The cerebellum and cognition: cerebellar lesions do not impair spatial working memory or visual associative learning in monkeys

Anatomical studies in non-human primates have shown that the cerebellum has prominent connections with the dorsal, but not the ventral, visual pathways of the cerebral cortex. Recently, it has been shown that the dorsolateral prefrontal cortex (DPFC) and cerebellum are interconnected in monkeys. This has been cited in support of the view that the cerebellum may be involved in cognitive functions, e.g. working memory. Six monkeys (Macaca fascicularis) were therefore trained on a classic test of working memory, the spatial delayed alternation (SDA) task, and also on a visual concurrent discrimination (VCD) task. Excitotoxic lesions were made in the lateral cerebellar nuclei, bilaterally, in three of the animals. When retested after surgery the lesioned animals were as quick to relearn both tasks as the remaining unoperated animals. However, when the response times (RT) for each task were directly compared, on the SDA task the monkeys with cerebellar lesions were relatively slow to decide where to respond. We argue that on the SDA task animals can prepare their responses between trials whereas this is not possible on the VCD task, and that the cerebellar lesions may disrupt this response preparation. We subsequently made bilateral lesions in the DPFC of the control animals and retested them on the SDA task. These monkeys failed to relearn the task. The results show that, unlike the dorsal prefrontal cortex, the cerebellum is not essential for working memory or the executive processes that are necessary for correct performance, though it may contribute to the preparation of responses.     

Flexible spatial learning requires both the dorsal and ventral hippocampus and their functional interactions with the prefrontal cortex

When faced with changing contingencies, animals can use memory to flexibly guide actions, engaging both frontal and temporal lobe brain structures. Damage to the hippocampus (HPC) impairs episodic memory, and damage to the prefrontal cortex (PFC) impairs cognitive flexibility, but the circuit mechanisms by which these areas support flexible memory processing remain unclear. The present study investigated these mechanisms by temporarily inactivating the medial PFC (mPFC), the dorsal HPC (dHPC), and the ventral HPC (vHPC), individually and in combination, as rats learned spatial discriminations and reversals in a plus maze. Bilateral inactivation of either the dHPC or vHPC profoundly impaired spatial learning and memory, whereas bilateral mPFC inactivation primarily impaired reversal versus discrimination learning. Inactivation of unilateral mPFC together with the contralateral dHPC or vHPC impaired spatial discrimination and reversal learning, whereas ipsilateral inactivation did not. Flexible spatial learning thus depends on both the dHPC and vHPC and their functional interactions with the mPFC.     

The medial prefrontal cortex—lateral entorhinal cortex circuit is essential for episodic‐like memory and associative object‐recognition

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item‐associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic‐like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic‐like (what‐where‐when) and object‐recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic‐like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic‐like and associative object‐recognition memory. © 2015 Wiley Periodicals, Inc.     

Excitotoxic lesions of the rhinal cortex in the baboon differentially affect visual recognition memory, habit memory and spatial executive functions

To specify the functional role of the rhinal cortex, baboons with bilateral excitotoxic lesions of the rhinal cortex (RH group) were tested on a series of computerized memory and learning tasks. Preoperatively, they were trained to and then tested on a delayed nonmatching-to-sample (DNMS) task with trial-unique stimuli. Postoperatively, this visual recognition memory task was given twice. As compared to a sham-operated group, the RH group showed good retention of rule learning and were unimpaired on the Delay memory subtest. Performance on the List Length memory subtest was, however, severely impaired at both postoperative evaluations, with a significant negative correlation between cognitive performance and neuronal loss in rhinal areas. Visual habit memory and spatial working memory were assessed postoperatively only, using a concurrent discrimination learning task and both a delayed-response task (with a two- and four-location choice) and a delayed alternation task, respectively. The RH group was unimpaired on the first two tasks and was even faster than the controls in learning the delayed-response task with four locations. Finally, most RH baboons failed to learn the delayed alternation task within the limits of testing. These results indicate that neuronal loss in the rhinal cortex is sufficient to impair visual recognition memory, and extend the implication of this area to spatial executive functions. Furthermore, the observation of impaired recognition memory and executive processes with preserved procedural memory and retrograde memory suggests that damage to the rhinal cortex probably participates in the cognitive deficits typical of the early stages of Alzheimer's disease.     

Effect of prefrontal cortex inactivation on behavioral and neurochemical abnormalities in rats with excitotoxic lesions of the entorhinal cortex

Morphological studies report reductions in the volume of medial temporal lobe structures and the prefrontal cortex in subjects with schizophrenia. The present study was performed to clarify the role of prefrontal-temporo-limbic system in the manifestation of psychosis, using entorhinal cortical lesion rats as a vulnerability animal model. Quinolinic acid (lesion group) or phosphate buffer (sham group) was infused into the left entorhinal cortex (EC) of male Wistar rats. On the 28th postoperative day, methamphetamine (MAP; 1 mg/kg, i.p.)-induced dopamine (DA) release in the nucleus accumbens (NAC) and the basolateral amygdala (BLA), as well as locomotor activity and prepulse inhibition (PPI), was measured following microinfusion of lidocaine or the cerebrospinal fluid (CSF) into the medial prefrontal cortex (mPFC). Lesions of the EC resulted in enhancement of MAP-induced DA release in the NAC and BLA. Further analysis revealed that the enhancement by EC lesions of MAP-induce DA release in the NAC was particularly evident in the lidocaine-infused rats. EC lesions also enhanced MAP-induced locomotor activity, especially in the lidocaine-treated animals. By contrast, infusion of lidocaine into mPFC attenuated MAP-induced DA release in the BLA, irrespective of the lesion status. Both EC lesions and lidocaine infusion disrupted PPI. These results indicate that inactivation of the mPFC, as well as structural abnormalities in the EC, leads to dysregulation of DAergic neurotransmissions in the limbic regions. The implications of these findings in relation to the neural basis for psychosis vulnerability are discussed.     

Conceptual and perceptual novelty effects in human medial temporal cortex

Medial temporal lobe (MTL) structures often respond to stimulus repetition with a reduction in neural activity. Such novelty/familiarity responses reflect the mnemonic consequences of initial stimulus encounter, although the aspects of initial processing that lead to novelty/familiarity responses remain unspecified. The current functional magnetic resonance imaging (fMRI) experiment examined the sensitivity of MTL to changes in the semantic representations/processes engaged across stimulus repetitions. During initial study blocks, words were visually presented, and participants made size, shape, or composition judgments about the named referents. During repeated study blocks, the initial words were visually re-presented along with novel words, and participants made size judgments for all items. Behaviorally, responses were faster to repeated words in which the same task was performed at initial and repeated exposure (i.e., size-->size) relative to repeated words in which the tasks differed (i.e., composition-->size and shape-->size). fMRI measures revealed activation reductions in left parahippocampal cortex following same-task and different-task repetition; numerically, the effect was larger in the same-task condition. Accordingly, left parahippocampal cortex demonstrates sensitivity to perceptual novelty/familiarity, and it remains unclear whether this region also is sensitive to novelty/familiarity in the conceptual domain. In left perirhinal cortex, a novelty/familiarity effect was observed in the same-task condition but not in the different-task condition, thus revealing sensitivity to the degree of semantic overlap across exposures but insensitivity to perceptual repetition of the visual word form. Perirhinal sensitivity to semantic repetition and insensitivity to perceptual repetition suggests that human perirhinal cortex receives conceptual inputs, with perirhinal contributions to declarative memory perhaps partially stemming from its role in processing semantic aspects of experiences.     

Interaction of frontal and perirhinal cortices in visual object recognition memory in monkeys

Monkeys were trained preoperatively in visual object recognition memory. The task was delayed matching‐to‐sample with lists of trial‐unique randomly generated visual stimuli in an automated apparatus, and the stimuli were 2D visual objects made from randomly generated coloured shapes. We then examined the effect of either: (i) disconnecting the frontal cortex in one hemisphere from the perirhinal cortex in the contralateral hemisphere by crossed unilateral ablations; (ii) disconnecting the magnocellular portion of the mediodorsal (MDmc) thalamic nucleus in one hemisphere from the perirhinal cortex in the contralateral hemisphere; or (iii) bilaterally ablating first the amygdala, then adding fornix transection, then finally perirhinal cortex ablation. We found that both frontal/perirhinal and MDmc/perirhinal disconnection had a large effect on visual object recognition memory, whereas both amygdalectomy and the addition of fornix transection had only a mild effect. We conclude that the frontal lobe needs to interact with the perirhinal cortex within the same hemisphere for visual object recognition memory, but that routes through the amygdala and hippocampus are not of primary importance.     

The egocentric spatial reference frame used in dorsal-lateral prefrontal working memory in primates

The dorsal-lateral prefrontal cortex (dlPFC) has been proposed to be the site of spatial working memory (WM), and this concept has had a profound influence on functional studies of the prefrontal cortex (PFC). The concept of spatial WM has been understood to mean that the location of an object is memorized for a short period of time. However, this concept of space is a simplification. To process the spatial information, different spatial frames can be used. In this review, the authors present data from their own laboratory to argue that the dlPFC is related to the egocentric spatial information processing (ESIP) in WM. The goal of this review is to introduce and discuss the egocentric spatial reference frame (ESRF) located in the dlPFC. The ESIP in the PFC might be involved in self-recognition.     

Depletion of MAP2 expression and laminar cytoarchitectonic changes in dorsolateral prefrontal cortex in adult autistic individuals

The neuropathological substrates underlying the characteristic clinical phenotype of autism are unknown. Neuroimaging studies have identified a decrease in task-related activation in the dorsolateral prefrontal cortex in autism. In the current study, we have analysed the dorsolateral prefrontal cortex in two adult individuals with a clinical diagnosis of autism, using Nissl staining and MAP2 immunohistochemistry. There was unchanged density of both neuronal and glial cell pools, although the autistic individuals had ill-defined neocortical cellular layers, substantially depleted MAP2 neuronal expression, and reduced dendrite numbers. Further studies on a larger number of individuals with autism are needed to establish the clinical relevance of the described changes, especially to determine whether the loss of dendritic markers is age associated or disease specific.     

Activation in dorsolateral prefrontal cortex in response to maternal criticism and praise in recovered depressed and healthy control participants.

BACKGROUND: High family levels of expressed emotion reliably predict relapse in patients with schizophrenia and mood disorders; however, the neural mechanisms linking expressed emotion and relapse are unexplored. Dysfunctional activity in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of depression. Functional magnetic resonance imaging (fMRI) was used to assess focal activation changes in DLPFC in response to a novel psychosocial challenge stimulus developed from the expressed emotion construct. METHODS: Healthy control subjects and fully remitted unipolar depressed participants completed blood oxygen level-dependent fMRI while they heard their own mothers making critical and praising comments about them. RESULTS: Relative to control subjects, participants with a history of depression failed to activate DLPFC when they heard critical remarks. There were no differences between the two groups in their DLPFC responses to maternal praise. CONCLUSIONS: Even if fully well at the time of testing, participants with a known vulnerability to depression respond differently to the psychosocial challenge of being criticized. These findings might have implications for our understanding of vulnerability to depression and to depressive relapse.     

Differential connections of the perirhinal and parahippocampal cortex with the orbital and medial prefrontal networks in macaque monkeys

Previous anatomical studies indicate that the orbital and medial prefrontal cortex (OMPFC) of monkeys is organized into an "orbital" network, which appears to be related to feeding and reward, and a "medial" network, related to visceral control and emotion. In this study, we examined the connections of the orbital and medial prefrontal networks with the perirhinal (areas 35 and 36) and parahippocampal (areas TF and TH) cortex with anterograde and retrograde axonal tracers. The perirhinal cortex is reciprocally connected with orbital network areas Iapm, Iam, Ial, 13m, 13l, 12r, and 11l. In contrast, the parahippocampal cortex is reciprocally connected with the medial network, especially areas around the corpus callosum (areas 24a/b, caudal 32, and 25), and with area 11m. Projections from the parahippocampal cortex also extend to areas 10m, 10o, Iai, and rostral area 32, as well as to dorsolateral areas 9 and 46. In addition, both the perirhinal and parahippocampal cortex are reciprocally connected with areas that are intermediate between the orbital and medial networks (areas 13a, 13b, and 14c) and with the supracallosal area 24a'/b'. Outside the frontal cortex, the perirhinal cortex and the orbital prefrontal network are both interconnected with the ventral part of the temporal pole (TG), area TE and the ventral bank and fundus of the superior temporal sulcus (STS), and the dysgranular insula. In contrast, the parahippocampal cortex and the medial prefrontal network are connected with the dorsal TG, the rostral superior temporal gyrus (STG) and dorsal bank of STS, and the retrosplenial cortex.     

Altered gray matter volume and disrupted functional connectivity of dorsolateral prefrontal cortex in men with heroin dependence

Aim

Chronic heroin use can cause various neuropathological characteristics that may compromise brain function. The present study evaluated the alteration of gray matter volume (GMV) and its resting‐state functional connectivity (rsFC) over the dorsolateral prefrontal cortex (DLPFC) among male heroin users.

Methods

Thirty heroin‐dependent men undergoing methadone maintenance therapy and 30 educational‐level‐ and age‐matched male controls were recruited for this study. To assess their GMV and rsFC, the participants were evaluated using spoiled gradient echo and gradient‐recalled echo planar imaging sequences with a 3‐Tesla General Electric MR scanner under resting state.

Results

The heroin‐dependent men showed lower GMV over the right DLPFC in comparison with the controls. Further evaluation of the rsFC of the right DLPFC revealed a marked decrease in interhemispheric DLPFC connectivity among those with heroin dependence under control of head movement and GMV of the right DLPFC.

Conclusion

Although the mechanism remains unclear, the present study shows that chronic heroin use is associated with alteration of morphology as well as rsFC over the right DLPFC. As the DLPFC plays an imperative role in various domains of cognitive function, service providers for heroin users should consider the impacts of possible DLPFC‐related cognitive deficits on treatment effectiveness.

     

Delayed spatial response alternation: effects of delay-interval duration and lesions of the medial prefrontal cortex on response accuracy of male and female Wistar rats

A delayed spatial response alternation procedure was used to assess behavioural differences between male and female Wistar rats, assumed to involve memory functioning. In Expt. I, subjects were required to alternate responses between two levers in an operant environment. The delay between response opportunities was varied between 1, 3, 7.5 and 15 s in different experimental conditions. Incorrect responses produced a time-out from experimental contingencies for the duration of the currently active delay interval. Response accuracy decreased for males as well as females as the duration of the delay interval was increased. Performance improved as subjects were exposed to the different delay interval durations during consecutive trials. Sex differences in behavioural accuracy were not observed. In Expt. II, some subjects who participated in Expt. I received lesions of the medial prefrontal cortex, while others were control-operated. When re-exposed to the 1 and 7.5 s delay conditions of the first experiment, lesioned subjects at first behaved less accurately than control-operated subjects. Accuracy, however, improved after prolonged exposure to the experimental conditions. Sex differences in behaviour after surgery could not be observed.     

Impaired associative memory in temporal lobe epilepsy subjects after lesions of hippocampus, parahippocampal gyrus, and amygdala

There has been growing interest in the differential role of medial temporal lobe structures in learning and memory. The goal of the present study was to clarify how lesions of hippocampus, parahippocampal gyrus, and amygdala interfere with associative learning and memory. Thirty subjects with pharmacoresistant medial temporal lobe epilepsy (TLE) and temporal lobe removal were compared with 30 matched healthy control subjects. A set of neuropsychological test measures and an associative learning task requiring the learning and recall of objects and faces were administered. The lesions of hippocampus, parahippocampal gyrus, amygdala, and fusiform gyrus of TLE subjects were determined by three-dimensional magnetic resonance imaging (3-D MRI) volumetric assessment. The results indicate that TLE subjects with combined large hippocampal lesions, large parahippocampal gyrus (i.e., perirhinal/entorhinal) lesions, and large amygdala lesions learned and recalled the associative task significantly worse than control subjects or subjects with small lesions of the hippocampus, parahippocampal gyrus, and amygdala. Regression analysis revealed that larger lesions of the parahippocampal gyrus (i.e., perirhinal/entorhinal cortices) were significantly related to increasing deficits on the task, and that hippocampal and amygdala lesion size did not significantly improve the prediction. Our results suggest that perirhinal and entorhinal cortices may contribute predominantly to the associative learning and recall of objects and faces.     

Dissociating the role of the caudate nucleus and dorsolateral prefrontal cortex in the monitoring of events within human working memory

There is evidence that the dorsolateral prefrontal cortex is involved in the monitoring of information held in memory whether it is self‐ordered or externally triggered. However, the functional contribution of the caudate nucleus in the monitoring of events has not yet been studied. We have previously proposed that the striatum is involved when a novel self‐initiated action needs to be generated. The present study aimed to test the hypothesis that the caudate nucleus is significantly more required when the monitoring is self‐ordered as opposed to externally triggered. Self‐ordered monitoring refers to keeping track of which items have been selected so far in order to perform the current selection. Externally triggered monitoring refers to keeping track of which items have been selected by an outside source. Thirteen healthy young adults were scanned using functional magnetic resonance imaging while performing a monitoring task with three conditions: self‐ordered, externally triggered and recognition. As predicted, a significant increase of activity was found in the dorsolateral prefrontal cortex bilaterally when the self‐ordered and externally triggered conditions were compared with the recognition condition. Most importantly, significantly increased activity was found in the right caudate nucleus when comparing the self‐ordered with the recognition condition or with the externally triggered condition, but not when comparing the externally triggered with the recognition condition. We suggest that the caudate nucleus is involved in the planning of a self‐initiated novel action, especially when no clear indication is given for the response choice, and that this may be the case across different domains of cognition.     

Characterization of perforant path lesions in rodent models of memory and attention

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.     

Selective effects of hippocampal and frontal cortex lesions on a spatial learning problem in two inbred strains of mice

The effects of dorsal hippocampal and medial frontal lesions of the cortex on a spatial learning problem were studied in two inbred strains of mice (C57BL/6 and DBA/2) which present both neuroanatomical differences of such structures and various patterns of spontaneous exploration. The results showed that hippocampal lesions produced impairments of the learning performance in each strain of mouse, but the temporal distribution of the errors over the experiment was found to be strain dependent. On the other hand, medial frontal cortex lesions selectively affected the learning performances since the acquisition process of only the C57BL/6 lesioned mice differed significantly from the other groups. The effects of these lesions are discussed in terms of genetically associated differences of brain structures and functions. It is suggested that investigations of such differences can provide an experimental model for the study of functional and structural recovery.