Lesions of the caudate nucleus selectively impair "reference memory" acquisition in the radial maze

Groups of Long-Evans rats with bilateral lesions of the caudate nucleus, sham lesions, or no lesions were given one trial per day in an eight-arm radial maze. The same four maze arms were baited on each trial. The remaining four arms never contained food. Optimal performance required animals to enter each of the baited arms only once on each trial and to avoid entering the arms in the unbaited set. Rats with caudate lesions learned to enter each of the baited arms only once on each trial. However, these rats were severely impaired in learning to avoid entering the arms in the unbaited set. Implications for dual-memory theories are discussed.     

Evidence for neocortical involvement in reference memory

Rats were trained on an eight-arm radial maze task using a procedure that provides for an assessment of both working and reference memory. Following training, rats received parietal cortex, medial prefrontal cortex, visual cortex, or nucleus basalis magnocellularis lesions. Rats with visual cortex lesions showed no change in performance on either working or reference memory. Rats with parietal cortex lesions displayed a temporary deficit in reference, but no deficit on working memory. Animals with medial prefrontal cortex lesions showed a temporary deficit on both working and reference memory. Rats with extensive lateral frontal and parietal cortex depletion of acetylcholinesterase following nucleus basalis magnocellularis lesions had a marked disruption only of reference but not of working memory. It is concluded that neocortex and possibly the cholinergic projections to neocortex play an important role in mediating reference memory.     

Medial dorsal thalamic lesions and working memory in the rat

Pigmented rats of the DA strain with either radiofrequency or ibotenic acid lesions of the thalamic nucleus medialis dorsalis were postoperatively given nonspatial and spatial tests of working memory. In the nonspatial task, delayed nonmatching-to-sample, rats with both types of thalamic lesions showed acquisition impairments. The subgroup of rats with nucleus medialis dorsalis lesions that were able to reach the acquisition criterion did, however, perform normally when the retention interval was extended to 60 s. In the spatial task, delayed forced-alternation, rats were tested with differing retention intervals and with both spaced and massed trials. Damage to nucleus medialis dorsalis had no effect on acquisition or on spaced trials, but a slight deficit was found in the animals with radiofrequency lesions under the massed trial condition. Much clearer deficits were, however, present in those animals in which the lesion extended appreciably into the anterior thalamic nuclei. The findings indicate that while cellular damage to nucleus medialis dorsalis may disrupt learning, some impairments in tests of spatial working memory attributed to this nucleus may reflect damage to the adjacent anterior thalamic nuclei.     

Post-trial injection of atropine into the caudate nucleus interferes with long-term but not with short-term retention of passive avoidance

One-trial passive avoidance training was given to Wistar rats and retention of the task was measured 30 min and 24 h later. Atropine (60 micrograms) was injected into the anterior caudate nucleus 2 min after training. Excellent retention was evident 30 min after training, whereas a significant deficit in memory was found when retention was tested 24 h after training. These results suggest that blockade of cholinergic activity of the caudate nucleus induced shortly after training interferes with the consolidation of long-term memory but not with short-term memory processes.     

Mediodorsal thalamic lesions impair trace eyeblink conditioning in the rabbit

Rabbits received lesions of the mediodorsal nucleus of the thalamus (MDN) or sham lesions and were subjected to classical eyeblink (EB) and heart rate (HR) conditioning. All animals received trace conditioning, with a.5-sec tone conditioned stimulus, a .5-sec trace period, and a 50-msec periorbital shock unconditioned stimulus. Animals with MDN lesions acquired the EB conditioned response (CR) more slowly than sham-lesioned animals. However, previous studies have shown that MDN damage does not affect delay conditioning using either .5-sec or 1-sec interstimulus intervals. The lesions had no significant effect on the HR CR. These results suggest that information processed by MDN and relayed to the prefrontal cortex is required for somatomotor response selection under nonoptimal learning conditions.     

Stria Terminalis Lesions Attenuate Memory Enhancement Produced by Intracaudate Nucleus Injections of Oxotremorine

The present study examined the role of the stria terminalis in modulating the memory enhancement produced by posttraining intracaudate nucleus injection of oxotremorine. Male Sprague–Dawley rats with either sham operations or bilateral lesions of the stria terminalis (ST) were trained on a one-trial inhibitory-avoidance task and received a unilateral posttraining intracaudate injection of either a buffer vehicle or the cholinergic agonist oxotremorine (0.3 μg/0.5 μl) into a medial region of the caudate nucleus innervated by the ST. Intracaudate injection of oxotremorine improved memory in sham-operated rats. Although ST lesions did not affect retention in rats given intracaudate injections of the buffer vehicle, ST lesions attenuated the memory enhancement produced by posttraining intracaudate injection of oxotremorine. In view of anatomical evidence indicating that amygdalostriatal projections are nonreciprocol, the present findings suggest that amygdalaoutputvia the ST is essential for memory enhancement produced by intracaudate injection of oxotremorine.     

Kainic acid lesions disrupt fear-mediated memory processing

Previous research has shown that hippocampal lesions impair the expression of fear conditioning. This fear conditioning deficit may be due to memory impairment or a reduction in fear in lesioned animals. To address these possibilities, the authors examined unconditioned and conditioned fear in male Sprague-Dawley rats that had received intracerebroventricular (ICV) infusions of kainic acid (KA) 30 days prior to testing. Animals that had received bilateral ICV infusions of KA (1.0 microl of 0.8 mg/ml solution per side) exhibited cell loss that was primarily confined to the CA3 region of the dorsal hippocampus. Kainic acid lesions impaired contextual and cued fear conditioning but did not affect unconditioned fear in a light:dark test of anxiety. Moreover, animals with KA lesions did not habituate to the light:dark apparatus when tested over a 3-day period. These data suggest that decreases in fear conditioning produced by hippocampal lesions reflect a memory deficit and not a lack of fear.     

Open-field and avoidance behavior after neostriatal lesions in male and female rats.

The behavioral effects of lesions of the anterodorsal or posteroventral parts of the caudate-putamen were studied in adult male and femle rats that were gonadectomized or left untreated prior to brain surgery. Anterodorsal (ADC) lesions consistently impaired acquistion of one-way avoidance behavior and tended to interfere with the development of a two-way avoidance response; comparable effects were observed in gonadectomized and intact animals of both sexes. By contrast, ADC lesions increased activity in the open field only in intact females and increased rearing only in ovariectomized females. Posteroventral caudate (PVC) lesions caused transient aphagia and adipsia in both sexes but did not consistently affect open-field activity or the acquistion of one-way avoidance responses by either sex. These lesions profoundly impaired acquistion of shuttle box avoidance responses by intact males. By contrast, castrated males and intact and ovariectomized females with PVC lesions avoided normally in the shuttle box. The present results suggest that localization of behavioral functions within the striatum differs with the sex of the subject, in part because of activational effects of gonadal hormones.     

Caudate nucleus and memory for egocentric localization

A large body of evidence suggests that the caudate nucleus (CN) plays a critical role in the processing of spatial localization information. Furthermore, evidence has begun to accumulate that the CN is involved in the processing of a very specific class of spatial cues, namely, egocentric cues (localization with reference to the organism). This is in contrast to allocentric localization, where an organism localizes on the basis of cues external to the organism. One would then predict that lesions to the CN should disrupt performance on any tasks that depend chiefly on egocentric spatial cues, while leaving performance on allocentric tasks intact. To test this prediction, two groups of rats were trained on two different egocentric memory tasks and two different allocentric memory tasks. Specifically, one group of rats was trained on an adjacent-arm (egocentric) and an 8-arm radial maze task (allocentric). A second group of rats was trained on a right-left discrimination (egocentric) and a place-learning task (allocentric). After training, both groups received bilateral lesions of the CN. Results showed that CN-lesioned animals were profoundly impaired on retention of the egocentric tasks. In sharp contrast to this, the same animals were not or were only transiently impaired or transiently affected on allocentric tasks. Sham-operated controls were either unimpaired or transiently affected on all tasks. These findings further support the idea that the CN plays a critical modulatory role in the processing of egocentric spatial and not allocentric spatial cues.     

Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy

192IgG-saporin (SAP) was used to selectively destroy cholinergic neurons in the rostral basal forebrain (e.g., medial septum (MS) and vertical limb of the diagonal band of Broca (VDB)) and/or the caudal basal forebrain (e.g., nucleus basalis magnocellularis (NBM)) of ovariectomized Sprague-Dawley rats. The effects of these lesions on two different cognitive tasks, a delayed matching to position (DMP) T-maze task, and a configural association (CA) operant conditioning task, were evaluated and compared. Injecting SAP into either the MS or NBM significantly impaired acquisition of the DMP task. Analysis showed that the effects were due largely to an affect on response patterns adopted by the rats during training, as opposed to an effect on working memory performance. Notably, the impairment in DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. Despite the deficit, most animals eventually learned the task and reached criterion; however by the end of training, controls and animals that received SAP into either the MS or NBM appeared more likely to use an allocentric place strategy to solve the task, whereas animals that received SAP into both the MS and NBM were more likely to use an egocentric response strategy. Cholinergic lesions also produced a small but significant affect on acquisition of the CA task, but only with respect to response time, and only in the SAP-NBM-treated animals. SAP-NBM lesions also produced small but significant impairments in both the number of responses and response time during the acquisition of simple associations, possibly reflecting an effect on alertness or attention. Notably, the effects on CA acquisition were small, and like the effects on DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. We conclude that selective basal forebrain cholinergic lesions produce learning deficits that are task specific, and that cholinergic denervation of either the frontal cortex or hippocampus can affect response patterns and strategy in ways that affect learning, without necessarily reflecting deficits in working memory performance.     

Differences in feedback- and inhibition-related neural activity in adult ADHD

The objective of this study was to examine response inhibition- and feedback-related neural activity in adults with attention deficit hyperactivity disorder (ADHD) using event-related functional MRI. Sixteen male adults with ADHD and 13 healthy/normal controls participated in this study and performed a modified Go/NoGo task. Behaviourally, attention and inhibition problems in the ADHD group were observed; no feedback-related differences between the groups were detected. The neuroimaging data showed that the ADHD group displayed more activation in the inferior frontal gyrus and putamen during response inhibition. During feedback-related processes, the ADHD group displayed less activation in the inferior frontal/orbitofrontal cortex, hippocampus/nucleus accumbens, and caudate nucleus, but more activity in the inferior frontal gyrus. These results indicate that at least two distinguishable underlying brain networks related to response inhibition and feedback are altered in adults with ADHD.     

Disconnection analysis of CA3 and DG in mediating encoding but not retrieval in a spatial maze learning task

The dentate gyrus (DG) subregion of the hippocampus has been shown to be involved in encoding but not retrieval in a spatial maze task (modified Hebb-Williams maze). The first experiment in this study examined whether a lesion to the CA3 would contribute to a similar encoding deficit. A DG group was included in order to replicate previous results. Relative to controls, animals receiving CA3 lesions were impaired in encoding, not retrieval, on the modified Hebb-Williams maze--similar to a group that received DG lesions. This suggests the possibility that CA3 and DG are working together to mediate encoding processes. The second experiment in this study was designed to test the interaction between CA3 and DG using a disconnection paradigm. Animals with contralateral lesions (CA3 lesioned in one hemisphere, DG lesioned in the other hemisphere) showed a significant disruption effect on encoding, but not retrieval, when compared with animals with ipsilateral lesions (CA3 and DG lesioned in the same hemisphere, leaving the other hemisphere intact). This suggests an interaction between CA3 and DG in supporting encoding but not retrieval processes in a spatial maze learning task.     

Lesions in the Central Nucleus of the Amygdala: Discriminative Avoidance Learning, Discriminative Approach Learning, and Cingulothalamic Training-Induced Neuronal Activity

The amygdala is critically involved in discriminative avoidance learning. Large lesions of the amygdala block discriminative avoidance learning and abolish cingulothalamic training-induced neuronal activity. These results indicated that amygdalar processing is critical for cingulothalamic plasticity. The larger lesions did not allow differentiation of the specific functioning of various amygdalar nuclei. Anatomical analysis showed that damage in the central (CE) nucleus of the amygdala was correlated with the severity of the behavioral deficit. The present study was carried out to determine whether smaller lesions, centered in the CE nucleus, would impair discriminative avoidance learning and block cingulothalamic plasticity. In addition, the possible role of the CE nucleus in appetitively motivated discriminative approach learning was examined for the first time. New Zealand White rabbits with CE nuclear lesions were first trained in the discriminative approach task. After attaining asymptotic performance, discriminative avoidance training sessions were alternated with continuing approach training sessions, one session each day. The rabbits with lesions were severely impaired in avoidance learning but showed no impairment of approach learning. Surprisingly, the attenuating effects of the lesions on cingulothalamic training-induced neuronal activity were more prevalent during approach learning than during avoidance learning. These results indicated that avoidance learning can be impaired by lesions centered in the CE nucleus that leave cingulothalamic plasticity largely intact and that the CE nucleus is involved in extra-cingulothalamic learning processes.     

Electrolytic, but not 5,7-dihydroxytryptamine, lesions of the nucleus medianus raphe impair acquisition of a radial maze task

We have previously reported that electrolytic lesions of the nucleus medianus raphe (MR) produce a deficit in the acquisition of an 8-arm radial maze task (Wirtshafter and Asin 1983). In an attempt to determine whether or not this deficit is secondary to serotonin depletion resulting from the lesion, we investigated and compared the effects of electrolytic and 5,7-dihydroxytryptamine (5,7-DHT) lesions of the MR on the acquisition of the radial maze task. Although forebrain serotonin levels after 5,7-DHT injections were reduced as much as those following electrolytic lesions, only rats with an electrolytic MR lesion were impaired on the acquisition of both a free-running maze task and on a related task, where animals were replaced into the same arm between arm choices. In contrast, 5,7-DHT-treated rats were unimpaired on both tasks compared to an ascorbate-injected control group. These findings provide further evidence that most of the profound behavioral deficits shown by rats with electrolytic MR damage are not due to serotonin depletion and are consistent with the results of other studies indicating strong similarities between the behavioral effects of limbic and MR lesions.     

Serotonin, the superior colliculus, and grooming behavior in cats with neocortical lesions.

Previous studies of cats with pontile lesions indicate that a serotonergic deficit exists in the superior colliculi and that this deficit is involved in the genesis of an abnormal grooming behavior. Cats with frontal neocortical lesions exhibit the same serotonergic deficit and the same abnormal grooming behavior. The present study established that the serotonergic deficit is involved in the mediation of the abnormal grooming behavior in cats with frontal neocortical lesions. Microinjections of 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) into the superior colliculi abolished or signigicantly reduced the abnormal behavior in cats with frontal neocortical lesions, whereas no effects of 5-HTP were observed after injections into the cerebrospinal fluid above the superior colliculi, into the tegmentum beneath the superior colliculi, or into the medial dorsal nucleus rostral to the superior colliculi. Other substances (tryptophan, noradrenaline, and gamma-amino-butyric acid) had no effect on the abnormal behavior when injected into the superior colliculi. Further evidence implicating a serotonergic deficit in the mediation of the abnormal behavior was obtained by systemic injections: The abnormal behavior was abolished with 5-HTP in cats with frontal neocortical lesions and in adrenalectomized cats that were previously treated with p-chlorophenylalanine.. The present study also demonstrated that the abnormal grooming behavior is induced by frontal neocortical lesions and not by more caudal lesions of the neocortex. The anatomical relations between the frontal neocortex and the superior colliculus and the role of these structures in grooming behavior are discussed.     

Evidence for the thalamic targets of the medial hypothalamic defensive system mediating emotional memory to predatory threats

Previous studies from our laboratory have documented that the medial hypothalamic defensive system is critically involved in processing actual and contextual predatory threats, and that the dorsal premammillary nucleus (PMd) represents the hypothalamic site most responsive to predatory threats. Anatomical findings suggest that the PMd is in a position to modulate memory processing through a projecting branch to specific thalamic nuclei, i.e., the nucleus reuniens (RE) and the ventral part of the anteromedial nucleus (AMv). In the present study, we investigated the role of these thalamic targets in both unconditioned (i.e., fear responses to predatory threat) and conditioned (i.e., contextual responses to predator-related cues) defensive behaviors. During cat exposure, all experimental groups exhibited intense defensive responses with the animals spending most of the time in the home cage displaying freezing behavior. However, during exposure to the environment previously associated with a cat, the animals with combined RE + AMv lesions, and to a lesser degree, animals with single AMv unilateral lesions, but not animals with single RE lesions, presented a reduction of contextual conditioned defensive responses. Overall, the present results provide clear evidence suggesting that the PMd’s main thalamic targets (i.e., the nucleus reuniens and the AMv) seem to be critically involved in the emotional memory processing related to predator cues.     

Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats

The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the nucleus basalis magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 microg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the nucleus basalis magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.     

Response biases do not underlie the radial maze deficit in rats with mediodorsal thalamus lesions

Previous results indicating that radial maze performance in animals with mediodorsal thalamic lesions is deficient cannot exclude the possibility that these impairments are due to altered motor mechanisms (response biases). The present study sought to eliminate this potentially confounding variable by using a procedure which tests memory for serial position. This procedure involved experimenter-controlled arm entry (number and order) on a radial arm maze. Following this sequence, animals were presented with one previously entered arm along with an arm not yet visited on that trial. Avoidance of the previously entered arm constituted memory for the prior sequence. Thus, this task represents a form of a win-shift or nonmatching-to-sample task. Seven animals were given ibotenic acid lesions of the mediodorsal nucleus and nine others were given sham operations; 2 weeks later testing in the above procedure was conducted. Results indicated that, although control subjects could differentiate between entered and unentered arms without difficulty, animals with lesions were unable to exhibit this distinction. Much of their memory for arms previously entered in a sequence was at chance level, regardless of the placement of the tested arm in the sequence. Some tendency toward increased errors with longer sequences of arm entries was noted. This may indicate that animals with lesions were susceptible to proactive interference from previous choices. Regardless, even without the opportunity to develop or exhibit response biases, animals lesioned in the mediodorsal nucleus were unable to perform this win-shift task reliably. Thus, discrimination among maze arms is impaired after lesion of the mediodorsal nucleus and this impairment is independent of the motor response patterns which emerge during solution of a conventional radial maze task.     

Neural correlates of social perception on response bias

Accurate person perception is crucial in social decision-making. One of the central elements in successful social perception is the ability to understand another’s response bias; this is because the same behavior can represent different inner states depending on whether other people are yea-sayers or naysayers. In the present study, we have tried to investigate how the internal biases of others are perceived. Using a multi-trial learning paradigm, perceivers made predictions about a target’s responses to various suggested activities and then received feedback for each prediction trial-by-trial. Our hypotheses were that (1) the internal decision criterion of the targets would be realized through repeated experiences, and (2) due to positive–negative asymmetry, yea-sayers would be recognized more gradually than naysayers through the probabilistic integration of repeated experiences. To find neural evidence that tracks probabilistic integration when forming person knowledge on response biases, we employed a model-based fMRI with a State-Space Model. We discovered that person knowledge about yea-sayers modulated several brain regions, including caudate nucleus, DLPFC, hippocampus, etc. Moreover, when person knowledge was updated with incorrect performance feedback, brain regions including the caudate nucleus, DLPFC, dmPFC, and TPJ were also involved. There were overlapping regions for both processes, caudate nucleus and DLPFC, suggesting that these regions take crucial roles in forming person knowledge with repeated feedback, while reflecting acquired information up to the current prediction.     

Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats.

Rats with cannulas aimed at the posteroventral (PV) or ventrolateral (VL) areas of the caudate nucleus were trained on a conditioned emotional response (CER) task. Post-training microinjections of the indirect catecholamine agonist, d-amphetamine (5 micrograms), or of the dopamine D2 receptor agonist, LY171555 (1 microgram), into the PV area improved retention of a CER with a visual CS, but had no effect on a CER with an olfactory CS. Post-training injections of the same two drugs into the VL area improved retention of a CER with an olfactory CS, but had no effect on a CER with a visual CS. Post-training injections of the dopamine D1 receptor agonist, SKF38393 (0.5, 1.0, 2.0 micrograms), into either site had no effects on either CER. These findings suggest that different areas of the caudate nucleus mediate acquisition of CERs with different CSs, possibly implicating the topographically organized corticostriatal innervation in the acquisition of certain types of memories in the caudate nucleus. The findings also suggest that dopamine D2 receptors in the caudate nucleus are involved in the acquisition of these CERs.