Presumed 'prefrontal cortex' lesions in pigeons: effects on visual discrimination performance.

The posterodorsolateral neostriatum (PDLNS) in pigeons may be an equivalent of the prefrontal cortex (PFC) in mammals. Here we report that lesions of this brain region in pigeons have a detrimental effect on various learned visual discriminations. Pigeons with lesions of the overlying area corticoidea dorsolateralis (CDL) served as controls. Both the postoperative re-learning to criterion of a preoperatively learned simultaneous double visual mirror pattern discrimination and the learning of a simple successive go, no-go discrimination were impaired by the PDLNS lesions. The PDLNS and CDL groups did not differ significantly in the postoperative learning of a reversal of the simultaneous discrimination. The results are discussed in relation to the presumed equivalence between the avian PDNLS and the mammalian PFC.     

The hippocampus plays a critical role at encoding discontiguous events for subsequent declarative memory expression in mice

The hypothesis that hippocampal activity at encoding is causally related to subsequent declarative memory expression is tested in the mouse, by using lidocaine inactivation of the hippocampus in combination with c-fos neuroimaging analysis. We employed a two-stage radial maze paradigm of spatial discrimination, which was previously shown to dissociate between declarative and nondeclarative expression of memory related to the same acquired material. In Stage 1 (encoding), mice learnt the constant location of food among a set of six arms (three baited, three unbaited) by being submitted repeatedly to discontiguous experiences with each arm separately ("go/no-go" discrimination). In Stage 2 (test-session), they are challenged with novel presentations of the arms, which are either combined into pairs of opposite valence ("two-choice" discrimination), or opened all six together ("six-choice" discrimination). Previous experiments have demonstrated that the "two-choice" situation is a critical test for declarative memory while "six-choice" discrimination may rely on procedural memory. We observed that (i) hippocampal activity measured by c-fos mRNA expression was increased by "go/no-go" learning, and this activation was blocked by pre-training local infusions of lidocaine; (ii) when performed just before each session of Stage 1, such inactivation spared the acquisition of "go/no-go" discrimination but produced, subsequently, a selective deficit in the "two-choice" test (not in the "six-choice" test). This study indicates that the hippocampus is "spontaneously" engaged in encoding processes necessary for long-term storage of discontiguous experiences under a form enabling flexible declarative memory expression.     

Neurotoxic lesions of the rat perirhinal and postrhinal cortices and their impact on biconditional visual discrimination tasks

It has been argued that damage to the perirhinal cortex should impair visual discriminations when the stimuli have overlapping features. In Experiment 1, rats with perirhinal cortex lesions were trained on a series of visual discriminations in a water tank, culminating in a biconditional discrimination. No evidence was found of a perirhinal lesion deficit, although the same rats showed an object recognition deficit. In Experiment 2 the lesions were extended to involve both the perirhinal and postrhinal cortices in a new group of rats. An impairment was now found on acquisition of the biconditional task, but this was not specific as impairments were also found on two elemental visual discriminations. Taken together, the study failed to find evidence that the rat perirhinal cortex is necessary for configural visual discriminations and so revealed that some ambiguous visual discriminations can be learnt when this area is removed. Furthermore, there was no evidence that the parahippocampal region is selectively dedicated to configural learning, even though the loss of this area can impair the acquisition of some configural tasks.     

Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions

Addictive drugs, such as cocaine, cause long-lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30 mg/kg/d, i.p.) or vehicle for 14 days and then trained after a 2-week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine-treated rats, who demonstrated long-lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long-lasting effects on orbitofrontal-dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine-induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization.     

No‐go dominant brain activity in human inferior prefrontal cortex revealed by functional magnetic resonance imaging

We investigated the response inhibition function of the prefrontal cortex associated with the go/no-go task using functional magnetic resonance imaging in five human subjects. The go/no-go task consisted of go and no-go trials given randomly with roughly equal probability. In go trials a green square was presented and the subjects had to respond by promptly pushing a button using their right or left thumbs, but in no-go trials a red square was presented and subjects were instructed not to respond. When brain activity in no-go trials is dominant over that in go trials in areas in the prefrontal cortex, this no-go dominant brain activity would reflect the neural processes for inhibiting inherent response tendency. We used a new strategy of image data analysis by which transient brain activity in go or no-go trials can be analysed separately, and looked for the prefrontal areas in which the brain activity in no-go trials is dominant over that in go trials. We found the no-go dominant foci in the posterior part of the right inferior frontal sulcus reproducibly among the subjects. This was true whether the right or left hand was used. These results suggest that this region in the prefrontal cortex is related to the neural mechanisms underlying the response inhibition function.     

Central serotonin depletion impairs both the acquisition and performance of a symmetrically reinforced go/no-go conditional visual discrimination

The involvement of central serotonin systems in behavioural disinhibition in the rat was assessed using a symmetrically reinforced go/no-go conditional visual discrimination task. Selective central 5-HT depletion (generally averaging more than 90% in neocortex, hippocampus and striatum) was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and dopaminergic re-uptake inhibitor. The lesioned animals failed to acquire the conditional visual discrimination. This deficit was due to an inability to withhold responding and thus correctly complete the no-go trials. The lesioned animals responded faster both correctly, during go trials, and incorrectly during no-go trials. Impulsive early responding during the initial 1.2 s of the stimulus presentation was also increased by 5-HT depletion. Subjects that were lesioned after stable performance of the task had been acquired showed a similar, but smaller effect. These animals displayed more accurate performance of the go trials, but poorer performance of the no-go trials. Once again, go trial response latencies were faster and early responses during the no-go trials were increased by the lesion. The results suggest that previous accounts of impulsive responding induced by 5-HT depletion fail to recognise the pervasive nature of this effect, which affects multiple behavioural indices of response disinhibition and can impede the acquisition and performance of discrimination tasks depending on their precise response requirements.     

Effects of selective thalamic and prelimbic cortex lesions on two types of visual discrimination and reversal learning

The effects of excitotoxic lesions of the mediodorsal nucleus of the thalamus, the anterior thalamic nuclei and of the prelimbic cortex were examined on two tests of discrimination and reversal learning. In experiment 1A (visual discrimination and reversal), rats were required to discriminate two stimuli, and respond to the stimulus associated with reward (the S+ stimulus). There was no effect of lesion on acquisition of this task. However, when stimulus-reward contingencies were reversed, animals with lesions of the mediodorsal nucleus of the thalamus made significantly more errors than control animals or animals of other lesion groups. In experiment 1B (conditional discrimination), animals were required to learn a rule of the type 'If stimulus A then go left, if stimulus B then go right'. No main effect of lesion on acquisition was observed in this experiment. To test the generality of the reversal effect obtained in experiment 1A, a second cohort of animals with the same lesions was tested on acquisition of the visuospatial conditional task immediately postsurgery, followed by the reversal of the conditional rule (experiment 2). As in experiment 1B, no main effect of lesion group was observed during acquisition of the task. However, lesions of the mediodorsal nucleus of the thalamus resulted in a mild impairment according to number of sessions required to attain criterion performance of the task when the response rule was reversed. The results of the present study provide evidence for a role for the mediodorsal nucleus of the thalamus in new learning, particularly when stimulus-reward contingencies are reversed. Furthermore, they show that the functions of this thalamic nucleus can be dissociated from those of the anterior thalamus and the prelimbic cortex.     

Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat

BACKGROUND: Recent evidence suggests that the neural correlates of reversal learning are localised to the orbitofrontal cortex whereas studies on the contribution of the medial prefrontal cortex to this capacity have produced equivocal results. This study examines the behavioural effects of selective lesions centred on orbitofrontal, infralimbic and prelimbic cortex on serial spatial reversal learning in the rat. METHODS: Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both 'cognitive flexibility' and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of reversals was presented. RESULTS: Bilateral excitotoxic lesions of the orbitofrontal cortex did not affect retention of a preoperatively acquired spatial discrimination but did impair reversal learning. This deficit manifested as increased perseverative responding on the previously correct lever. Although impairments were evident during reversal 1, OFC-lesioned animals performed significantly better than controls on reversal 2. There were no significant effects of infralimbic and prelimbic lesions on the retention of a spatial discrimination or reversal learning. CONCLUSIONS: These results indicate that the orbitofrontal cortex is critical for flexible responding in serial spatial reversal learning. The present findings may be relevant to deficits in reversal learning and response inhibition in such neuropsychiatric disorders as obsessive-compulsive disorder.     

Suppression of visually initiated hand movement by stimulation of the prefrontal cortex in the monkey

Five adult monkeys (Macaca fuscata) were trained for the go/no-go hand movement task with discrimination between two different color stimuli. The go stimulus was accompanied by a reward when a monkey lifted a lever by wrist extension within the stimulus duration (500 ms). Whereas the no-go stimulus was not. The monkey revealed the potential specific to the no-go response in the prefrontal cortex, called 'no-go potential', i.e. surface-negative, depth-positive deflexions in the cortex of the dorsal bank of the principal sulcus and of the rostroventral corner of the prefrontal region. Effects of electrical stimulation of these prefrontal areas upon the go response were observed and analyzed in order to study functional significances of the no-go potential. The surface and depth (2.0-3.0 mm) electrodes chronically implanted respectively in various cortical areas of both hemispheres, originally used for recording cortical field potentials, were utilized for bipolar stimulation of the cortical area. A train of brief electrical pulses was delivered to the loci producible of the no-go potential at different times after the onset of go visual stimulus. The stimulation suppressed the go movement by cancelling and delaying. The grade of the suppressor effect depended on the timing of electrical stimulation after the onset of visual stimulus, and was maximal at around the time of appearance of the no-go potential. The suppressor effect was compared with that produced by stimulating some other areas in the prefrontal cortex and the premotor cortex, and was found rather unique in those areas producible of the no-go potential.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlations among behavioral measures of orbitofrontal function

Orbitofrontal cortex plays an important role in guiding behavior based on emotional input and rewards. It receives multimodal higher order sensory information and mediates reinforcement for primary as well as secondary or conditioned forms of reinforcement (e.g., monetary rewards). Several behavioral measures have demonstrated putative sensitivity to orbitofrontal function: smell identification, delayed alternation, and response inhibition (go/no-go and antisaccades). A correlational study of performances on these tasks by healthy controls demonstrated some interrelationships: go/no-go correlated with antisaccades, left nostril smell correlated with go/no-go, and right nostril smell correlated with delayed alternation. Further analysis showed that certain smells correlated with tasks more strongly than others. Given the diversity of these tasks, it is suggested that these intercorrelations results from at least the partial overlap of the neural substrates for olfactory identification and tasks requiring response modification based on reinforcement contingencies.     

CORRELATIONS AMONG BEHAVIORAL MEASURES OF ORBITOFRONTAL FUNCTION

Orbitofrontal cortex plays an important role in guiding behavior based on emotional input and rewards. It receives multimodal higher order sensory information and mediates reinforcement for primary as well as secondary or conditioned forms of reinforcement (e.g., monetary rewards). Several behavioral measures have demonstrated putative sensitivity to orbitofrontal function: smell identification, delayed alternation, and response inhibition (go/no-go and antisaccades). A correlational study of performances on these tasks by healthy controls demonstrated some interrelationships: go/no-go correlated with antisaccades, left nostril smell correlated with go/no-go, and right nostril smell correlated with delayed alternation. Further analysis showed that certain smells correlated with tasks more strongly than others. Given the diversity of these tasks, it is suggested that these intercorrelations result from at least the partial overlap of the neural substrates for olfactory identification and tasks requiring response modification based on reinforcement contingencies.     

Neurobehavioral correlates of impulsivity: evidence of prefrontal involvement

Impulsivity is associated with the functioning of prefrontal-subcortical circuits particularly, the orbitofrontal circuit, which is shown in neuro-imaging studies of neurological and psychological disorders. Objective behavioral measures, such as go/no-go, antisaccades, and delayed alternation, have demonstrated sensitivity to prefrontal function. This study examined the relationship between orbitofrontal-sensitive measures and impulsivity in healthy adults, as measured by the Barratt Impulsiveness Scale-11 (BIS). Go/no-go and antisaccades correlated positively and delayed alternations correlated negatively with BIS subscales, even after controlling for demographic influences. The results add to the validity of the BIS and support a role for prefrontal cortex in impulse control.     

NEUROBEHAVIORAL CORRELATES OF IMPULSIVITY: EVIDENCE OF PREFRONTAL INVOLVEMENT

Impulsivity is associated with the functioning of prefrontal-subcortical circuits particularly, the orbitofrontal circuit, which is shown in neuro-imaging studies of neurological and psychological disorders. Objective behavioral measures, such as go/no-go, antisaccades, and delayed alternation, have demonstrated sensitivity to prefrontal function. This study examined the relationship between orbitofrontal-sensitive measures and impulsivity in healthy adults, as measured by the Barratt Impulsiveness Scale-11 (BIS). Go/no-go and antisaccades correlated positively and delayed alternations correlated negatively with BIS subscales, even after controlling for demographic influences. The results add to the validity of the BIS and support a role for prefrontal cortex in impulse control     

Orbitofrontal cortex dysfunction in attention-deficit hyperactivity disorder revealed by reversal and extinction tasks

Attention-deficit hyperactivity disorder (ADHD) has been considered a mental illness in which the frontal lobe is dysfunctional. The orbitofrontal cortex (OFC) controls emotional and motivational behaviors which are impaired in ADHD. Patients with OFC damage have shown impaired performance in reversal and extinction tasks in a simple go/no-go paradigm. We assigned ADHD subjects the two tasks to examine a hypothesized dysfunction of OFC. ADHD subjects indeed showed a performance deficit in the tasks, supporting OFC dysfunction in ADHD. Furthermore, a discriminat analysis using the task performance variables correctly classified 89.7% of the participants among ADHD patients and normal controls.     

Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats

Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imaging studies have suggested that these features may result from deficits in prefrontal cortical structure and function, and thereby impaired top‐down inhibitory control over limbic–striatal mechanisms of drug‐seeking behaviour. We tested the hypothesis that selective damage to distinct subregions of the prefrontal cortex, or to the amygdala, after a short history of cocaine taking would: (i) result in compulsive cocaine seeking at a time when it would not usually be displayed; or (ii) facilitate relapse to drug seeking after abstinence. Rats with selective, bilateral excitotoxic lesions of the basolateral amygdala or anterior cingulate, prelimbic, infralimbic, orbitofrontal or anterior insular cortices were trained to self‐administer cocaine under a seeking–taking chained schedule. Intermittent mild footshock punishment of the cocaine‐seeking response was then introduced. No prefrontal cortical lesion affected the ability of rats to withhold their seeking responses. However, rats with lesions to the basolateral amygdala increased their cocaine‐seeking responses under punishment and were impaired in their acquisition of conditioned fear. Following a 7‐day abstinence period, rats were re‐exposed to the drug‐seeking environment for assessment of relapse in the absence of punishment or cocaine. Rats with prelimbic cortex lesions showed decreased seeking responses during relapse, whereas those with anterior insular cortex lesions showed an increase. Combined, these results show that acute impairment of prefrontal cortical function does not result in compulsive cocaine seeking after a short history of self‐administering cocaine, but further implicates subregions of the prefrontal cortex in relapse.     

Differential involvement of the basolateral amygdala and orbitofrontal cortex in the formation of sensory-specific associations in conditioned flavor preference and magazine approach paradigms

Four experiments examined the roles of the basolateral amygdala and orbitofrontal cortex in the formation of sensory-specific associations in conditioned flavor preference and conditioned magazine approach paradigms using unconditioned stimulus (US) devaluation and selective Pavlovian-instrumental transfer procedures in Long Evans rats. Experiment 1 found that pre-training amygdala and orbitofrontal cortex lesions had no detectable effect on the formation or flexible use of sensory-specific flavor-nutrient associations in a US devaluation task, where flavor cues were paired either simultaneously or sequentially with nutrient rewards in water-deprived subjects. In Experiment 2, pre-training amygdala and orbitofrontal cortex lesions both attenuated outcome-specific Pavlovian-instrumental transfer. Experiment 3 indicated that amygdala lesions have no effect on the formation of sensory-specific flavor-nutrient associations in a US devaluation task in food-deprived subjects. Finally, Experiment 4 demonstrated that the outcomes used in Experiment 3 were sufficiently motivationally significant to support conditioned flavor preference. These findings suggest that, although both orbitofrontal cortex and amygdala lesions attenuate the acquisition of sensory-specific associations in magazine approach conditioning, neither lesion reduces the ability to appropriately respond to a flavor cue that was paired with a devalued outcome.     

Potential related to no-go reaction in go/no-go hand movement with discrimination between tone stimuli of different frequencies in the monkey

Monkeys were trained for go/no-go reaction-time hand movement with discrimination between tone stimuli of different frequencies, and field potentials related to the discriminative movement were recorded with electrodes implanted in various cortical areas and analysed by averaging procedure. In the cortex of the dorsal bank of the principal sulcus, surface-negative, depth-positive (s-N, d-P) potentials were recorded specifically on the no-go trial. The same monkey was also examined for go/no-go reaction-time hand movement with color discrimination. In the same monkey, the potentials related to the no-go reaction on the auditory stimulus were recorded in the rostral part of the dorsal bank of the principal sulcus, whereas the s-N, d-P potentials on the no-go visual stimulus were observed in the caudal part of the same bank. It is suggested that the dorsal bank of the principal sulcus is essentially related to the integrative functions such as judgement not to move and suppression of motor execution, and that different loci in this cortical area are respectively active for the functions of different sensory modalities.     

Willingness to wait and altered encoding of time-discounted reward in the orbitofrontal cortex with normal aging

Normal aging has been associated with cognitive changes, including shifts in responding for time-discounted rewards. The orbitofrontal cortex, an area previously associated with aging-related cognitive changes, is critical for normal discounting. Previously we have shown in a choice task that rats prefer immediate over delayed reward and that neural representations of delayed reward in orbitofrontal cortex were attenuated, whereas immediate reward elicited strong responses. Changes in choice performance were correlated with changes in firing rate in orbitofrontal neurons, suggesting that these reward representations were critical to the rats' ability to wait for reward. Here we asked whether age-dependent changes in discounting behavior were related to changes in the representation of delayed reward in the orbitofrontal cortex. Young (3-6 months) and aged (22-26 months) rats were trained on the same discounting paradigm used previously. We found that aged rats showed less sensitivity to increasing delay preceding reward delivery, shifting behavior away from the delayed reward more slowly than younger rats. This sensitivity was specific to delay, since choice performance did not differ between the two groups when delay was held constant and reward size varied. Aged rats exhibited a corresponding increase in the prevalence of neurons that fired more strongly for delayed reward. Again this change was specific to delay; there was no change in encoding of different-sized rewards. These results suggest that natural aging results in altered representations of reward in orbitofrontal cortex. These changes may relate to the increased ability to delay gratification and reduced impulsivity associated with aging.     

The representation of information about faces in the temporal and frontal lobes

Neurophysiological evidence is described showing that some neurons in the macaque inferior temporal visual cortex have responses that are invariant with respect to the position, size and view of faces and objects, and that these neurons show rapid processing and rapid learning. Which face or object is present is encoded using a distributed representation in which each neuron conveys independent information in its firing rate, with little information evident in the relative time of firing of different neurons. This ensemble encoding has the advantages of maximising the information in the representation useful for discrimination between stimuli using a simple weighted sum of the neuronal firing by the receiving neurons, generalisation and graceful degradation. These invariant representations are ideally suited to provide the inputs to brain regions such as the orbitofrontal cortex and amygdala that learn the reinforcement associations of an individual's face, for then the learning, and the appropriate social and emotional responses, generalise to other views of the same face. A theory is described of how such invariant representations may be produced in a hierarchically organised set of visual cortical areas with convergent connectivity. The theory proposes that neurons in these visual areas use a modified Hebb synaptic modification rule with a short-term memory trace to capture whatever can be captured at each stage that is invariant about objects as the objects change in retinal view, position, size and rotation. Another population of neurons in the cortex in the superior temporal sulcus encodes other aspects of faces such as face expression, eye gaze, face view and whether the head is moving. These neurons thus provide important additional inputs to parts of the brain such as the orbitofrontal cortex and amygdala that are involved in social communication and emotional behaviour. Outputs of these systems reach the amygdala, in which face-selective neurons are found, and also the orbitofrontal cortex, in which some neurons are tuned to face identity and others to face expression. In humans, activation of the orbitofrontal cortex is found when a change of face expression acts as a social signal that behaviour should change; and damage to the orbitofrontal cortex can impair face and voice expression identification, and also the reversal of emotional behaviour that normally occurs when reinforcers are reversed.     

The nature of the medial wall deficit in the rat

Spatial and temporal (go/no-go) alternation tasks were run in a computerized Y-maze apparatus in an attempt to characterize the behavioral deficit which results from frontopolar and medial cortical lesions in rats. The medial cortex lesions caused a severe behavioral impairment on both tasks. The deficit is characterized as an inability to temporally organize recent events. This interpretation is consistent with theories of primate frontal lobe function based on similar data obtained in non-human primates and man.