Taxonomies of psychological individual differences: biological perspectives on millennia-long challenges.

This Editorial highlights a unique focus of this theme issue on the biological perspectives in deriving psychological taxonomies coming from neurochemistry, neuroanatomy, neurophysiology, genetics, psychiatry, developmental and comparative psychology-as contrasted to more common discussions of socio-cultural concepts (personality) and methods (lexical approach). It points out the importance of the distinction between temperament and personality for studies in human and animal differential psychophysiology, psychiatry and psycho-pharmacology, sport and animal practices during the past century. It also highlights the inability of common statistical methods to handle nonlinear, feedback, contingent, dynamical and multi-level relationships between psychophysiological systems of consistent psychological traits discussed in this theme issue.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.

Habits.

What is a habit? One problem with the concept of habit has been that virtually everyone has their own ideas of what is meant by such a term. Whilst not eschewing folk psychology, it is useful to re-examine dictionary definitions of 'habit'. The Oxford Dictionary of English defines habit as "a settled or regular tendency or practice, especially one that is hard to give up" and also "an automatic reaction to a specific situation". The latter, reassuringly, is not too far from what has come to be known as stimulus-response theory.

Divergent subcortical activity for distinct executive functions: stopping and shifting in obsessive compulsive disorder.

BACKGROUND: There is evidence of executive function impairment in obsessive compulsive disorder (OCD) that potentially contributes to symptom development and maintenance. Nevertheless, the precise nature of these executive impairments and their neural basis remains to be defined. METHOD: We compared stopping and shifting, two key executive functions previously implicated in OCD, in the same task using functional magnetic resonance imaging, in patients with virtually no co-morbidities and age-, verbal IQ- and gender-matched healthy volunteers. The combined task allowed direct comparison of neural activity in stopping and shifting independent of patient sample characteristics and state variables such as arousal, learning, or current symptom expression. RESULTS: Both OCD patients and controls exhibited right inferior frontal cortex activation during stopping, and left inferior parietal cortex activation during shifting. However, widespread under-activation across frontal-parietal areas was found in OCD patients compared to controls for shifting but not stopping. Conservative, whole-brain analyses also indicated marked divergent abnormal activation in OCD in the caudate and thalamus for these two cognitive functions, with stopping-related over-activation contrasting with shift-related under-activation. CONCLUSIONS: OCD is associated with selective components of executive function, which engage similar common elements of cortico-striatal regions in different abnormal ways. The results implicate altered neural activation of subcortical origin in executive function abnormalities in OCD that are dependent on the precise cognitive and contextual requirements, informing current theories of symptom expression.

Innovative solutions to novel drug development in mental health.

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance.

BACKGROUND: Recent evidence suggests that an abnormal response to performance feedback may contribute to the wide-ranging neuropsychological deficits typically associated with depressive illness. The present research sought to determine whether the inability of depressed patients to utilize performance feedback advantageously is equally true for accurate and misleading feedback. METHOD: Patients with major depression and matched controls completed: (1) a visual discrimination and reversal task that featured intermittent and misleading negative feedback; and (2) feedback and no-feedback versions of a computerised test of spatial working memory. In the feedback version, negative feedback was accurate, highly informative, and could be used as a mnemonic aid. RESULTS: On the Probability Reversal task, depressed patients were impaired in their ability to maintain response set in the face of misleading negative feedback as shown by their increased tendency to switch responding to the 'incorrect' stimulus following negative reinforcement, relative to that of controls. Patients' ability to acquire and reverse the necessary visual discrimination was unimpaired. On the Spatial Working Memory task, depressed patients made significantly more between-search errors than controls on the most difficult trials, but their ability to use negative feedback to facilitate performance remained intact. CONCLUSIONS: The present results suggest that feedback can have different effects in different contexts. Misleading, negative feedback appears to disrupt the performance of depressed patients, whereas negative but accurate feedback does not. These findings are considered in the context of recent studies on reinforcement systems and their associated neurobiological substrates.

Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington's disease.

Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.

"Pray or Prey?" dissociation of semantic memory retrieval from episodic memory processes using positron emission tomography and a novel homophone task.

One problem in studying the neural basis of semantic memory using functional neuroimaging is that it is often difficult to disentangle activation associated with semantic memory retrieval from that associated with episodic memory encoding and retrieval. To address this issue, a novel homophone task was used in which subjects were PET scanned whilst learning a series of real words (e.g., prey). In a subsequent scan, the subjects were presented with homophone pairs (e.g., prey vs pray) and were required to choose the one that had been shown previously. In two corresponding baseline tasks, the subjects were scanned whilst learning and recognizing pronounceable nonwords. Thus, while all of these tasks recruited either episodic memory encoding or retrieval processes, only the homophone tasks involved semantic memory retrieval. A conjunction analysis designed to isolate activation associated with semantic memory retrieval, revealed changes in several left lateral frontal regions (BA 9/10, 9/45), the left middle temporal cortex (BA 21), and in the left inferior temporoparietal cortex (BA 39). In contrast, a conjunction analysis designed to isolate activation associated with episodic memory encoding, revealed significant changes in the left hippocampus, as well as in the frontopolar cortex (BA 10) bilaterally, the left inferior parietal cortex (BA 40), and the left superior temporal gyrus (BA 22, 28). The present results clarify and extend recent attempts to understand the neural basis of semantic memory retrieval, by actively controlling for the confounding effects of episodic memory encoding and retrieval processes.

Selective behavioral and neurochemical effects of cholinergic lesions produced by intrabasalis infusions of 192 IgG-saporin on attentional performance in a five-choice serial reaction time task.

The effects of the cholinergic immunotoxin 192 IgG-saporin (SAP) (0.0, 0.15, or 0.45 microg/microl; 0.5 microl/hemisphere) infused into the area of the nucleus basalis magnocellularis (NBM) of rats were tested in a five-choice serial reaction time task (5CSRTT) designed to assess visual attention. The effects of this manipulation on acetylcholine efflux in the medial frontal cortex were determined using in vivo microdialysis during the 5CSRTT. Rats with extensive lesions of the NBM (SAP HIGH) showed an array of behavioral deficits in the 5CSRTT hypothesized to represent deficits in central executive function that were associated with severe deficits in accuracy. Lengthening the stimulus duration ameliorated these deficits. Rats with restricted lesions of the NBM (SAP LOW) showed impairments over time on task when tested under standard conditions that were exacerbated by increases in the event rate. The number of choline acetyltransferase-immunoreactive cells in the area of the NBM but not the vertical limb of the diagonal band correlated significantly with accuracy in the task. SAP HIGH rats had significantly lower levels of cortical acetylcholine (ACh) efflux relative to SHAM both before and during the 5CSRTT. SAP LOW rats showed significantly higher levels of cortical ACh efflux before but not during the 5CSRTT. Cortical ACh efflux increased in all rats with the onset of the attentional task. These data provide the first direct evidence for a relationship between selective damage in the basal forebrain with decreased cortical ACh efflux and impaired attentional function.

Selective deficits in attentional performance on the 5-choice serial reaction time task following pedunculopontine tegmental nucleus lesions.

Sustained attention requires the integrity of basal forebrain cholinergic systems. The pedunculopontine tegmental nucleus (PPTg) has direct and indirect connections (via the thalamus) with the basal forebrain, suggesting that the PPTg may also play an important role in attentional processes. We examined this hypothesis by testing the effects of PPTg lesions in rats on performance in the 5-choice serial reaction time test. Bilateral lesions reduced accuracy, increased errors of omission, and increased the latency to correct responses. The deficits were more severe when neuronal damage was bilateral and concentrated in the posterior PPTg. Attentional demands of the task were increased by decreasing the stimulus duration, the stimulus brightness, or the inter-trial interval, and by introducing random bursts of white noise. These challenges impaired performance of all animals, but the magnitude of deficit was increased in the lesioned group. Conversely, lesion-induced deficits were partially alleviated when the attentional demands of the task were reduced. This pattern of results suggests that PPTg lesions produce a global deficit in attention, rather than a specific impairment in one process. The PPTg may control attentional processes through its direct projections to the forebrain cholinergic system or, indirectly, through activation of thalamocortical projections.

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.

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.

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.

Effects of the neuroleptic alpha-flupenthixol on latent inhibition in aversively- and appetitively-motivated paradigms: evidence for dopamine-reinforcer interactions.

Three experiments examined the influence of the dopamine (DA) D1/D2 receptor antagonist alpha-flupenthixol on the latent inhibition (LI) effect. LI is a phenomenon which is manifest when non-reinforced pre-exposure to a stimulus retards subsequent conditioning to that stimulus, and has been proposed as an animal model of the selective attentional processes that are disrupted in acute schizophrenia. Experiment 1 extended previous findings that neuroleptics enhance the LI effect in conditioned suppression paradigms in rats to alpha-flupenthixol (0.23 mg/kg). Experiment 2 demonstrated that this enhancement of the LI effect was also seen in a parallel appetitively-motivated conditioning paradigm at the same dose. In both Experiment 1 and Experiment 2, the enhancement of the LI effect by alpha-flupenthixol appeared to be accompanied by a decrease in the impact of the reinforcer (be it appetitive or aversive). Experiment 3 investigated the possible role of the reinforcer in the effect of alpha-flupenthixol on the LI effect in the aversive, conditioned suppression paradigm by increasing the intensity of footshock in rats treated with alpha-flupenthixol. Increasing the intensity of the footshock completely abolished the enhancement of LI found following injection of alpha-flupenthixol, a result which could not be attributed to a floor effect. The results provide no support for interpretations of the influence of DA manipulations on the LI effect that draw parallels with deficits in selective attention observed in acute schizophrenia.

6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine.

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Effects of excitotoxic lesions of the septum and vertical limb nucleus of the diagonal band of Broca on conditional visual discrimination: relationship between performance and choline acetyltransferase activity in the cingulate cortex.

Four experiments examined the role of the cholinergic projections from the septum and vertical limb nucleus of the diagonal band of Broca (VDB) in acquisition and performance of a conditional visual discrimination. In experiments 1-3, excitotoxic lesions were made of the septum and VDB in rats using quisqualic acid, which resulted in significant reductions in ChAT activity in the hippocampus and cingulate cortex, but with no effects on cortical monoamines. In experiment 1, there were significant impairments in acquisition of the conditional discrimination, which did not result from motivational impairments. Experiment 2 repeated these results with lesion parameters, which produced variable effects on hippocampal and cingulate ChAT activity. Those rats with reductions in predominantly cingulate ChAT were most impaired in acquisition, but those with predominantly hippocampal reductions were relatively unimpaired. Experiment 3 showed that quisquate-induced lesions of the VDB, but not of the more caudal VDB and horizontal limb nucleus of the diagonal band, produced deficits, and a model incorporating the results of experiments 1-3 showed a highly significant correlation between errors of commission and cingulate cortical ChAT activity (r = -0.82, p < 0.001). Experiment 4 used the excitotoxin AMPA to lesion the VDB in rats pretrained on a modified form of the conditional discrimination task. In one subgroup of rats this excitotoxin produced profound and regionally selective reductions in ChAT activity. This subgroup was also impaired in relearning the discrimination to criterion. Again, there was a significant inverse relationship between the number of errors of commission made in relearning the discrimination and cingulate ChAT activity (r = -0.94, p < 0.001). These experiments suggest that excitotoxic lesions of the septum/VDB produce deficits in conditional discrimination learning and performance, and that the integrity of the projection to the cingulate cortex is more crucial than that to the hippocampus in this effect. Moreover, there is a close relationship between discrimination performance and cholinergic function in the cingulate cortex. In conjunction with other results, these data suggest that different aspects of cognition and memory are modulated by cholinergic activity in different cortical regions.

AMPA-induced excitotoxic lesions of the basal forebrain: a significant role for the cortical cholinergic system in attentional function.

The aim of the present study was to clarify the role of the basal forebrain (BF)-cortical cholinergic system in visual attentional function by investigating the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-induced lesions of the basal forebrain on performance of a five-choice serial reaction time task. AMPA lesions in the present study produced a profound effect on performance of the task, as measured by choice accuracy and correct response latency. This deficit was significantly greater than that observed in earlier studies following ibotenate- or quisqualate-induced lesions of the BF. However, detailed histological and biochemical analysis revealed three rather different BF lesions depending upon the batch of AMPA supplied. In one group of animals (BF/1) the deficits in task performance were substantially greater and longer lasting compared to another group of lesioned animals (BF/2), which showed behavioral recovery several months following the lesion. The former sustained severe pallidal damage in addition to marked reductions in cortical ChAT activity. Support for the attentional nature of these deficits was obtained by the ability to improve task performance in BF/1 lesioned animals by increasing the duration of the visual stimulus and thus reducing the attentional load placed on these animals. In contrast, performance deficits could be reinstated in those animals showing behavioral recovery (BF/2) by reducing the duration of the visual stimulus and thus increasing attentional load. In the second experiment more discrete lesions of the magnocellular cholinergic neurons were made, resulting in extensive reduction of cortical ChAT activity with considerably less neuronal loss from the dorsal pallidum compared to the BF/1 lesion group. Once again, deficits on the task were substantially greater than observed previously following either quisqualate- or ibotenate-induced BF lesions. Furthermore, the cholinergic specificity of these deficits was supported by the attenuation of behavioral impairments following administration of the anti-cholinesterase physostigmine. Taken together with our earlier work, which has failed to demonstrate mnemonic deficits following lesions to the magnocellular neurons of the nucleus basalis of Meynert, these results suggest that the most consistent deficit produced following lesions of the BF-cortical cholinergic system is attentional dysfunction Analogous deficits in visual attention are also seen in patients with Alzheimer's disease, which can also be improved by anti-cholinesterase treatment.

Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition.

A series of experiments examined the effects of 8 weeks of social isolation on spontaneous locomotor activity, prepulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI) in a conditioned suppression paradigm, and basal and d-amphetamine stimulated dopamine (DA) release in the ventral striatum, as measured by in vivo microdialysis. Both isolation-reared animals (those isolated from the weaning age) and isolation-housed animals (those isolated as adults) were hyperactive when placed in a novel environment. Social isolation also led to deficits in PPI of the acoustic startle response that were specific to isolation-reared animals. Isolation rearing was without effect on the expression of LI but did lead to an enhanced response to systemic d-amphetamine in terms of striatal DA release. The data are discussed with respect to the involvement of ventral striatal DA mechanisms in the expression of PPI and LI, differences in the impact of social isolation in young and adult animals, and the utility of social isolation model as a nonlesion, nonpharmacologic means of perturbing ventral striatal DA function.

Comparative effects of excitotoxic lesions of the hippocampus and septum/diagonal band on conditional visual discrimination and spatial learning.

Several experiments compared the effects of excitotoxic lesions of the septal/vertical limb nuclei of the diagonal band of Broca (VDB) complex with those of the hippocampus (sparing the subiculum) on different forms of visual discrimination learning. The septal/VDB lesions, which produced significant reductions in choline acetyltransferase activity in the hippocampus and the cingulate cortex, impaired acquisition of a conditional visual discrimination in an operant chamber, while the hippocampal lesion had no effect, unless there was a delay interposed between the discriminative stimulus and the response. Neither lesion affected simple visual or spatial discrimination or reversal learning, also carried out in operant chambers, but both significantly impaired the acquisition and retention of a spatial navigation task (Morris water maze), with the septal/VDB lesions again producing greater deficits than the hippocampal lesions. Possible explanations for this surprising result are discussed and it is concluded that; (1) additional cholinergic de-afferentation of the cingulate cortex produced by the septal/VDB lesion is of functional significance; (2) this may lead to deficits in conditional rule learning, which can contribute to spatial navigation performance under certain circumstances; and (3) the contribution of septal-hippocampal cholinergic projections to spatial learning is in need of re-appraisal.

Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia.

Schizophrenic patients exhibit deficits in the prepulse inhibition of startle, an operational measure of the sensorimotor gating deficits that are theorized to contribute to cognitive disorganization. In rats, the activation of mesolimbic dopamine (DA) disrupts prepulse inhibition, providing a useful model of the similar deficits in sensorimotor gating in schizophrenic patients. Rats reared in isolation exhibit neurochemical and behavioral abnormalities suggestive of hyperactivity in mesolimbic DA systems. In the present studies, rats reared in social groups or in isolation were tested in startle response paradigms using 120 or 105 dB acoustic pulses, some of which were preceded (100 msec) by prepulses that were 2, 4, 8, or 16 dB above the 65 dB background. Isolation-reared animals were hyperreactive only in response to the initial few startle stimuli. The amount of prepulse inhibition was decreased significantly in isolation-reared animals, particularly when midrange 8 dB prepulses were used. A subsequent study replicated the effect of isolation rearing on prepulse inhibition and suggested that the deficit in sensorimotor gating exhibited by isolation-reared animals may be normalized by the administration of the DA antagonist raclopride (0.05 mg/kg). Hence, isolation rearing provides a nonpharmacological way to induce in rats a deficit in sensorimotor gating that is exhibited by schizophrenic patients.

Effects of medial dorsal thalamic and ventral pallidal lesions on the acquisition of a conditioned place preference: further evidence for the involvement of the ventral striatopallidal system in reward-related processes.

In our previous work, it has been established that the basolateral amygdala and ventral striatum are part of a neural system that is involved in reward-related processes. However, it is unclear how information processed in this limbic-motor interface may come to affect incentive motivational responses. The present experiments have investigated the involvement of post-striatal elements of the ventral striatopallidal system in the rat. Lesions of the anterior or posterior domains of the ventral pallidum, which receives the major outflow from the ventral striatum, or the nucleus medialis dorsalis of the thalamus, which receives projections from both the ventral pallidum and also the basolateral amygdala, were made by infusing the excitotoxin, ibotenic acid. The effects of the lesions on the acquisition of a place preference conditioned by exposure of hungry rats to sucrose were then measured. Lesions of either the anterior or posterior ventral pallidum significantly attenuated, whereas lesions of the medial dorsal thalamus completely abolished, the acquisition of a conditioned place preference, provided that the latter lesions included the medial-lateral extent of the nucleus. Medial dorsal thalamic lesions did not damage the stria medullaris or medial habenula. Ingestion of sucrose following 23 h deprivation was unaffected by either ventral pallidal or medial dorsal thalamus lesions and thus disruption of place preference acquisition was not secondary to changes in primary motivation. The results indicate that reward-related processes, as measured in the place preference conditioning paradigm, may depend upon ventral striatopallidal outflow that engages medial dorsal thalamus-frontal cortex mechanisms, in addition to the previously highlighted direct outflow to brainstem elements of the motor system.