions of the CAUD were impaired in the acquisition of a visual version of the task, and rats with 6-OHDA lesions of the NAS were not reliably impaired. Even when the rats with CAUD lesions had acquired the discrimination, they were still significantly slower to collect earned food pellets. Both CAUD and NAS lesions reduced a bias to respond to the faster of the two discriminative stimuli. In Expt. 2, rats with 6-OHDA lesions of CAUD were markedly impaired in their accuracy and speed of responding when they had been trained to criterion preoperatively. These effects could not be mimicked in controls by prefeeding (which had only minor effects on performance). Rats with 6-OHDA-induced lesions of the NAS were unimpaired in either visual or auditory discrimination performance, but were slower to extinguish responding than controls. In Expt. 3, alpha-flupenthixol (0.1-0.56 mg/kg, i.p.) produced dose-dependent impairments in both latency to respond and choice accuracy in visual and auditory versions of the task. In conjunction with other results, these data suggest that (1) dopamine receptor blockade and central dopamine depletion can impair discrimination performance under certain conditions (2) dopamine depletion from the ventral and dorsal striatum, respectively, have dissociable effects on behaviour controlled by conditioned reinforcers and discriminative stimuli and (3) the disruption of discrimination performance by dorsal striatal dopamine depletion is probably attributable to several factors.

Animals↗

PubMed1990

Increased sensitivity to amphetamine and reward-related stimuli following social isolation in rats: possible disruption of dopamine-dependent mechanisms of the nucleus accumbens.

These experiments compared isolation-reared and socially-reared rats in two complementary paradigms for measuring responding to signals of reward, both undrugged and following either systemic or intraaccumbens d-amphetamine (AMPH). In experiment 1, locomotor activity conditioned to food presentation was measured in rats exposed to a restricted feeding schedule. The interaction between this conditioned activity, AMPH administration (0.5, 2.0, 3.5, 5.0 mg/kg IP) and motivational state was measured. In experiment 2, hungry rats were trained to associate a compound light/noise stimulus with sucrose reward and were then implanted with guide cannulae in the nucleus accumbens. In the test phase, responding on one of two novel levers produced the compound stimulus (conditioned reinforcer; CR). Responses on the other lever had no effect. Each rat received four counterbalanced intra-accumbens infusions of AMPH (0, 3, 10, 20 micrograms). In both experiments, isolated rats responded more with stimuli associated with reward and this differential rearing effect was further exaggerated by AMPH. The isolation-induced sensitivity to these stimuli and to AMPH was critically dependent on motivational variables. Thus, in experiment 1 there were no differences between the groups when sated or during extinction and in experiment 2 the increased responding was restricted to the lever providing CR. Measurements of the locomotor response to intra-accumbens AMPH (0, 3, 10 micrograms) also revealed that isolated rats were more sensitive to a low dose of the drug when tested food-deprived in a relatively novel environment. These results suggest that the experience of isolation-rearing interacts either directly or indirectly with dopamine-dependent mechanisms of the nucleus accumbens to enhance the effects of reward-related stimuli.

Animals↗

PubMed1990

Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type.

Patients with dementia of the Alzheimer type (DAT) received two tests of visual selective attention, together with tests of spatial and visual recognition memory and visuospatial conditional learning previously used to show deficits early in the course of DAT. One set of attentional tests compared visual discrimination learning along intra- and extra-dimensional shifts, using a "total change" design. In the 12 DAT patients capable of attempting the extra-dimensional shift (subgroup 1), performance was equivalent to that of controls. This subgroup was also unimpaired at simple and compound discrimination learning and reversal and an intra-dimensional shift. They were as accurate as controls on a visual search task requiring matching of stimuli on two dimensions with variable numbers of alternatives, but were significantly impaired in the tests of recognition memory and learning. By contrast, the other 13 patients showed marked impairments in the attentional tasks. This subgroup was also significantly worse than subgroup 1 in performance on the visual recognition and conditional learning tasks, and showed greater severity on most of the clinical ratings of dementia. The sparing of attentional shifting in patients early in the course of DAT is contrasted with the impairments previously described in patients with Parkinson's disease with only mild or absent memory loss. The implications of this double dissociation of deficits for understanding the neural bases of the cognitive deficits in these two neurodegenerative diseases are discussed and their significance for the staging of DAT is considered.

Aged↗

PubMed1990

Planning and spatial working memory following frontal lobe lesions in man.

Twenty-six patients with unilateral or bilateral frontal lobe excisions were compared with age and IQ matched controls on a computerized battery of tests of spatial working memory and planning. A computerized test of spatial short term memory capacity revealed no significant impairment in the patients' ability to execute a given sequence of visuo-spatial moves. In contrast, a paradigm designed to assess spatial working memory capacity, revealed significant impairments in the patient group in both possible types of search errors. Furthermore, additional analysis showed that the frontal lobe patients were less efficient than controls in their usage of a strategy for improving performance on this test. Higher level planning was also investigated using a test based on the "Tower of London" problem [SHALLICE, T. Phil. Trans. R. Soc. Lond. B. 298, 199-209, 1982]. Patients with frontal lobe damage required more moves to complete the problems and a yoked motor control condition revealed that movement times were significantly increased in this group. Taking both of these factors into consideration, initial thinking (planning) time was unimpaired in the patient group although the thinking time subsequent to the first move was significantly prolonged. These data are compared to previous findings from patients with idiopathic Parkinson's disease and are discussed in terms of an impairment of higher cognitive functioning following frontal lobe damage.

Attention↗

PubMed1990

The effects of excitotoxic lesions of the basal forebrain on the acquisition, retention and serial reversal of visual discriminations in marmosets.

The effects of N-methyl-D-aspartate-induced lesions of the basal forebrain (which included the cholinergic cells of the nucleus basalis of Meynert) were studied on three aspects of visual discrimination; learning, retention and reversal performance, in the marmoset. Neurobiological investigations revealed that the lesion produced large reductions in choline acetyltransferase activity within anterior regions of cortex, particularly prefrontal. In Experiment 1 lesioned animals showed impaired retention, one week after surgery, of a visual discrimination learned immediately prior to surgery and subsequently showed impaired performance over a series of reversals. The reversal deficit could be characterized as a tendency to perseverate on the previously correct stimulus on the first reversal and as a failure to show serial reversal learning on subsequent reversals. Acquisition of a novel discrimination was not impaired five weeks after surgery. As time of testing may have been a confounding factor, in Experiment 2 the effects of the same lesion on new learning were examined immediately following surgery and the effects on retention a month later. The lesion was found to disrupt new learning but did not affect retention. From the two experiments it is clear that, whereas disruption of retention and new learning was relatively transient, the impairments in reversal performance were more long lasting. In addition, lesioned animals exhibited behavioural hyperactivity and elevations in consummatory and schedule-controlled licking. The disinhibitory and preservative effects observed following lesions of the basal forebrain in this study are similar to those following lesions of the orbitofrontal cortex while the disruption of serial reversal learning is commonly seen following damage to the amygdala. Therefore, these results are consistent with the hypothesis that the range of behavioural effects of the lesion result from damage to the cholinergic afferents to orbitofrontal cortex and to the amygdala, two structures intimately connected to one another.

Animals↗

PubMed1990

Cortical, hippocampal, and striatal mediation of schedule-induced behaviors.

The sequential occurrence of licking, locomotor activity, entries into the food magazine (panel pressing), and nonreenforced lever pressing engendered by a periodic schedule of food presentation were measured in each 60-s interreenforcement interval in normal and brain-damaged rats. The development of these responses was measured over 20 days in different groups of food-deprived rats that had received aspirations of the hippocampus, small lesions of the cortex overlying the hippocampus (hippocampal-operated control group), decortication, or 6-hydroxy-dopamine lesions of the caudate nucleus or nucleus accumbens. All lesions produced distinctive patterns of change in the measured behaviors, and dissociations as well as similarities in their effects were evident. These results are discussed with respect to dissociations in the motor and motivational effects of the various lesions and in terms of contemporary hypotheses of schedule-induced behavior.

Animals↗

PubMed1990

The case of frontostriatal dysfunction in schizophrenia.

A frontostriatal hypothesis of schizophrenia is advanced which takes into account evidence from studies of neurochemical pathology, functional imaging, cognitive neuropsychology, and experimental and clinical psychopharmacology, in addition to factor analyses of the symptomatic heterogeneity of this disorder. This evidence is illuminated by the recent characterization of anatomically segregated, functionally distinct corticostriatal loops which provide possible substrates for understanding the significance of functional changes in striatal and cortical dopaminergic activity interacting with other forms of structural pathology in schizophrenia.

Animals↗

PubMed1990

Physiological correlates of schedule-induced activities in rats.

Oxygen consumption and heart rate as well as a range of behavior variables were tracked continuously as rats adapted to a schedule of food delivery. Over 15 days of observation a majority of the subjects developed characteristic patterns of schedule-induced polydipsia (SIP) in which bouts of drinking reliably followed food delivery. Variations in food tray entries, oxygen consumption, heart rate, and, in the final stage of the experiment, rates of general activity were also time locked to food delivery in both rats exhibiting SIP and nondrinkers. However, the patterns of variation in these measures differed consistently between these two groups. Oxygen consumption varied over a wider range and reached higher levels in drinkers than nondrinkers. Additionally, heart rate was lower in the drinkers, which, in the final stage of the experiment, also exhibited depressed rates of food tray entries and general activity relative to the nondrinkers. Each of these between-subject differences was paralleled by differences within the drinking group between trials on which drinking occurred and trials on which it did not occur. The implications of these results on the utility of unidimensional energetic constructs are discussed.

Animals↗

PubMed1990

Enhanced behavioral conditioning to context and impaired behavioral and neuroendocrine responses to conditioned stimuli following ceruleocortical noradrenergic lesions: support for an attentional hypothesis of central noradrenergic function.

This study tested the hypothesis that cortical noradrenaline (NA) depletion induced by 6-hydroxydopamine (6-OHDA) widens attentional span, impairing the acquisition of conditioning to an explicit stimulus while enhancing conditioning to contextual stimuli. Sham-operated and NA-depleted rats were exposed to pairings of an auditory (clicker) CS and (footshock) US in a distinctive environment. Half of the lesioned and half of the control animals were trained with a short trace interval between presentations of clicker and shock, and half with a long trace. Associative learning theory predicts that a long trace interval should bias intact animals towards stronger contextual conditioning and, in contrast, a short trace interval should bias controls towards stronger CS conditioning. During testing, NA-depleted animals showed impaired fear conditioning to explicit cues, compared with controls, indicated by their reduced suppression of drinking when the CS was introduced into a separate, lick-operant chamber. In contrast, the same animals exhibited enhanced fear of contextual cues, as shown by their greater preference for a "safe" environment over the one in which they were shocked. The behavioral and plasma corticosterone responses of individual animals to the CS were positively correlated in both the lesion and sham groups. Corticosterone levels corroborated the impairment in CS conditioning caused by the lesion. In contrast, behavioral and corticosterone responses to contextual stimuli were not significantly correlated in either group, and there was no enhancement of the corticosterone response to contextual stimuli in the lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

PubMed1989

Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes.

Two experiments examined the effects of excitotoxic lesions of the substantia innominata on cholinergic activity in the neocortex and on performance in a paradigm measuring selective attention in the rat. In Expt. 1, ibotenate-induced lesions produced approximately 30% reductions in cortical choline acetyltransferase (ChAT) activity, and damage to wide regions of the substantia innominata and ventral pallidum. The rats were impaired in their ability to localize brief visual targets in a serial reaction time task, as measured by reduced choice accuracy. This impairment was particularly evident at short stimulus durations, but the lesioned rats did not exhibit evidence of primary visual sensory dysfunction and exhibited only minor deficits when the stimuli were presented unpredictably. The deficit was exacerbated when distracting white noise was interpolated into the task. The rats with lesions were also slower to respond correctly, probably resulting partly from the adoption of a speed/error trade-off strategy, and were slower to collect earned food pellets, although they made no more errors of omission than controls. In Expt. 2, quisqualate-induced lesions produced fewer signs of non-specific damage and 50% reductions in cortical ChAT activity. This lesion produced generally qualitatively similar, but weaker effects to those of ibotenate-induced lesions. It was notable that many of the deficits following either ibotenate- or quisqualate-induced lesions lasted for several months after surgery. The results are discussed in terms of the cholinergic hypothesis of cognitive dysfunction. It is argued that lesions of the substantia innominata, including the magnocellular cholinergic neurons of the nucleus basalis of Meynert, produce deficits in attentional processing, which may not result from damage specifically to cholinergic cells. However, the longevity of the effects makes these preparations suitable for further exploration of the restorative effects of cholinergic treatments.

Animals↗

PubMed1989

Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: implications for theories of selective attention and arousal.

Six experiments examined the effects of 6-hydroxydopamine (6-OHDA) induced lesions of the nucleus accumbens septi (NAS) on performance of a spatial discrimination. The behavioral paradigm used was an analogue of Leonard's 5-choice serial reaction time task for humans. The 6-OHDA lesion produced an 87% depletion of dopamine (DA) in the NAS, only a minor (25%) depletion of DA in the anterior caudate, and a 75% depletion of neocortical noradrenaline (NA). The lesion transiently attenuated both the speed and impulsivity of responding on the baseline schedule, but did not affect discriminative accuracy. In addition, the lesion attenuated the increase in premature responding caused by both systemic administration of D-amphetamine and bursts of loud white noise, presented just prior to the onset of the visual discriminanda. However, the lesion did not affect discriminative accuracy in these 2 conditions. The lesion also only had extremely minor effects on performance of this paradigm when the intertrial intervals were unpredictable. These results contrast with the previously reported pattern of behavioral effects resulting from forebrain NA depletion in the same behavioral paradigm. They therefore complete a double dissociation of effects on accuracy and vigour of responding, supporting theories of a division of arousal-type processes.

Animals↗

PubMed1989

Effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on visual discrimination acquisition, performance and reversal in the rat.

Rats received infusions of ibotenic acid into the substantia innominata, in the region of the nucleus basalis of Meynert (nbM), before and after training on simple (simultaneous) and conditional visual discriminations. The ibotenate infusions reduced cortical choline acetyltransferase (ChAT) levels by about 20%, destroyed many ChAT-immunoreactive neurons in the nbM, but also caused the loss of many neurons in the substantia innominata and adjacent areas. These lesions did not impair the acquisition and performance of a simple visual discrimination, but did impair reversal of the discrimination and the performance of a conditional visual discrimination. However, the degree of impairment was unrelated to the degree of cortical ChAT loss. Ibotenic acid lesions to the dorsal globus pallidus also impaired reversal of discrimination but left acquisition and performance unaffected. Striatal dopamine depletion produced by 6-hydroxydopamine (6-OHDA) infusions into the mid-ventral caudate nucleus impaired performance of the simultaneous visual discrimination. Cortical noradrenaline depletion produced by 6-OHDA lesions of the dorsal noradrenergic bundle either alone or in combination with ibotenic acid lesions of the substantia innominata had no effect on acquisition of the discrimination. It is concluded that ibotenic acid lesions of the substantia innominata or to the dorsal globus pallidus affect learning and performance of conditional visual discrimination performance and impair reversal learning without affecting the capacity to discriminate visual events. These results are compared to those following cortical noradrenaline depletion or striatal dopamine loss.

Animals↗

PubMed1989

The effects of ibotenic acid lesions of the nucleus accumbens on spatial learning and extinction in the rat.

Rats with ibotenic acid lesions of the nucleus accumbens (N. Acc) were studied in two spatial learning paradigms: a T-maze and a Morris water maze. Learning of a spatial discrimination task and its reversal in the T-maze were disrupted by the N. Acc lesions. As both original and reversal learning were impaired, there was no evidence of a specific lesion effect on reversal learning. The lesioned rats did not perseverate excessively in their choice of the previously reinforced arm. There was evidence of behavioural inflexibility during extinction when the lesioned rats failed to slow the pace at which they ran the maze in the absence of reward. Spontaneous alternation was not significantly affected by the lesion. Acquisition of the second spatial task, locating the hidden platform in the Morris water maze, was also impaired. The lesioned rats did eventually learn the task and successfully reached the platform with similar latencies and heading errors to controls. Thus, the N. Acc lesion impaired but did not abolish spatial learning in the T-maze and the water maze. The deficits observed in this study may reflect a role for the N. Acc in the reorganisation of behaviour in response to external change.

Animals↗

PubMed1989

Impaired extra-dimensional shift performance in medicated and unmedicated Parkinson's disease: evidence for a specific attentional dysfunction.

Groups of patients with Parkinson's disease, either medicated, or unmedicated and early in the course, together with age- and IQ-matched control subjects were tested in two paradigms measuring different aspects of selective attention. The first set of tests compared visual discrimination learning following intra- and extra-dimensional shifts, using a "total change" design in which each shift was made in the presence of novel exemplars of the compound stimuli used as discriminanda. The second test consisted of a visual search task in which the number of alternatives was varied. The results of the first experiment showed a selective deficit in both groups of Parkinsonian subjects in their ability to perform an extra-dimensional shift. In the visual search task, the patients were less accurate, but responded with equivalent choice reaction times to those of controls. The results are discussed in terms of the nature of the attentional dysfunction that occurs in Parkinson's disease.

Aged↗

PubMed1989

Isolation-rearing retards the acquisition of schedule-induced polydipsia in rats.

Rats were reared from weaning either in isolation or in social groups for 10 weeks and were then tested for the acquisition of schedule-induced polydipsia (SIP). Isolation-reared rats were impaired in the development of this behaviour when compared to socially-reared controls. This reduction in drinking was specific to this test situation. Home cage water consumption and drinking in the SIP test chamber without a schedule of food delivery were unaltered and home cage drinking following water deprivation was significantly higher in the isolates. Housing adult rats in isolation did not impair SIP. The locomotor hyperactivity induced by isolation was also specific to rearing conditions. The inverse relationship between water consumption on the last day of testing and plasma corticosterone levels observed in both the socially-reared and socially-housed rats was absent in both the isolation-reared and isolation-housed rats.

Animals↗

PubMed1989

Effects of unilateral dorsal and ventral striatal dopamine depletion on visual neglect in the rat: a neural and behavioural analysis.

Rats were trained in a specially designed apparatus to detect brief, unpredictable visual stimuli presented to either side of the head. In one condition, rats reported the detection of the visual stimulus by removing their heads from a central location and responding in one of two adjacent side-holes where the visual stimulus had occurred. In the other condition, rats were trained to respond in the hole on the opposite side to where the visual stimulus had occurred. Following training all rats received striatal infusions of 6-hydroxydopamine leading to profound striatal dopamine depletion. One group received unilateral intra-nucleus accumbens 6-hydroxydopamine infusions. Two groups received 6-hydroxydopamine unilaterally into the caudate nucleus. Two other groups received two infusions of 6-hydroxydopamine, intra-accumbens and intra-caudate, on either the same side or on opposite sides. The results showed that all groups, except that receiving only intra-accumbens 6-hydroxydopamine, exhibited a significant bias in responding towards the side of the lesion which correlated with dopamine depletion in the head of the caudate nucleus, regardless of the type of discrimination or pre-operative strategy. These biased groups were also slower to initiate, but not to complete, contralateral responses. Detailed analysis of the behavioural evidence suggested that unilateral striatal dopamine depletion does not produce sensory loss or sensory inattention but rather an output type neglect, perhaps related to hemiakinesia or "intentional neglect". The bias recovered to preoperative levels by 7 weeks after surgery, but could be reinstated by pretreatment with alpha-methyl-para-tyrosine, thus suggesting the involvement of presynaptic mechanisms in recovery. Although unilateral dopamine depletion from the nucleus accumbens alone had no effects on visual neglect, it produced a lateralized bias in premature responding away from the side of the lesion, contrasting with the bias towards the side of the lesion seen in all of the other groups. These effects appeared to summate in this and in another condition in which a more eccentric response was required for stimulus detection, to suggest an interaction in function between the dorsal and ventral striatum.

Animals↗