Refining the taxonomy of memory.
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Amnesia↗
Biomedical subjects
T W Robbins
Publications and source records attributed to T W Robbins.
Deficits in memory and hippocampal long-term potentiation in mice with reduced calbindin D28K expression.
The influx of calcium into the postsynaptic neuron is likely to be an important event in memory formation. Among the mechanisms that nerve cells may use to alter the time course or size of a spike of intracellular calcium are cytosolic calcium binding or "buffering" proteins. To consider the role in memory formation of one of these proteins, calbindin D28K, which is abundant in many neurons, including the CA1 pyramidal cells of the hippocampus, transgenic mice deficient in calbindin D28K have been created. These mice show selective impairments in spatial learning paradigms and fail to maintain long-term potentiation. These results suggest a role for calbindin D28K protein in temporally extending a neuronal calcium signal, allowing the activation of calcium-dependent intracellular signaling pathways underlying memory function.
Animals↗
Prepulses inhibit startle-induced reductions of extracellular dopamine in the nucleus accumbens of rat.
In vivo brain microdialysis was used to monitor extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) of rats during exposure to startling acoustic stimuli. Ten rats were prepared with guide cannulae into which dialysis probes were inserted 1 d before testing. Two to three hours after the start of perfusion, rats were placed into the startle chamber and exposed to a continuous 70 dB(A) background noise. Dialysis samples (2.0 microliter/min) were collected at 6 min intervals. Startle pulses (120 dB[A] noise) were presented in 20-trial blocks lasting 5 min. In some blocks, an 86 dB[A] prepulse preceded each of the 20 pulses by 100 msec, with the order of presentation of pulse-alone or prepulse + pulse blocks being counterbalanced between animals. Three to six sample periods intervened between stimulus-containing blocks. Monoamine and metabolite levels were measured using HPLC with electro-chemical detection. During the presentations of startling stimuli, DA levels in the NAc decreased relative to the immediately preceding 12 min baseline. This decrease in DA was maintained for only one additional sample period. By contrast, the presentation of prepulse + pulse trials failed to affect dialysate levels of NAc DA during or immediately after the stimulation. Thus, startling acoustic stimuli produce significant and transient decreases in dialysate levels of DA in the NAc. Furthermore, prepulse stimuli effectively inhibit these neurochemical effects of starting stimuli, in parallel with their establish ability to inhibit the amplitude the behavioral startle response.
3,4-Dihydroxyphenylacetic Acid↗
Dissociation in prefrontal cortex of affective and attentional shifts.
The prefrontal cortex is implicated in such human characteristics as volition, planning, abstract reasoning and affect. Frontal-lobe damage can cause disinhibition such that the behaviour of a subject is guided by previously acquired responses that are inappropriate to the current situation. Here we demonstrate that disinhibition, or a loss of inhibitory control, can be selective for particular cognitive functions and that different regions of the prefrontal cortex provide inhibitory control in different aspects of cognitive processing. Thus, whereas damage to the lateral prefrontal cortex (Brodmann's area 9) in monkeys causes a loss of inhibitory control in attentional selection, damage to the orbito-frontal cortex in monkeys causes a loss of inhibitory control in 'affective' processing, thereby impairing the ability to alter behaviour in response to fluctuations in the emotional significance of stimuli. These findings not only support the view that the prefrontal cortex has multiple functions, but also provide evidence for the distribution of different cognitive functions within specific regions of prefrontal cortex.
Affect↗
The biological, social and clinical bases of drug addiction: commentary and debate.
This article summarizes the main discussions at a meeting on the biological, social and clinical bases of drug addiction focused on contemporary topics in drug dependence. Four main domains are surveyed, reflecting the structure of the meeting: psychological and pharmacological factors; neurobiological substrates; risk factors (including a consideration of vulnerability from an environmental and genetic perspective); and clinical treatment. Among the topics discussed were tolerance, sensitization, withdrawal, craving and relapse; mechanisms of reinforcing actions of drugs at the behavioural, cognitive and neural levels; the role of subjective factors in drug dependence; approaches to the behavioural and molecular genetics of drug dependence; the use of functional neuroimaging; pharmaceutical and psychosocial strategies for treatment; epidemiological and sociological aspects of drug dependence. The survey takes into account the considerable disagreements and controversies arising from the discussions, but also reaches a degree of consensus in certain areas.
Brain↗
Retarded acquisition and reduced expression of conditioned locomotor activity in adult rats following repeated early maternal separation: effects of prefeeding, d-amphetamine, dopamine antagonists and clonidine.
Adult hooded rats exposed to a repeated maternal separation procedure during the neonatal period showed a blunted expression of locomotor hyperactivity conditioned to the presentation of the daily food ration. We have demonstrated that the expression of food-conditioned anticipatory hyperactivity is sensitive to the response-enhancing effects of systemic d-amphetamine (0.5; 1.0 mg/kg) and to the response-attenuating effects of the selective dopamine D2 antagonist sulpiride (8; 20 mg/kg), the selective dopamine D1 antagonist SCH 23390 (0.01; 0.022 mg/kg) and the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (5; 15 micrograms/kg) in a dose dependent manner. Animals from the early separation groups showed a reduced enhancement of activity in response to 0.5 mg/kg d-amphetamine and a greater attenuation of activity in response to 8 mg/kg sulpiride and 5 micrograms/kg clonidine. Female separated rats also exhibited an attenuated locomotor response to the unconditioned stimulant effects of 0.5 mg/kg systemic d-amphetamine. The experiments confirm that early maternal separation attenuates the response to conditioned appetitive cues in adult rats and implicate altered dopaminergic and noradrenergic function in the changes. It is possible that early maternal separation in the rat may offer a useful preparation for investigation of the neural substrates mediating affective development and affective psychopathology.
Adrenergic alpha-Agonists↗
Neural systems engaged by planning: a PET study of the Tower of London task.
The functional anatomy of planning was investigated using the Tower of London task. Activation was observed in a distributed network of cortical areas incorporating prefrontal, cingulate, premotor, parietal and occipital cortices. Activation in corresponding areas has been observed in visuospatial working memory tasks with the exception of the rostral prefrontal cortex. This area may be identified with the executive components of planning comprising response selection and evaluation. Enhanced neural activity in both this rostral prefrontal area and the visuospatial working memory system was associated with increased task difficulty.
Adolescent↗
Repeated maternal separation of preweanling rats attenuates behavioral responses to primary and conditioned incentives in adulthood.
Early social experience has profound effects on a wide spectrum of behaviors and neurochemical correlates in the rat. Repeated separation of rat pups from their dam during the early neonatal period causes acute perturbation of neuroendocrine and physiological status. The chronic sequelae of repeated separations have not been studied as extensively as the acute responses. Altered social experience at a later developmental stage, postweaning isolation rearing, is known to induce enduring changes in the behavioral responses to reward and reward-related stimuli in maturity. We have evaluated the influence of repeated early maternal separation on the responses to both primary and conditioned incentives in mature rats. Separated animals showed enhanced weight gain, a blunted locomotor response to a novel environment and a blunting of the response to both negative and positive contrast effects. Female separated animals, but not males, exhibited a profound attenuation of the acquisition of a conditioned anticipatory locomotor response to the presentation of food. These data are discussed with respect to the putative involvement of ventral striatal dopamine systems in reward mechanisms and the potential utility of early maternal separation as an animal model of depression.
Animals↗
Dissociable effects of AMPA-induced lesions of the vertical limb diagonal band of Broca on performance of the 5-choice serial reaction time task and on acquisition of a conditional visual discrimination.
The aim of the present study was to investigate the role of the cholinergic innervation of the cingulate cortex in visual attentional function and acquisition of a visual conditional discrimination task. Following AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) lesions of the vertical limb diagonal band of Broca (VDB) which provides the main cholinergic projection to cingulate cortex, animals were not significantly impaired on the 5-choice serial reaction time task. This task, which provides a continuous performance test of visual attention, has previously been shown to be sensitive to AMPA lesions of the nucleus basalis magnocellularis (nbM). In contrast to the results obtained for visual attentional function, lesions of the VDB did significantly affect the acquisition of a visual conditional discrimination. While showing a significant facilitation in the early learning stage of acquiring this task animals with lesions of the VDB were significantly impaired during the late stages of learning this task. This late learning deficit was not the result of the animals being unable to learn the task due to the presence of the lesion throughout task acquisition as the results of a second experiment revealed that when animals were pre-trained to 70% accuracy on the task and then lesioned, the impairment in late learning was still apparent. In light of the results presented in the accompanying paper (Bussey et al., Behav. Brain Res., 1996), these results suggest that the early learning effects may be due to cholinergic denervation of the anterior cingulate cortex while the late learning effects may be due to denervation of the posterior cingulate cortex. Taken together with previous work indicating a role for the nbM cholinergic system in visual attentional function, these results suggest a role for the cholinergic innervation of the cingulate cortex in conditional learning but not for continuous attentional performance.
Animals↗
Dissociable effects of anterior and posterior cingulate cortex lesions on the acquisition of a conditional visual discrimination: facilitation of early learning vs. impairment of late learning.
Two experiments investigated the effects of quinolinic acid induced lesions of the anterior and posterior cingulate cortices on the acquisition and performance of a conditional visual discrimination (CVD) task, in which rats were required to learn a rule of the type: "If lights are flashing FAST, press the right lever; if SLOW press left". In Experiment 1, animals with lesions of the anterior cingulate cortex (ANT group) demonstrated a significant enhancement in learning during the early stages of task acquisition. Conversely, animals with lesions of the posterior cingulate cortex (POS group) were impaired in learning during the later stages of acquisition. There were no significant differences between the ANT and POS groups on the performance of the task when either variable inter-trial intervals or reduced stimulus durations were imposed. In Experiment 2, the specificity of the lesion effects for processes operative during the early and late stages of learning was tested. Animals were trained to a criterion of 70% correct choices on two consecutive sessions prior to lesioning, and subsequently allowed to continue to acquire the task to the mean asymptotic performance level of 85% correct choices on two consecutive sessions. Animals of the POS group were impaired in learning during this later stage of task acquisition, thus replicating the pattern of results obtained in Experiment 1. The animals in Experiment 2 were then tested following a 30-day retention interval and during extinction (removal of sucrose from the magazine). The extinction test revealed an impairment in the ability of animals in the ANT group to omit lever responses in the absence of reinforcement. These results indicate that the anterior and posterior cingulate cortices are functionally dissociable, and suggest that they may form part of complementary, but competing, learning and memory systems.
Animals↗
Neurobehavioural mechanisms of reward and motivation.
The analysis of the behavioural and neural mechanisms of reinforcement and motivation has benefited from the recent application of learning theory and better anatomical knowledge of the connectivity of certain key neural structures, such as the nucleus accumbens. This progress has enabled the dissection of motivational processes into components that can begin to be related to the functioning of specific limbic cortical structures that project to different compartments of the ventral striatum.
Animals↗
Neuropsychological impairments in unipolar depression: the influence of perceived failure on subsequent performance.
The CANTAB battery of neuropsychological tests was used to compare the performance of 28 patients with unipolar depression with that of 22 age and IQ matched controls. The patients were impaired on almost all tests studied with deficits in pattern and spatial recognition memory, matching to sample, spatial span, spatial working memory and planning. Most of the patients showed at least some impairment and deficits were seen across cognitive domains. An important finding was the detrimental effect of failure on subsequent performance; having solved one problem incorrectly, patients were far more likely than controls to fail the subsequent problem. Superimposed on the general deficits, there were also specific deficits in executive tasks characteristic of frontostriatal dysfunction and deficits in mnemonic tasks characteristic of temporal lobe dysfunction. This combination of a specific form of motivational deficit, resulting in oversensitivity to negative feedback, and superimposed specific neuropsychological deficits were correlated with severity of depression. The most significant correlations were seen between mnemonic deficits and clinical rating scores. Comparisons of the deficits seen in the depressed patients in this study with other patient groups assessed with the CANTAB neuropsychological battery, showed that one of the hypotheses of the neuropsychological deficits in depression, that of "frontosubcortical' or "frontostriatal' dysfunction, was not supported. These findings are discussed in relation to the likely neural substrates of depression.
Adult↗
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.
Afferent Pathways↗
Primate analogue of the Wisconsin Card Sorting Test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset.
Using a primate analogue of the Wisconsin Card Sort Test, this study demonstrated, for the first time, that lesions of the prefrontal cortex in monkeys produce a qualitatively similar impairment in attentional set-shifting to that seen following prefrontal cortical damage in humans. Although damage to the prefrontal cortex did not disrupt the ability of marmosets, a New World monkey, to maintain an attentional set, it did disrupt their ability to shift an attentional set. It also impaired their performance on discrimination reversal, object retrieval, and spatial delayed response, consistent with the effects of prefrontal damage in Old World monkeys. Comparison of the cognitive processes underlying discrimination reversal, object retrieval, and attentional set-shifting reveals the various types of inhibitory control provided by the prefrontal cortex.
Animals↗
Effects of excitotoxic lesions of the central amygdaloid nucleus on the potentiation of reward-related stimuli by intra-accumbens amphetamine.
The present study examined the effects of lesions of the central nucleus of the amygdala (CeA) on the acquisition of a new response with conditioned reinforcement (CR) and its potentiation by intra-accumbens infusions of d-amphetamine (1, 3, 10, and 20 microg/microl). Rats were trained to associate a light-plus-noise compound stimulus with the availability of a sucrose solution before receiving both bilateral ibotenic acid lesions of the CeA and cannulas implanted above the nucleus accumbens. Lesions of the central nucleus did not impair the performance of positively reinforced discriminated approach, nor did they impair the acquisition of a new response with conditioned reinforcement. However, the potentiation of responding with CR following intra-accumbens amphetamine was blocked in lesioned animals. These results are discussed in terms of the possible interactions between associative mechanisms in the amygdala and the mesolimbic dopamine projection.
Amygdala↗
Double dissociations of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man.
Thirty-two neurosurgical patients with unilateral or bilateral frontal lobe excisions, 41 patients with unilateral temporal lobe lesions and 19 patients who had undergone unilateral amygdalo-hippocampectomy were compared with matched controls on a computerized test of spatial working memory. A significant deficit was observed in the frontal lobe group, even at the least challenging level of task difficulty and this impairment was found to relate to the inefficient use of a particular searching strategy shown to improve performance on this task. In contrast, deficits in the temporal lobe group and the amygdalo-hippocampectomy group were only observed at the most difficult level of the task and in neither group could the deficit be related to the inefficient use of any particular searching strategy. In a follow-up study, the three patient groups were compared on analogous computerized tests of visual and verbal working memory. No deficits were observed in the frontal lobe group. By comparison, both the temporal lobe patients and the amygdalo-hippocampectomy group were significantly impaired in the visual working memory condition but not in the verbal working memory condition. These deficits were clearly evident at all levels of task difficulty and were not related to any particular searching strategy. The data are discussed in terms of the relative contributions of "executive' and "mnemonic' mechanisms to the contrasting, material dependent deficits observed in the frontal and temporal lobe groups.
Adult↗
Executive and mnemonic functions in early Huntington's disease.
Eighteen patients with early Huntington's disease were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function taken from the Cambridge Neuropsychological Test Automated Battery. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, spatial planning and visual discrimination learning/attentional set shifting were employed. These tests have previously been found to be sensitive to the later stages of Huntington's disease. Patients with early Huntington's disease were found to have a wide range of cognitive impairments encompassing both visuospatial memory and executive functions, a pattern distinct from those seen in other basal ganglia disorders. In contrast to patients with more advanced Huntington's disease, early Huntington's disease patients were not impaired at simple reversal learning, but were impaired at performing an extradimensional shift (EDS). The results will be discussed in relation to the hypothesized neuropathological staging of Huntington's disease and to the anatomical connectivity of the striatum.
Adult↗
Neuropsychology--dementia and affective disorders.
The neuropsychology of dementia and depression is surveyed with a focus on dementia of Alzheimer type (DAT) and depression in old age. Some of the main cognitive deficits in DAT are identified as loss of memory for events and attentional or executive deficit. The course of deterioration across various cognitive domains in DAT is consistent with a posterior-to-anterior spread of pathology in the cerebral cortex. Depressed, elderly patients exhibit a generalised profile of deficits, with impairments in tests shown to be sensitive to temporal or frontal cortex dysfunction. The depressed also exhibit a specific deficit in response to negative feedback (failure) which may contribute to different forms of cognitive dysfunctioning. Gross similarities in the deficits presented by subjects in depression or DAT necessitate a search for qualitative differences between the two, in order to facilitate their differential diagnosis: one such difference is the reversibility of certain of the cognitive deficits following recovery from depression.
Brain↗