Cerebellar Contribution to Spatial Event Processing: Morris Water Maze and T-maze

Recently, a cognitive function of cerebellar networks has been challenging the traditional view of the cerebellum as a motor control centre. Among the cognitive abilities reported to be affected by cerebellar deficits is the capacity to solve a spatial problem. We investigated the influence of a cerebellar lesion on spatial abilities by behavioural analysis of rats that had undergone surgical hemicerebellectomy (HCb; HCbed rats). Experiments were performed with a Morris water maze (MWM) and a water T-maze in both cue and place versions (visible or hidden platform respectively). Results indicate a severe impairment in coping with spatial information in all phases of MWM testing as well as in the T-maze paradigm. However, if the MWM cue phase was prolonged, HCbed rats displayed some ability to learn platform position, although at a level significantly different from controls. They succeeded in finding the platform, even in a pure place paradigm, such as finding a hidden platform with the starting points sequentially changed. Retention testing was also performed, demonstrating that HCb affects acquisition but not retention of spatial information. HCbed animals exhibit such disrupted exploration behaviour that they can display only peripheral circling, and they can acquire spatial relations only when proximal cues are available. Furthermore, in all phases of testing, platform finding for HCbed animals is essentially based on place strategies. Thus, a specific pattern of spatial behaviour, markedly different from that displayed following hippocampal or cortical lesions, characterizes cerebellar lesioned rats. These results are discussed taking into account the role in procedural learning recently assigned to cerebellar networks, demonstrating that the cerebellar circuits represent the keystone of the procedural components of spatial event processing.     

Cerebellar contribution to spatial event processing: involvement in procedural and working memory components

Spatial function is one of the cognitive functions altered in the presence of cerebellar lesions. We investigated the cerebellar contribution to the acquisition of spatial procedural and working memory components by means of a radial maze. To establish whether a cerebellar lesion would cause a deficit in solving the radial maze, a first experiment was carried out by using a full-baited maze procedure in different experimental groups, with or without cerebellar lesion and with or without pretraining. Non-pretrained hemicerebellectomized (HCbed) animals exhibited impaired performances in all (motor, spatial and procedural) task aspects. Pre-trained HCbed animals performed similarly to control animals in the task aspects linked to the processing of spatial and procedural factors. To distinguish procedural from working memory components, a forced-choice paradigm of the radial maze was used in the second experiment. Non-pretrained HCbed rats continued to make a lot of errors and show severe perseverative tendencies, already observed in the first experiment, supporting a specific cerebellar role in acquiring new behaviours and in modifying them in relation to the context. Interestingly, hindered from putting the acquired explorative patterns into action and compelled to use only working memory abilities, the pretrained HCbed group exhibited a dramatic worsening of performance. In conclusion, the present findings demonstrate that cerebellar damage induces a specific behaviour in radial maze tasks, characterized by an inflexible use of the procedures (if indeed any procedure was acquired before the lesion) and by a severe impairment in working memory processes.     

丹参改善大鼠颞叶梗死后空间认知加工障碍的研究

目的探讨丹参对大鼠单侧颓叶梗死后空间认知加工能力的改善作用。方法采用立体定向光化学诱导脑梗死技术选择性地导致大鼠左侧颞对皮层梗死，术前30min及术后第3天分别给丹参组大鼠按体重腹腔注射丹参10g／kg，行为实验装置由Morris水迷宫及图像自动监视系统（morrismazeexperimentalassistantsystem，MMEAS）组成。结果丹参组大鼠在Morris迷宫中搜索目标的反应时和行程显著缩短，且较多地使用了正常的认知策略，其由随机式过渡到趋向和直线式策略的进程也与正常对照组无明显差异。结论丹参可明显改善大鼠单侧颞叶梗死后的空间认知加工障碍。本研究在丹参治疗脑梗死、预防痴呆发生方面进行了有益的探索。     

Nociceptin/Orphanin FQ Microinjected into Hippocampus Impairs Spatial Learning in Rats

The newly discovered peptide nociceptin/orphanin FQ has been found to increase reactivity to pain and to influence locomotor activity after intracerebroventricular administration. This study investigated the possible role of hippocampal nociceptin/orphanin FQ in spatial learning and in spontaneous locomotion. Male rats were trained in the Morris water task after microinjection of 10 nmol nociceptin/orphanin FQ or artificial cerebrospinal fluid (as control) into the CA3 region of the dorsal hippocampus. Nociceptin/orphanin FQ was found to severely impair spatial learning without interfering with swimming performance. Itrahippocampal injection of nociceptin/orphanin FQ markedly decreased exploratory locomotor activity including vertical movements (rearing). The data suggest that nociceptin/orphanin FQ is a potent modulator of synaptic plasticity within the hippocampus.     

What is Right and What is Left in Semantic Processing: A Reply to Chiarello

We welcome this opportunity to discuss further our study (Koivisto & Laine, 2000, this issue) and the theoretical conclusions we presented as a model on hemispheric mechanisms in semantic processing. The model put forth claims that when semantic priming occurs within the left visual field/right hemisphere (LVF/RH), it is attributable to postlexical semantic integration, and when priming can be attributed to automatic semantic activation, it only occurs within the right visual field/left hemisphere (RVF/LH). Chiarello (2000, this issue) argues in her commentary that (1) our data supporting this account are weak, (2) our model cannot accommodate the data, and (3) the support for our account from prior literature is not as strong as we claimed.     

Contribution of the anterior thalamic nuclei to conditional learning in rats

The anterior thalamic region is intimately linked anatomically and functionally with the hippocampus, which is critical for various forms of spatial learning. Rats with lesions to the anterior thalamic nuclei and a control group were trained on a visual-spatial conditional associative learning task in which they had to learn to go to one of two locations depending on the particular visual cue presented on each trial; the rats approached the cues from different directions. The animals were subsequently tested on a spatial working memory task, the eight-arm radial maze. Performance on both these tasks had previously been shown to be impaired by hippocampal lesions. Rats with anterior thalamic damage were able to acquire the conditional associative task at a rate comparable to that of the control animals, but were impaired on the radial maze task. The finding of a dissociation between the effects of lesions of the anterior thalamic nuclei on two different classes of behavior known to be associated with hippocampal function suggest that while different neural stations within the extended hippocampal circuit may all play a role in spatial learning, the role of each of these regions in such learning may be more selective than previously considered.     

Evidence for the Involvement of the Mammillary Bodies and Cingulum Bundle in Allocentric Spatial Processing by Rats

Comparisons were made between the behavioural effects of lesions in three inter-related limbic structures: the mammillary bodies, the fornix and the cingulum bundle/cingulate cortex. Cytotoxic lesions of the mammillary nuclei produced a marked deficit on reinforced T-maze alternation, but performance gradually improved with practice. Subsequent tests in a cross-maze and a radial-arm maze showed that the animals with mammillary body lesions failed to use allocentric cues, but were able to perform normally in an egocentric discrimination. Three groups of rats with different patterns of either crossed or unilateral radio frequency lesions of the cingulate region were given the same tasks. The profile of results indicated that disruption of those fibres in the cingulum bundle connecting the anterior thalamic nuclei with the hippocampal/retrohippocampal region was responsible for the observed impairments to T-maze alternation and radial-arm maze performance. There was also evidence that disconnection of frontal connections in the cingulum bundle might affect perseverative behaviour, but not allocentric processing. The results add support to the notion of a functional circuit that involves projections from the hippocampus to the mammillary bodies and anterior thalamic nuclei, and from there back to hippocampal/ retrohippocampal regions via the cingulum bundle. This circuit appears to be vital for normal allocentric processing.     

Rats use hippocampus to recognize positions of objects located in an inaccessible space

Rat hippocampus plays a crucial role in many spatial tasks, including recognition of position of objects, which can be approached and explored. Whether hippocampus is also necessary for recognizing positions of objects located in an inaccessible part of the environment remains unclear. To address this question, we conditioned rats to press a lever when an object displayed on a distant computer screen was in a particular position (“reward position”) and not to press the lever when the object was in other positions (“nonreward positions”). After the rats had reached an asymptotic performance, the role of the dorsal hippocampus was assessed by blocking its activity with muscimol. The rats without functional dorsal hippocampus did not discriminate the reward position from the nonreward positions. Then the same rats were trained to discriminate light and dark conditions. The hippocampal inactivation did not disrupt the ability to discriminate these two conditions. It indicated that the inactivation itself had no major effect on the operant behavior and its control by visual stimuli. We conclude that rats use dorsal hippocampus for recognizing positions of objects located in an inaccessible part of the environment. © 2012 Wiley Periodicals, Inc.     

Ibotenate Lesions of Hippocampus and/or Subiculum: Dissociating Components of Allocentric Spatial Learning

This study examined the effects of ibotenic acid-induced lesions of the hippocampus, subiculum and hippocampus +/- subiculum upon the capacity of rats to learn and perform a series of allocentric spatial learning tasks in an open-field water maze. The lesions were made by infusing small volumes of the neurotoxin at a total of 26 (hippocampus) or 20 (subiculum) sites intended to achieve complete target cell loss but minimal extratarget damage. The regional extent and axon-sparing nature of these lesions was evaluated using both cresyl violet and Fink - Heimer stained sections. The behavioural findings indicated that both the hippocampus and subiculum lesions caused impairment to the initial postoperative acquisition of place navigation but did not prevent eventual learning to levels of performance almost as effective as those of controls. However, overtraining of the hippocampus + subiculum lesioned rats did not result in significant place learning. Qualitative observations of the paths taken to find a hidden escape platform indicated that different strategies were deployed by hippocampal and subiculum lesioned groups. Subsequent training on a delayed matching to place task revealed a deficit in all lesioned groups across a range of sample choice intervals, but the subiculum lesioned group was less impaired than the group with the hippocampal lesion. Finally, unoperated control rats given both the initial training and overtraining were later given either a hippocampal lesion or sham surgery. The hippocampal lesioned rats were impaired during a subsequent retention/relearning phase. Together, these findings suggest that total hippocampal cell loss may cause a dual deficit: a slower rate of place learning and a separate navigational impairment. The prospect of unravelling dissociable components of allocentric spatial learning is discussed.     

Cerebral Processing of Timbre and Loudness: fMRI Evidence for a Contribution of Broca’s Area to Basic Auditory Discrimination

Sound timbre and sound volume processing are basic auditory discrimination processes relevant for human language abilities. Regarding lateralization effects, the prevailing hypotheses ascribe timbre processing to the right hemisphere (RH). Recent experiments also point to a role of the RH for volume discrimination. We investigated the relevance of the RH for timbre and volume processing, aiming at finding possible differences in cerebral representation of these acoustic parameters. Seventeen healthy subjects performed two auditory discrimination tasks on tone pairs, differing either in timbre or volume. FMRI was performed using an EPI-sequence on a 1.5 T scanner. Hemodynamic responses emerged in both tasks within a bilateral network of areas, including cingulate and cerebellum, peaking in primary and secondary auditory cortices (core and belt areas). Laterality analyses revealed a significant leftward dominance at the temporal cortex. Task comparison revealed significant activation within Broca’s area during the timbre task and a trend for an increase of right parietal responses during volume processing. These results contribute to a more differentiated view of timbre processing. Additionally to the engagement of the right temporal cortex during processing of musical timbre, there seem to be language related aspects of timbre that are preferentially processed in the left hemisphere. These findings are discussed within the framework of a model of timbre perception comprising two differentially lateralized subprocesses. Processing of spectral cues (harmonic structure) linked to the right hemisphere and processing of temporal cues (i.e. attack-decay dynamics) linked to the left hemisphere. Moreover, activation of Broca’s area linked to the timbre task indicates a participation of this area in discriminating phonetic changes of the vowel-like non-speech signals, encouraging the argument that basic acoustic cue processing at a pre- or non-speech level is represented within this “classical language area.”     

Selective Lesioning of the Basal Forebrain Cholinergic System by Intraventricular 192 IgG–saporin: Behavioural, Biochemical and Stereological Studies in the Rat

The elucidation of the functional role of the basal forebrain cholinergic system will require access to a highly specific and efficient cholinergic neurotoxin. Recently, selective depletion of the nerve growth factor (NGF) receptor-bearing cholinergic neurons in the rat basal forebrain and a dramatic loss of cholinergic innervation in the related cortical regions have been obtained following intraventricular injection of a newly introduced immunotoxin, 192 IgG-saporin. Here we extend these initial findings and report that administration of increasing doses (1.25, 2.5, 5.0 or 10 μg) of the 192 IgG-saporin conjugate into the lateral ventricles of adult rats induced dose-dependent impairments in the water maze task and passive avoidance retention, but only weak and inconsistent effects on locomotor activity. These behavioural changes were paralleled by a reduction in choline acetyltransferase activity in hippocampus and several cortical areas (up to 97%) and selective depletions of NGF receptor-positive cholinergic neurons in the septal-diagonal band area and nucleus basalis magnocellularis (up to 99%). By contrast, the non-cholinergic parvalbumin-containing neurons in the septum were completely spared, and other cholinergic projection systems (such as in the striatum, thalamus, brainstem and spinal cord) were unaffected even at the highest dose. The observed changes in the water maze and passive avoidance tasks, as well as the cholinergic cell loss, were maintained up to at least 8 months following the intraventricular injection of a single dose (5 μg) of the immunotoxin. The results confirm the usefulness of the 192 IgG-saporin toxin for selective and profound lesions of the basal forebrain cholinergic neurons and provide further support for a role of the basal forebrain cholinergic system in cognitive functions.     

The Effects of AMPA-induced Lesions of the Medial Septum and Vertical Limb Nucleus of the Diagonal Band of Broca on Spatial Delayed Non-matching to Sample and Spatial Learning in the Water Maze

These experiments investigated in the rat the impact on spatial delayed non-matching to sample and on acquisition of the Morris water maze of (i) AMPA-induced lesions of the medial septal nucleus, which produced a marked reduction of hippocampal choline acetyltransferase activity and acetylcholine levels (measured using in vivo dialysis) together with lesser reductions in cholinergic markers in the cingulate cortex and (ii) similar AMPA-induced lesions of the vertical limb nucleus of the diagonal band of Broca (vDB), which produced more marked reductions in cholinergic markers in the cingulate cortex than in the hippocampus. Medial septal lesions produced a delay-dependent deficit in spatial working memory, while lesions of the vDB resulted in a delay-independent performance deficit. In addition, rats with vDB lesions adopted biased response strategies during the imposition of long delays. Neither lesion significantly affected the acquisition of a spatial reference memory task, the Morris water maze. The results are discussed in terms of cholinergic- and GABAergic-dependent functions of the hippocampal formation and cingulate cortex in spatial short-term and reference memory.     

Learning: Neural analysis in the isolated brain of a previously trained mollusc,Pleurobranchaea californica

The neural manifestations of food avoidance learning in the mollusc, Pleurobranchaea, survive the surgical reduction of the preparation to the nearly isolated brain. These manifestations include increased synaptic inhibition and reduced synaptic excitation of the phasic paracerebral feeding command interneurons (PCps) in the brain in response to food stimulation of chemosensory structures left attached to the brain. The same changes are not evident, however, in brains removed from naive, control or satiated specimens. Therefore the nearly isolated brain preparation permits analysis of the cellular substrates of learning in relative isolation from non-associative motivational variables. The isolated brain preparation is here used to show that the increased synaptic inhibition consequent to associative training is distributed not only to the PCps but also to their identified central presynaptic inputs, including other identified feeding command interneurons (PSEs and ETIIs; ref. 21). The decrease in PCp excitation is explained in part by a training-induced inhibition of excitatory inputs to the PCps, and in part by a training-induced reduction in the efficacy of an identified polysynaptic excitatory pathway presynaptic to the PCps.     

Fact learning in complex arithmetic and figural‐spatial tasks: The role of the angular gyrus and its relation to mathematical competence

Neuroimaging studies have revealed a strong link between mental calculation and the angular gyrus (AG) which has been interpreted to reflect arithmetic fact retrieval. Moreover, a stronger AG activation in individuals with higher mathematical competence has been reported. The present fMRI study investigates the specificity of the AG for arithmetic fact learning and the interplay between training and mathematical competence on brain activation. Adults of lower and higher mathematical competence underwent a five‐day training on sets of complex multiplication and figural‐spatial problems. In the following fMRI test session, trained and untrained problems were presented. Similar training effects were observed in both problem types, consisting of AG activation increases bilaterally and wide‐spread activation decreases in frontal and parietal regions. This finding indicates that the AG is not specifically involved in the learning of arithmetic facts. Competence‐related differences in the AG only emerged in untrained but not in trained multiplication problems. The relation between AG activation and mathematical competence in arithmetic problem solving therefore seems to be due to differences in arithmetic fact retrieval which can be attenuated through training. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Fitness to Stand Trial in One Australian Jurisdiction: The Role of Cognitive Abilities,Neurological Dysfunction and Psychiatric Disorders

In Australia, limited research of the factors determining fitness to stand trial (FST) has been conducted. In particular, the relevance of cognitive abilities and neurological dysfunction in accordance with the legal standard of R v. Presser (1958) has not been comprehensively explored. In the largest known sample of court-determined FST cases in Australia examined to date, expert reports for 153 unfit and 91 fit defendants in New South Wales (NSW) over a five-year period were retrospectively reviewed. Data related to cognitive assessment, psychiatric disorders, neurological dysfunction, demographic factors and expert opinion were extracted. The results showed that cognitive abilities, in particular verbal memory, nonverbal skills, and executive functioning, were influential in differentiating between fit and unfit groups and determining FST. However, quantitative analysis was limited as few reports contained test scores or comprehensive psychometric analysis. Defendants with neurological dysfunction alone or with a dual diagnosis of a psychiatric disorder or intellectual disability were more likely to be found unfit to stand trial. Expert opinion was biased toward the referring agent and psychologists were less likely than psychiatrists to examine all of the relevant legal criteria. Comprehensive cognitive assessment in specific cases and more standardised assessment practices are indicated.     

Nitric oxide synthase in learning-relevant nuclei of the chick brain: Morphology,distribution, and relation to transmitter phenotypes

Nitric oxide (NO) has been implicated in learning in the hatchling chicken. To examine morphological and neurochemical properties of neurons that contain NO synthase (NOS) in brain regions known to be involved in learning and memory, the NADPH-diaphorase technique was used in conjunction with immunocytochemistry and tract tracing. A distinct cell type was NOS-labeled in the lobus parolfactorius (LPO) in the telencephalon, and neurons were labeled in the area ventralis of Tsai (AVT), the substantia nigra (nucleus tegmenti pedunculo-pontinus, pars compacta, TPc), and the locus coeruleus in the brainstem. Thus, NO may influence processes of learning and memory in the forebrain after release from intrinsic neurons and/or from extrinsic NOS-projections originating from the brainstem. DiI-tracing revealed that most of the NOS-positive neurons in the AVT/TPc project to the basal forebrain. The majority of tyrosine hydroxylase-positive (presumptive dopaminergic) neurons in the AVT and TPc expressed NOS. Double-labeling with antibodies to tyrosine hydroxylase, choline acetyltransferase, somatostatin, and the neurotrophin receptor as a marker for noradrenergic coeruleus neurons showed that NOS was not colocalized with noradrenergic or somatostatinergic neurons, and that less than a third of the cholinergic neurons were double-labeled for NOS. Injections of 6-hydroxydopamine into the brainstem did not reduce the density of NOS-labeled fibers in the LPO, indicating that most of the NO in the LPO originates from intrinsic neurons in the basal forebrain. Thus, NOS-containing presumptive local circuit neurons in the LPO are the most likely source of NO involved in learning of passive avoidance tasks in hatchling chicks. J. Comp. Neurol. 383:135–152, 1997. © 1997 Wiley-Liss Inc.     

Hippocampal function in the rat: Cognitive mapping or vicarious trial and error?

The most prominent hypothesis of hippocampal function likens the hippocampus to a “cognitive map,” a term used by a famous learning theorist, E. C. Tolman, to explain maze learning. The usual application of this concept of cognitive map, as it applies to the hippocampus, is to what is called spatial learning, mainly in the radial-arm maze of Olton and the Morris water maze. In a recent Hippocampus Forum, evidence for the cognitive map hypothesis was reviewed in a lead article by Nadel, followed by a series of commentaries by leading investigators of hippocampal function. This speculative commentary offers an alternative not represented in the forum—that the function of the hippocampus in spatial learning is not as a cognitive map, but that it subserves another function proposed by Tolman in his work on simple discrimination learning, vicarious trial and error, based on incipient, conflicting dispositions to approach and avoid.     

Differential Temporal Evolution of Post-Training Changes in Regional Brain Glucose Metabolism Induced by Repeated Spatial Discrimination Training in Mice: Visualization of the Memory Consolidation Process?

The present study analyses the effects of the stage of learning on the spatial patterns and time-course of [¹⁴C] glucose uptake in BALB/c mice brain regions produced by spatial discrimination training in an eight-arm radial maze. Our particular approach was designed to follow, during the post-training period, the level of functional activity in individual brain areas which may underlie the memory consolidation process. Regional mapping of relative [¹⁴C] glucose uptake was assessed at three post-training time intervals (5 min, 1 and 3 h) after either the first (Day 1), the fourth (Day 4) or the last (Day 9) daily training session of the discrimination task and compared with sham-conditioned animals placed in the same experimental environment. The results indicated that numerous subcortical and cortical brain regions exhibit metabolic alterations following the acquisition of the spatial discrimination task. These alterations, which were specifically related to learning since they did not appear in sham-conditioned animals, were functions both of the post-training interval studied and of the degree of mastery of the task. On Day 1, a progressive, time-dependent and sequential increase in labelling was found from subcortical (5 min post-training) to cortical regions (3 h post-training). On Day 4, a peak of cortical metabolic activation was identified at 1 h post-training. In contrast, on Day 9, maximum labelling was found 5 min post-training in all subcortical and cortical regions followed by a general monotonic decline at 1 and 3 h post-training. These findings, which show widely distributed changes of metabolic activity in the brain, are consistent with the hypothesis that learning involves distributed neural networks. The sequential activation from subcortical to cortical regions seems to indicate a general mechanism whose function would ultimately be to store cortical memory representations. The acquisition-dependent shifts in the patterns of post-training metabolic labelling observed as a function of task mastery may be taken to represent a visualization of the spatio-temporal evolution of the networks of brain structures actively engaged in the memory consolidation process. In particular, the present data suggest that the duration of post-acquisition memory processing is a function of the quantity of new information which has to be dealt with by the central nervous system.     

Source of Stress-Induced Increase in Plasma Met-Enkephalin in Rats: Contribution of Adrenal Medulla and/or Sympathetic Nerves*

The contribution of the adrenal medulla and/or the sympathetic nerves to the plasma levels of Met-enkephalin was investigated. Rats were divided into four groups: sham-operated/saline, sham-operated/guanethidine, adrenal-demedullated/saline, demedulla-ted/guanethidine. After 4 weeks of injection with either saline or guanethidine (25 mg/kg/day), animals were cannulated in the left carotid artery for blood sampling. Three days later, blood samples were taken before and at 2 and 30 min of restraint stress. Adrenal demedullation lowered basal plasma epinephrine levels markedly and prevented entirely the increase induced by restraint stress. Chronic guanethidine treatment lowered basal plasma norepinephrine levels and decreased the response to stress. Guanethidine treatment increased the basal plasma epinephrine level without affecting the response to stress. The combination of guanethidine plus adrenal demedullation lowered basal plasma concentrations of all three catecholamines and further attenuated the norepinephrine response. Restraint stress increased plasma native and peptidase-derivable Met-enkephalin. Adrenal demedullation, resulting in greater than 95% depletion of adrenal catecholamines and significant depletion of adrenal Met-enkephalin, did not inhibit the stress-induced increase in plasma Met-enkephalin, and in fact, was associated with a potentiated response to stress. Guanethidine treatment with or without demedullation increased baseline plasma native Met-enkephalin and abolished the stress-induced increase in plasma native and peptidase-derivable Met-enkephalin. Thus, the stress-induced increase in plasma Metenkephalin results from release from sympathetic nerves, rather than adrenal medulla. However, the sympathetic nerves and adrenal medulla together do not appear to account entirely for basal concentrations of circulating Met-enkephalin. Hepatic portal vein plasma concentration of native Met-enkephalin was greater than that in the carotid artery, suggesting contribution from the gastrointestinal tract; however, evisceration did not decrease plasma native Met-enkephalin. Some compensatory mechanism results in elevation of basal plasma native Met-enkephalin in sympathectomized rats. Also, in the absence of the adrenal medulla there is a compensatory increase in the amount of Met-enkephalin released into the circulation in response to stress.