The Effects of Muscarinic Cholinergic Receptor Blockade in the Rat Anterior Cingulate and Prelimbic/Infralimbic Cortices on Spatial Working Memory

Previous findings indicate that cholinergic input to the medial prefrontal cortex may modulate mnemonic processes. The present experiment determined whether blockade of muscarinic cholinergic receptors in the rodent anterior cingulate and prelimbic/infralimbic cortices impairs spatial working memory. In a 12-arm radial maze, a working memory for spatial locations task was employed using a continuous recognition go/no-go procedure. Rats were allowed to enter 12 arms for a reinforcement. Of the 12 arm presentations, 3 or 4 arms were presented for a second time in a session that did not contain a reinforcement. The number of trials between the first and second presentations of an arm ranged from 0 to 6 (lags). Infusions of scopolamine (1, 5, and 10 μg), a muscarinic cholinergic antagonist, into the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, significantly impaired spatial working memory in a lag- and dose-dependent manner. The deficit induced by scopolamine (10 μg) was attenuated by concomitant intraprelimbic/infralimbic injections of oxotremorine (2 μg), a muscarinic cholinergic agonist. A separate group of rats was tested on a successive spatial discrimination task. Injections of scopolamine (1, 5, and 10 μg) into the prelimbic/infralimbic cortices did not impair performance on the spatial discrimination task. These findings suggest that muscarinic transmission in the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, is important for spatial working memory.     

Memory for Duration: Role of Hippocampus and Medial Prefrontal Cortex

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).     

Medial prefrontal cortex lesions abolish contextual control of competing responses

There is much debate as to the extent and nature of functional specialization within the different subregions of the prefrontal cortex. The current study was undertaken to investigate the effect of damage to medial prefrontal cortex subregions in the rat. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two different contexts. At test, they received presentations of audiovisual compounds of these training stimuli in extinction. These compounds had dictated either the same (congruent trials) or different (incongruent trials) responses during training. In sham-operated controls, contextual cues came to control responding to conflicting information provided by incongruent stimulus compounds. Experiment 1 demonstrated that this contextual control of responding was not evident in individual rats with large amounts of damage that included the prelimbic and cingulate subregions of the prefrontal cortex. Experiment 2 further dissociated the result of Experiment 1, demonstrating that lesions specific to the anterior cingulate cortex were sufficient to produce a deficit early on during presentation of an incongruent stimulus compound but that performance was unimpaired as presentation progressed. This early deficit suggests a role for the anterior cingulate cortex in the detection of response conflict, and for the medial prefrontal cortex in the contextual control of competing responses, providing evidence for functional specialization within the rat prefrontal cortex.     

Differential involvement of prefrontal cortex,striatum, and hippocampus in DRL performance in mice

Behavioral effects of neurotoxic lesions of the hippocampus, medial prefrontal (prelimbic, infralimbic and anterior cingulate) cortex or dorsal striatum were assessed using a DRL-10s schedule in mice. Post-operative acquisition data indicate that mice with hippocampal, but not prefrontal or striatal lesions received fewer reinforcements during daily 30-min sessions, and were less efficient in the timing of their responses. Additional analysis of inter-response-time (IRT) distributions revealed that the responses of hippocampal-lesioned mice exhibited undistinguishable responses for short IRTs (up to 9s). In addition, prefrontal-lesioned mice demonstrated a degradation of performance with further testing, and a flattened IRT distribution at late test phase, while striatal-lesioned mice behaved similarly to sham-lesioned mice. These results are interpreted in terms of known functions of the hippocampus in behavioral inhibition, and of the prefrontal cortex in executive control/decision making (and time production).     

The effects of prelimbic and infralimbic lesions on working memory for visual objects in rats.

The present experiment investigated the effects of quinolinic acid (90 mM) lesions of the prelimbic-infralimbic cortices on working memory for visual objects and on acquisition of a visual object discrimination. In both tests a GO/NO-GO procedure was used. In the working memory task, rats were tested before and after surgery. A continuous recognition procedure was used to assess working memory, which involved successive exposure to different three-dimensional objects that could be displaced to receive a cereal reinforcement. Of the 12 object presentations/session, 4 objects were presented for a second time in which displacing the object did not result in a reinforcement. The number of trials between the first and second presentations of an object ranged from 0 to 3 (lags). Memory was assessed by the latency to displace an object during the second presentation. In the visual object discrimination, rats had successive exposure to two different objects. Displacement of one object resulted in a cereal reinforcement, while displacement of the other did not. The findings indicated that prelimbic-infralimbic lesions significantly impaired memory for visual objects across all lags. Prelimbic-infralimbic lesions did not impair acquisition of the visual object discrimination. The results suggest that the prelimbic-infralimbic areas are part of neural system important in the short-term memory for visual objects.     

A neural circuit analysis of visual recognition memory: role of perirhinal, medial, and lateral entorhinal cortex

Using a continuous recognition memory procedure for visual object information, we sequentially presented rats with eight novel objects and four repeated objects (chosen from the 8). These were selected from 120 different three-dimensional objects of varying sizes, shapes, textures, and degree of brightness. Repeated objects had lags ranging from 0 to 4 (from 0 to 4 different objects between the first and repeated presentation). An object was presented on one side of a long table divided in half by an opaque Plexiglas guillotine door, and the latency between opening the door and the rat moving the object was measured. The first presentation of an object resulted in reinforcement, but repeated presentations did not result in a reinforcement. After completion of acquisition training (significantly longer latencies for repeated presentation compared with the first presentation of an object), rats received lesions of the perirhinal, medial, or lateral entorhinal cortex or served as sham operated controls. On the basis of postsurgery testing and additional tests, the results indicated that rats with perirhinal cortex lesions had a sustained impairment in performing the task. There were no sustained deficits with medial or lateral entorhinal cortex lesions. The data suggest that recognition memory for visual object information is mediated primarily by the perirhinal cortex but not by the medial or lateral entorhinal cortex.     

The synergy of working memory and inhibitory control: behavioral, pharmacological and neural functional evidences

Concomitant deficits in working memory and behavioral inhibition in several psychiatric disorders like attention-deficit/hyperactivity disorder, addiction or mania, suggest that common brain mechanisms may underlie their etiologies. Based on the theoretical assumption that a continuum exists between health and mental disorders, we explored the relationship between working memory and inhibition in healthy individuals, through spontaneous inter individual differences in behavior, and tested the hypothesis of a functional link through the fronto-striatal dopaminergic system. Rats were classified into three groups, showing good, intermediate and poor working memory and were compared for their inhibitory abilities. These two functions were simultaneously modulated by a dose-effect of d-amphetamine and in situ hybridization was used to quantify dopaminergic receptor (RD1) mRNAs in prefrontal cortex and striatal areas. A functional relationship between working memory and inhibition abilities was revealed. Both functions were similarly modulated by d-amphetamine according to an inverted-U shaped relationship and depending on initial individual performances. D-amphetamine selectively improved working memory and inhibition of poor and intermediate performers at low doses whereas it impaired both processes in good performers at a higher dose. D1 receptors were less expressed in prelimbic, infralimbic and anterior cingulate cortices of good compared to intermediate and poor performers, whereas no difference was observed between groups in striatal areas. The synergy of working memory and inhibitory abilities, observed in both healthy and psychiatric populations, may originate from endogenous variability in dopaminergic prefrontal cortex activity. Such findings confirm the validity of a dimensional approach, based on the concept of continuity between health and mental disorders for identifying endophenotypes of mental disorders.     

Incidental visual memory for objects in scenes

Three experiments were conducted to investigate the existence of incidentally acquired, long-term, detailed visual memory for objects embedded in previously viewed scenes. Participants performed intentional memorization and incidental visual search learning tasks while viewing photographs of real-world scenes. A visual memory test for previously viewed objects from these scenes then followed. Participants were not aware that they would be tested on the scenes following incidental learning in the visual search task. In two types of memory tests for visually specific object information (token discrimination and mirror-image discrimination), performance following both the memorization and visual search conditions was reliably above chance. These results indicate that recent demonstrations of good visual memory during scene viewing are not due to intentional scene memorization. Instead, long-term visual representations are incidentally generated as a natural product of scene perception.     

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.     

Recognition memory for complex visual discriminations is influenced by stimulus interference in rodents with perirhinal cortex damage

Rats with perirhinal cortex (PRC), hippocampal, or sham lesions were trained on a successive discrimination go/no-go task to examine recognition memory for an array of visual objects with varying interference among the objects in the array. Rats were trained to recognize a target array consisting of four particular objects that could be presented in any one of four possible configurations to cover baited food wells. If the four target objects were presented, the rat should displace each object to receive food. However, if a novel object replaced any one or more of the target objects, then the rat should withhold its response. The number of novel objects presented on nonrewarded trials varied from one to four. The fewer the number of novel objects in the array, the more interference the array shared with the target array, therefore increasing task difficulty. An increased number of novel objects should result in less interference with the target array and decreased task difficulty. Although accuracy was slightly lower in rats with hippocampal lesions compared with controls, the learning of the groups was not statistically different. In contrast, rats with PRC lesions were significantly impaired in learning compared with both control and hippocampal-lesioned rats. The results suggest that recognition memory for complex visual discriminations is affected by stimulus interference in rodents with PRC damage.     

Encoding and retrieval are differentially processed by the anterior cingulate and prelimbic cortices: A study based on trace eyeblink conditioning in the rabbit

A growing body of literature suggests that structures along the midline of the prefrontal cortex (mPFC), including Brodmann’s area 32 (prelimbic cortex) and area 24 (anterior cingulate cortex) in the rabbit play a role in retrieval of learned information. The present studies compared the effects of post-training lesions produced either immediately or 1-week following learning, to either prelimbic (area 32) or anterior cingulate (area 24) cortex on trace eyeblink (EB) conditioning. Further, because recent evidence suggests that the mPFC may play an even greater role in learning and memory when emotional arousal is low, these studies compared the effects of lesions in groups conditioned with either a relatively low-arousal corneal airpuff, or a more aversive periorbital eyeshock unconditioned stimulus (US). A total of six groups were tested, which received selective ibotenic acid or “sham” control lesions to either area 32 or 24, immediately or 1-week following asymptotic learning, and conditioned with an eyeshock US or an airpuff US. Results showed that the greatest lesion deficits were found when conditioning with the less aversive airpuff US. Further, lesions produced to area 32 one-week, but not immediately following learning, caused significant deficits in performance, while lesions produced to area 24 immediately, but not 1-week following learning, caused significant deficits in performance. These findings add to the body of evidence which shows that area 32 of the mPFC regulates retrieval, but not acquisition or storage of information, while area 24 mediates a less specific reacquisition process, but not permanent storage or retrieval of information during relearning of memories abolished by mPFC damage. These findings were, however, specific to those experiments in which the relatively non-aversive airpuff was the US.     

Dissociation between the effects of damage to perirhinal cortex and area TE

Perirhinal cortex and area TE are immediately adjacent to each other in the temporal lobe and reciprocally interconnected. These areas are thought to lie at the interface between visual perception and visual memory, but it has been unclear what their separate contributions might be. In three experiments, monkeys with bilateral lesions of the perirhinal cortex exhibited a different pattern of impairment than monkeys with bilateral lesions of area TE. In experiment 1, lesions of the perirhinal cortex produced a multimodal deficit in recognition memory (delayed nonmatching to sample), whereas lesions of area TE impaired performance only in the visual modality. In experiment 2, on a test of visual recognition memory (the visual paired comparison task) lesions of the perirhinal cortex impaired performance at long delays but spared performance at a very short delay. In contrast, lesions of area TE impaired performance even at the short delay. In experiment 3, lesions of the perirhinal cortex and lesions of area TE produced an opposite pattern of impairment on two visual discrimination tasks, simple object discrimination learning (impaired only by perirhinal lesions), and concurrent discrimination learning (impaired only by TE lesions). Taken together, the findings suggest that the perirhinal cortex, like other medial temporal lobe structures, is important for the formation of memory, whereas area TE is important for visual perceptual processing.     

Perseverative interference with object-in-place scene learning in rhesus monkeys with bilateral ablation of ventrolateral prefrontal cortex

Surgical disconnection of the frontal cortex and inferotemporal cortex severely impairs many aspects of visual learning and memory, including learning of new object-in-place scene memory problems, a monkey model of episodic memory. As part of a study of specialization within prefrontal cortex in visual learning and memory, we tested monkeys with bilateral ablations of ventrolateral prefrontal cortex in object-in-place scene learning. These monkeys were mildly impaired in scene learning relative to their own preoperative performance, similar in severity to that of monkeys with bilateral ablation of orbital prefrontal cortex. An analysis of response types showed that the monkeys with lesions were specifically impaired in responding to negative feedback during learning: The post-operative increase in errors was limited to trials in which the first response to each new problem, made on the basis of trial and error, was incorrect. This perseverative pattern of deficit was not observed in the same analysis of response types in monkeys with bilateral ablations of the orbital prefrontal cortex, who were equally impaired on trials with correct and incorrect first responses. This may represent a specific signature of ventrolateral prefrontal involvement in episodic learning and memory.     

Does scene context always facilitate retrieval of visual object representations?

An object-to-scene binding hypothesis maintains that visual object representations are stored as part of a larger scene representation or scene context, and that scene context facilitates retrieval of object representations (see, e.g., Hollingworth, Journal of Experimental Psychology: Learning, Memory and Cognition, 32, 58-69, 2006). Support for this hypothesis comes from data using an intentional memory task. In the present study, we examined whether scene context always facilitates retrieval of visual object representations. In two experiments, we investigated whether the scene context facilitates retrieval of object representations, using a new paradigm in which a memory task is appended to a repeated-flicker change detection task. Results indicated that in normal scene viewing, in which many simultaneous objects appear, scene context facilitation of the retrieval of object representations-henceforth termed object-to-scene binding-occurred only when the observer was required to retain much information for a task (i.e., an intentional memory task).     

Cortical dynamics of contextually cued attentive visual learning and search: spatial and object evidence accumulation

How do humans use target-predictive contextual information to facilitate visual search? How are consistently paired scenic objects and positions learned and used to more efficiently guide search in familiar scenes? For example, humans can learn that a certain combination of objects may define a context for a kitchen and trigger a more efficient search for a typical object, such as a sink, in that context. The ARTSCENE Search model is developed to illustrate the neural mechanisms of such memory-based context learning and guidance and to explain challenging behavioral data on positive-negative, spatial-object, and local-distant cueing effects during visual search, as well as related neuroanatomical, neurophysiological, and neuroimaging data. The model proposes how global scene layout at a first glance rapidly forms a hypothesis about the target location. This hypothesis is then incrementally refined as a scene is scanned with saccadic eye movements. The model simulates the interactive dynamics of object and spatial contextual cueing and attention in the cortical What and Where streams starting from early visual areas through medial temporal lobe to prefrontal cortex. After learning, model dorsolateral prefrontal cortex (area 46) primes possible target locations in posterior parietal cortex based on goal-modulated percepts of spatial scene gist that are represented in parahippocampal cortex. Model ventral prefrontal cortex (area 47/12) primes possible target identities in inferior temporal cortex based on the history of viewed objects represented in perirhinal cortex.     

Anterior cingulate cortex and cognitive control: Neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex

Whereas neuroimaging studies of healthy subjects have demonstrated an association between the anterior cingulate cortex (ACC) and cognitive control functions, including response monitoring and error detection, lesion studies are sparse and have produced mixed results. Due to largely normal behavioral test results in two patients with medial prefrontal lesions, a hypothesis has been advanced claiming that the ACC is not involved in cognitive operations. In the current study, two comparably rare patients with unilateral lesions to dorsal medial prefrontal cortex (MPFC) encompassing the ACC were assessed with neuropsychological tests as well as Event-Related Potentials in two experimental paradigms known to engage prefrontal cortex (PFC). These included an auditory Novelty Oddball task and a visual Stop-signal task. Both patients performed normally on the Stroop test but showed reduced performance on tests of learning and memory. Moreover, altered attentional control was reflected in a diminished Novelty P3, whereas the posterior P3b to target stimuli was present in both patients. The error-related negativity, which has been hypothesized to be generated in the ACC, was present in both patients, but alterations of inhibitory behavior were observed. Although interpretative caution is generally called for in single case studies, and the fact that the lesions extended outside the ACC, the findings nevertheless suggest a role for MPFC in cognitive control that is not restricted to error monitoring.     

Time-courses of Fos expression in rat hippocampus and neocortex following acquisition and recall of a socially transmitted food preference

The present study examined expression of the immediate-early gene, c-Fos, following acquisition, 48-h (recent) recall, and 1-week (remote) recall of a socially transmitted food preference (STFP) in multiple brain regions implicated in learning and memory. In comparisons with controls, trained Long-Evans rats had increased Fos immunoreactivity in the ventral hippocampus following acquisition and recent recall. In the parahippocampal cortices, Fos was increased in the lateral entorhinal cortex after acquisition. In the orbitofrontal cortex, increased Fos immunoreactivity was observed in the lateral orbital cortex following both recent and remote recall and in the ventral orbital cortex following remote recall, indicating a role for the orbitofrontal cortex in the remote recall of STFP memory. In contrast, in the medial prefrontal cortex, increased Fos-ir was found following acquisition in the prelimbic cortex and following recent recall in the prelimbic and infralimbic cortices. No differences in Fos expression were found between trained rats and controls in the dorsal hippocampus, posterior parietal cortex, or amygdala. The present findings support a time-limited role of the hippocampus in the acquisition and recall of STFP memory and implicate neocortical regions involved in STFP acquisition, recent, and remote recall.     

视空工作记忆负载对场景主旨加工的影响

本研究采用工作记忆任务和场景辨别任务相结合的双任务范式探究客体工作记忆负载 (实验1)和空间工作记忆负载 (实验2) 对场景主旨辨别的影响。结果发现: (1) 与无负载条件相比, 客体负载条件下的非参辨别力指数(A’)明显下降, 而空间负载条件下A’无明显变化; (2) 随着场景图片呈现时间的延长, 场景辨别任务的A’逐渐提高; (3) 对自然场景和人工场景匹配情况下的A’ 明显高于对自然与自然或者人工与人工匹配情况下的A’。由此可见, 场景主旨识别, 特别是基本水平的场景主旨辨别, 与客体工作记忆共享部分认知资源, 而不与/很少与空间工作记忆共享认知资源; 在识别过程中, 上级水平范畴识别优先于基本水平范畴识别, 进一步支持了上级水平范畴优先的主旨层级加工观点。     

Extinction partially reverts structural changes associated with remote fear memory

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic (ILC) cortices 36 d following contextual fear conditioning. Upon extinction, aCC spine density returned to baseline, but the enhanced proportion of large spines did not. Differently, ILC spine density remained elevated, but the size of spines decreased dramatically. Thus, extinction partially erases the remote memory network, suggesting that the preserved network properties might sustain reactivation of extinguished conditioned fear.     

Object-position binding in visual memory for natural scenes and object arrays

Nine experiments examined the means by which visual memory for individual objects is structured into a larger representation of a scene. Participants viewed images of natural scenes or object arrays in a change detection task requiring memory for the visual form of a single target object. In the test image, 2 properties of the stimulus were independently manipulated: the position of the target object and the spatial properties of the larger scene or array context. Memory performance was higher when the target object position remained the same from study to test. This same-position advantage was reduced or eliminated following contextual changes that disrupted the relative spatial relationships among contextual objects (context deletion, scrambling, and binding change) but was preserved following contextual change that did not disrupt relative spatial relationships (translation). Thus, episodic scene representations are formed through the binding of objects to scene locations, and object position is defined relative to a larger spatial representation coding the relative locations of contextual objects.