Extrahippocampal Brain Regions Research Articles

Contribution of the lateral occipital and parahippocampal cortices to pattern separation of objects and contexts.

Contextual features are integral to episodic memories; yet, we know little about context effects on pattern separation, a hippocampal function promoting orthogonalization of overlapping memory representations. Recent studies suggested that various extrahippocampal brain regions support pattern separation; however, the specific role of the parahippocampal cortex-a region involved in context representation-in pattern separation has not yet been studied. Here, we investigated the contribution of the parahippocampal cortex (specifically, the parahippocampal place area) to context reinstatement effects on mnemonic discrimination, using functional magnetic resonance imaging. During scanning, participants saw object images on unique context scenes, followed by a recognition task involving the repetitions of encoded objects or visually similar lures on either their original context or a lure context. Context reinstatement at retrieval improved item recognition but hindered mnemonic discrimination. Crucially, our region of interest analyses of the parahippocampal place area and an object-selective visual area, the lateral occipital cortex indicated that while during successful mnemonic decisions parahippocampal place area activity decreased for old contexts compared to lure contexts irrespective of object novelty, lateral occipital cortex activity differentiated between old and lure objects exclusively. These results imply that pattern separation of contextual and item-specific memory features may be differentially aided by scene and object-selective cortical areas.

Differential Expression of the Metabotropic P2Y Receptor Family in the Cortex Following Status Epilepticus and Neuroprotection via P2Y1 Antagonism in Mice.

Purinergic signaling via P2 receptors is now widely accepted to play a critical role during increased states of hyperexcitability and seizure-induced pathology. In the setting of seizures and epilepsy, most attention has been paid to investigating the fast-acting ATP-gated P2X receptor family. More recent evidence has now also provided compelling evidence of an involvement of the slower-acting P2Y receptor family during seizures. This includes data demonstrating expression changes of P2Y receptors in the hippocampus following acute seizures and during epilepsy and anticonvulsive properties of P2Y-targeting drugs; in particular drugs targeting the P2Y1 subtype. Seizures, however, also involve damage to extra-hippocampal brain regions such as the cortex, which is thought to contribute to the epileptic phenotype. To analyze expressional changes of the P2Y receptor family in the cortex following status epilepticus and to determine the impact of drugs interfering with P2Y1 signaling on cortical damage, we used a unilateral mouse model of intraamygdala kainic acid-induced status epilepticus. Analysis of cortical tissue showed that status epilepticus leads to a global up-regulation of the P2Y receptor family in the cortex including P2Y1, P2Y2, P2Y4, and P2Y6, with the P2Y1 and P2Y4 receptor subtypes showing the strongest increase. Supporting a detrimental role of P2Y1 activation during status epilepticus, treatment with the P2Y1 agonist MRS2365 exacerbated high frequency high amplitude spiking, synonymous with injury-causing electrographic activity, and treatment with the P2Y1 antagonists MRS2500 protected against seizure-induced cortical damage. Suggesting P2Y1-mediated effects are predominantly due to increased microglia activation, treatment with the broad-spectrum anti-inflammatory drug minocycline abolished the observed neuroprotective effects of P2Y1 antagonism. In conclusion, our results further support a role for P2Y1-mediated signaling during seizure generation and seizure-induced neurodegeneration, suggesting P2Y1-targeting therapies as novel treatment for drug-refractory status epilepticus.

Extrahippocampal Contributions to Age-Related Changes in Spatial Navigation Ability.

Age-related decline in spatial navigation is well-known and the extant literature emphasizes the important contributions of a hippocampus-dependent spatial navigation system in mediating this decline. However, navigation is a multifaceted cognitive domain and some aspects of age-related navigational decline may be mediated by extrahippocampal brain regions and/or systems. The current review presents an overview of some key cognitive domains that contribute to the age-related changes in spatial navigation ability, and elucidates such domains in the context of an increased engagement of navigationally relevant extrahippocampal brain regions with advancing age. Specifically, this review focuses on age-related declines in three main areas: (i) allocentric strategy use and switching between egocentric and allocentric strategies, (ii) associative learning of landmarks/locations and heading directions, and (iii) executive functioning and attention. Thus far, there is accumulating neuroimaging evidence supporting the functional relevance of the striatum for egocentric/response strategy use in older adults, and of the prefrontal cortex for mediating executive functions that contribute to successful navigational performance. Notably, the functional role of the prefrontal cortex was particularly emphasized via the proposed relevance of the fronto-locus coeruleus noradrenergic system for strategy switching and of the fronto-hippocampal circuit for landmark-direction associative learning. In view of these putative prefrontal contributions to navigation-related functions, we recommend future spatial navigation studies to adopt a systems-oriented approach that investigates age-related alterations in the interaction between the prefrontal cortex, the hippocampus, and extrahippocampal regions, as well as an individual differences approach that clarifies the differential engagement of prefrontal executive processes among older adults.

MRI compatible optrodes for simultaneous LFP and optogenetic fMRI investigation of seizure-like afterdischarges

In preclinical studies, implanted electrodes can cause severe degradation of MRI images and hence are seldom used for chronic studies employing functional magnetic resonance imaging. In this study, we developed carbon fiber optrodes (optical fiber and electrode hybrid devices), which can be utilised in chronic longitudinal studies aiming to take advantage of emerging optogenetic technologies, and compared them with the more widely used tungsten optrodes. We find that optrodes constructed using small diameter (~130 μm) carbon fiber electrodes cause significantly reduced artifact on functional MRI images compared to those made with 50 μm diameter tungsten wire and at the same time the carbon electrodes have lower impedance, which leads to higher quality LFP recordings. In order to validate this approach, we use these devices to study optogenetically-induced seizure-like afterdischarges in rats sedated with dexmedetomidine and compare these to sub (seizure) threshold stimulations in the same animals. The results indicate that seizure-like afterdischarges involve several extrahippocampal brain regions that are not recruited by subthreshold optogenetic stimulation of the hippocampus at 20 Hz. Subthreshold stimulation led to activation of the entire ipsilateral hippocampus and septum, whereas afterdischarges additionally produced activations in the contralateral hippocampal formation, neocortex, cerebellum, nucleus accumbens, and thalamus. Although we demonstrate just one application, given the ease of fabrication, we anticipate that carbon fiber optrodes could be utilised in a variety of studies that could benefit from longitudinal optogenetic functional magnetic resonance imaging.

Glutamatergic Dysbalance and Oxidative Stress in In Vivo and In Vitro Models of Psychosis Based on Chronic NMDA Receptor Antagonism

BackgroundThe psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia.MethodsThe NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats.ResultsChronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/− 10.4% S.E.M of control; p = 0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro.ConclusionThe combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.

Neural changes associated with relational learning in schizophrenia.

Relational learning, which is learning the relationship among items, is impaired in schizophrenia but can be improved with training. This study investigated neural changes with functional magnetic resonance imaging before and after training on a relational learning task in schizophrenia and healthy control subjects. Despite their acquiring similar relational learning performance, the groups exhibited different neural activation patterns before and following training. Controls engaged regions within the relational learning network that included frontal, parietal, and medial temporal lobe, before and following training. Controls also exhibited activation reductions in region and spatial extent with relational learning proficiency, a commonly observed phenomenon in successful learning. In contrast, subjects with schizophrenia displayed no positive activations compared with the control condition before training. After training, subjects with schizophrenia displayed bilateral inferior parietal region activation as predicted. Contrary to hypothesis, hippocampal activation was not observed following training in schizophrenia. These findings suggest that the parietal lobe may be receptive to cognitive training interventions and that successful relational learning may be achieved in schizophrenia through the use of alternative extrahippocampal brain regions.

Video game play changes spatial and verbal memory: rehabilitation of a single case with traumatic brain injury

IntroductionTraumatic brain injury (TBI) occurs when mechanicalforce causes damage to brain tissue resulting in the dis-ruption of brain functioning. Cognition is frequentlydamaged after TBI; although the effects of TBI can bevariable, the domains of memory, attention, and executivefunctioning are consistently impaired. Memory deficit isone of the most (if not the most) common and disablingimpairments caused by TBI (Vakil 2005).Theuseof3D video games inbraindamagerehabilitationis a very little explored resource at the present time. 3Dvideo games are based on virtual reality technology. Theadvantage of using VR in cognitive rehabilitation is tosimulate many real life situations, thereby providing theopportunity for more ecologically valid and dynamicassessment and training (Rose et al. 2005). The utility of thismethod has been established through some spatial memorystudies (see Rose et al. 2005). It has been shown that navi-gation ofavirtualenvironmentallowsparticipantstoencodethe spatial layout of the virtual environment and activate anetwork of areas as the Hippocampus involved in memoryprocessing(Maguireetal.1998).Someauthorsassumedthathippocampal activations are more likely to be observedwhen the knowledge acquired concerns a complex anddetailed large-scale spatial layout (Woollett et al. 2008).The aim of this exploratory study was to assess themodifications occurring in cognitive functions, in particularspatial and verbal memory, and a potential fMRI increaseof signal in hippocampal and extrahippocampal brainregions in a TBI patient after a 3D video game rehabili-tation training.MethodsThe present study describes the rehabilitation of a 24-year-old, right-handed man, with 8 years of education. Hismedical history was unremarkable till when he wasinvolved in a motor vehicle crash and sustained a TBI ofmoderate severity. His Glasgow Coma Scale score was 5.He was diagnosed with trauma cranial injury. The patientwas tested 7 months after the event and was not in the post-traumatic amnesia (PTA) stage.Neuropsychological assessment indicated the presenceof a severe anterograde (recall and recognition) and retro-grade amnesia and deficits in spatial learning (supra-spanon Corsi’s test).Thetraining consistedofaseries of1.5 hsessions thriceaweek(totallengthofintervention:5 weeks).Thevideogamewas a driving simulator. During the training the participantwas requested to explore a complex virtual town from aground-levelperspective.Ineachtrainingsessionthesubjectinterchanged 20 min of navigation with 7 min of break.The patient was evaluated before and after training bymeans of a fMRI and a standardized neuropsychologicalassessment. He was then re-tested 1 and 2 months after thelast memory training session for two follow-up testingsessions.

The precision of remote context memories does not require the hippocampus

Although the clarity of many memories fades with time, some memories may maintain their original precision. Here we used a context discrimination procedure to evaluate whether the hippocampus is important in maintaining precision as memories mature. Spared discrimination in hippocampal-lesioned mice indicated that precise, remote context memories may be supported by extra-hippocampal brain regions.

Selective disruption of hippocampus-mediated recognition memory processes after episodes of transient global amnesia

Transient global amnesia (TGA) is characterized by the abrupt onset of severe amnesia without concomitant focal neurological symptoms. Recent studies revealed that small and punctate MR-signal diffusion-weighted imaging (DWI) lesions can be found within the hippocampus of TGA patients during the post-acute phase. On the basis of dual-process models of recognition memory, the present study examined the hypothesis that hippocampal dysfunction as suggested by these DWI lesions disrupts hippocampus-mediated recollection in patients with TGA, whereas familiarity-based recognition memory that is assumed to be supported by extra-hippocampal brain regions should be unaffected. We administered a recognition memory task for faces and words to eleven TGA patients during the post-acute phase and to eleven matched controls. Receiver operating characteristics (ROCs) were obtained in order to derive estimates of familiarity and recollection by applying a formal dual-process model of recognition memory. Analyses of ROC curves revealed a disruption of recollection in TGA patients’ memory for words [ t(20) = 2.70, p < .05], but no difference in familiarity-based recognition memory between patients and controls [ t(20) = −1.10, p = .284]. Post hoc analyses indicated that the deficit in recollection is more pronounced in TGA patients who show visible hippocampal lesions on diffusion-weighted MR imaging compared to those without detectable hippocampal lesions. In conclusion, consistent with recent neuroanatomical dual-process models of recognition memory, hippocampal dysfunction in patients with TGA is associated with a selective effect on specific recognition memory subprocesses.

Voxel‐based T2 Relaxation Rate Measurements in Temporal Lobe Epilepsy (TLE) with and without Mesial Temporal Sclerosis

Quantitative measurements of T(2) relaxation in the hippocampus for focus lateralization in mesial temporal lobe epilepsy (mTLE) are well established. Less is known to what degree such relaxation abnormalities also affect regions beyond the ipsilateral hippocampus. Therefore, the aim of this study was to characterize extent and distribution pattern of extrahippocampal relaxation abnormalities in TLE with (TLE-MTS) and without MRI evidence of mesial-temporal sclerosis (TLE-no). Double spin echo images (TE1/2: 20/80 ms) acquired in 24 TLE-MTS and 18 TLE-no were used to calculate relaxation rate maps. These maps were analyzed by SPM2 and by selecting regions of interest (ROI) in the hippocampus and several extrahippocampal brain regions. In TLE-MTS, the results of the SPM and ROI analysis were in good agreement and showed the most severe relaxation rate decreases in the ipsilateral hippocampus but also in other ipsilateral temporal regions, orbitofrontal, and parietal regions and to a lesser degree in contralateral frontal regions. The relaxation rate decreases in TLE-no were confined to small regions in the ipsilateral anterior inferior and medial temporal lobe in the SPM analysis while ROI analysis showed additional regions in the ipsilateral hippocampus, amygdala, and anterior cingulate. TLE-MTS showed extensive, widespread but predominantly ipsilateral temporal and also extratemporal T(2) relaxation rate decreases. In contrast, the findings of the SPM and ROI analyses in TLE-no suggested that if relaxation rate decreases are present, they are less uniform and generally milder than in TLE-MTS. This further supports the hypothesis that TLE-no is a distinct clinicopathological entity from TLE-MTS and probably heterogeneous in itself.

Extrahippocampal Contributions to Age Differences in Human Spatial Navigation

The hippocampus (HC) and associated neural structures are hypothesized to contribute to individual differences in human spatial navigation. However, functional imaging studies and theoretical models underscore the importance of extrahippocampal regions as well. The purpose of the present study was to examine age differences in virtual environment navigation and to assess possible relationships between navigation and structural integrity of hippocampal and extrahippocampal brain regions. Healthy adult volunteers completed a virtual navigation task and underwent magnetic resonance imaging to assess volumes of the caudate nucleus (CN), cerebellum, HC, prefrontal, and primary visual cortices. Results demonstrated robust age-related differences in place learning. Moreover, individual differences in regional brain volumes as well as performance on the tests of memory and executive functions contributed to age differences in human place learning. High performance in a virtual navigation task was associated with larger volume of the CN and prefrontal gray and white matter. Larger hippocampal volume was associated with improved performance in the young but not old participants. We conclude that human navigation requires both hippocampal and extrahippocampal brain systems and draws on executive resources for successful performance.

Fast track to the medial prefrontal cortex

Studies of brain-damaged patients have provided remarkable insights into how our memories are organized (1). In particular, these studies have established that memory consolidation is a dynamic process involving gradual (but quite dramatic) reorganization of the circuits supporting memory over time (2, 3). A pioneer in this field was the French psychologist Theodule Ribot. In the late part of the 19th century, Ribot described how memory loss after brain insult tended to be related to the age of the memory: the effect on more recent memories was typically greater than that on older (or more remote) memories (4). Later studies established that damage to the medial temporal lobe (5), and more specifically the hippocampus (1), is responsible for this typical graded amnesia. This Ribot gradient has suggested that the hippocampus is only temporarily involved in the storage and recall of certain types of memory, and that these functions must be subsumed by extrahippocampal structures as memories mature (2, 6). Hippocampal damage in experimental animals also preferentially disrupts recent memory. Such examples, from mice to monkeys, suggest that time-dependent memory reorganization is an evolutionarily conserved process for memory consolidation (3). However, differences do exist between human and experimental animal studies, and these differences have made it difficult to come up with a unified mechanistic account of memory consolidation. For example, the lengths of the gradients vary dramatically from days or weeks (for example, in rodents) to years (in humans), suggesting that the rate of reorganization may vary greatly across species. Second, although studies in experimental animals have begun to successfully identify extrahippocampal brain regions that support remote memory recall, the evidence from human studies of remote memory has been much less consistent, and it has even been suggested that autobiographical memories may never become truly independent of the …

Cortical and hippocampal volume deficits in temporal lobe epilepsy.

To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE). Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA). As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe. Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.

Combination therapy with nimodipine and dizocilpine in a rat model of transient forebrain ischemia.

We explored the effectiveness of dual blockade of calcium channels in preventing ischemic necrosis in a rat model of transient forebrain ischemia. To assess all the major brain regions, the entire brain was subserially sectioned and examined histologically 1 week after ischemia in 44 male Wistar rats. Brain temperature was monitored and controlled to avoid hypothermia or intergroup temperature differences at the time drugs were administered. All regimens were begun 20 minutes after ischemia. Treated animals received either the L-type calcium channel blocker nimodipine (0.25 microgram/min x 24-hour i.v. infusion), the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine; 5 mg/kg i.v.), or both regimens in combination. In the neocortex (p less than 0.05) and striatum (p less than 0.05), only double-treated animals showed a statistically significant reduction in neuronal necrosis. Dual therapy eliminated neuronal necrosis in the caudate nucleus entirely. In the septal (densely ischemic) hippocampus, protection was weak and inconsistent (0.012 less than p less than 0.788), but in the temporal (incompletely ischemic) hippocampus, the dual-treated group showed the most significant reduction (p less than 0.006). We conclude that the combination of nimodipine and MK-801, if begun 20 minutes after ischemia, may offer a neuroprotective effect against neuronal necrosis in transient forebrain ischemia and that protection is maximal in the major extrahippocampal brain regions.

Effect of systemic kainate administration on cerebral quinolinic acid metabolism in the rat

Systemic administration of kainic acid (12 mg/kg, i.p.), causing the established epileptic syndrome and the associated specific pattern of limbic nerve cell loss, led to substantial time-dependent increases in the brain metabolism of the endogenous excitotoxin, quinolinic acid. These changes preferentially affected biosynthesis of quinolinic acid and were noted only in regions of kainic acid-induced neurodegeneration. Increased quinolinic acid production is likely to be related to astrocytic proliferation and may be involved in the precipitation of secondary lesions in extrahippocampal brain regions.

Altered synaptic transmission in dentate gyrus of rats reared in complex environments: evidence from hippocampal slices maintained in vitro.

Pre- and postsynaptic responses to activation of medial perforant path (MPP) axons were examined in hippocampal slices taken from rats reared for 3-4 wk in relatively complex (EC) or individual cage (IC) environments. Three types of extracellular field potentials were recorded in the infrapyramidal blade of the dentate gyrus: 1) granule cell population spikes (PSs), which reflect the number and synchrony of discharging granule cells (2), 2) population excitatory postsynaptic potentials (EPSPs), which reflect the amount of excitatory synaptic current flow into dendrites (28), and 3) presynaptic fiber volleys (FVs), which reflect the number of activated axons (28). Stimulation of the MPP evoked significantly larger PSs in slices taken from EC rats. There was no significant effect of rearing environment on PS/EPSP relationships. The slopes of EPSPs recorded at the site of synaptic activation in the dentate molecular layer and at the major current source in the dentate granule cell layer were significantly greater in slices taken from EC rats. The presynaptic FV was recorded at the site of synaptic activation in the molecular layer. FV amplitude did not differ significantly as a function of rearing environment. To examine possible differences in tissue impedance, granule cells were activated by stimulating granule cell axons in the dentate hilus and recording the antidromic PS in the granule cell layer. Antidromic PS amplitude was not significantly affected by rearing environment. The relative permanence of the experience-dependent alterations in synaptic transmission was assessed by comparing slices taken from rats that had been reared for 4 wk in complex environments followed by 3-4 wk in individual cages with those from rats reared for 7-8 wk in individual cages. There were no significant differences in MPP synaptic transmission between these groups of animals. The results suggest that experience in a relatively complex environment is associated with greater MPP synaptic transmission arising from an increased synaptic input to granule cells; the greater MPP synaptic transmission associated with behavioral experience can occur independent of behavioral state, influences from extrahippocampal brain regions and intrahippocampal inhibitory activity; and the experience-dependent synaptic alterations in the dentate gyrus are transient, in contrast to experience-dependent morphological alterations described in occipital cortex. The possible relationship of these alterations to the phenomenon of long-term enhancement is discussed.