[show abstract][hide abstract] ABSTRACT: The present study examined the consequences of retrosplenial cortex lesions in rats on two novel spatial tasks. In the first experiment, rats discriminated opposing room views from the same general location, along with their opposing directions of travel ('Perspective' task). Rats were trained with food rewards using a go/no-go design. Extensive retrosplenial cortex lesions involving both the granular and dysgranular areas impaired acquisition of this discrimination, which relied on distal visual cues. The same rats were then trained on a non-spatial go/no-go discrimination between different digging media. No lesion effect was apparent. In the final experiment, rats discriminated between two locations within a room ('Location' task) such that direction of travel at each location would be of less help in solving the problem. Both extensive retrosplenial lesions and selective dysgranular retrosplenial lesions impaired this Location task. These results highlight the importance of the retrosplenial cortex (areas 29 and 30), including the dysgranular cortex (area 30), for the effective use of distal visual cues to solve spatial problems. The findings, which help to explain the bias away from visual allocentric solutions that is shown by rats with retrosplenial cortex lesions when performing spatial tasks, also support the notion that the region assists the integration of different categories of visuospatial information.
Behavioural brain research 01/2014; · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: The cingulum is a prominent white matter tract that supports prefrontal, parietal, and temporal lobe interactions. Despite being composed of both short and long association fibres, many MRI-based reconstructions (tractography) of the cingulum depict an essentially uniform tract that almost encircles the corpus callosum. The present study tested the validity of dividing this tract into subdivisions corresponding to the 'parahippocampal', 'retrosplenial', and 'subgenual' portions of the cingulum. These three cingulum subdivisions occupied different medial-lateral locations, producing a topographic arrangement of cingulum fibres. Other comparisons based on these different reconstructions indicate that only a small proportion of the total white matter in the cingulum traverses the length of the tract. In addition, both the radial diffusivity and fractional anisotropy of the subgenual subdivision differed from that of the retrosplenial subdivision which, in turn, differed from that of the parahippocampal subdivision. The extent to which the radial diffusivity scores and the fractional anisotropy scores correlated between the various cingulum subdivisions proved variable, illustrating how one subdivision may not act as a proxy for other cingulum subdivisions. Attempts to relate the status of the cingulum, as measured by MRI-based fibre tracking, with cognitive or affective measures will, therefore, depend greatly on how and where the cingulum is reconstructed. The present study provides a new framework for subdividing the cingulum, based both on its known connectivity and MRI-based properties.
[show abstract][hide abstract] ABSTRACT: In two related experiments, neurotoxic lesions were placed in the anterior thalamic nuclei of adult rats. The rats were then trained on behavioral tasks, immediately followed by the immunohistochemical measurement of molecules linked to neural plasticity. These measurements were made in limbic sites including the retrosplenial cortex, the hippocampal formation, and parahippocampal areas. In Experiment 1, rats with unilateral anterior thalamic lesions explored either novel or familiar objects prior to analysis of the immediate-early gene zif268. The lesions reduced zif268 activity in the granular retrosplenial cortex and postsubiculum. Exploring novel objects resulted in local changes of hippocampal zif268, but this change was not moderated by anterior thalamic lesions. In Experiment 2, rats that had received either bilateral anterior thalamic lesions or control surgeries were exposed to novel room cues while running in the arms of a radial maze. In addition to zif268, measurements of c-AMP response element binding protein (CREB), phosphorylated CREB (pCREB), and growth associated protein43 (GAP-43) were made. As before, anterior thalamic lesions reduced zif268 in retrosplenial cortex and postsubiculum, but there were also reductions of pCREB in granular retrosplenial cortex. Again, the hippocampus did not show lesion-induced changes in zif268, but there were differential effects on CREB and pCREB consistent with reduced levels of hippocampal CREB phosphorylation following anterior thalamic damage. No changes in GAP-43 were detected. The results not only point to changes in several limbic sites (retrosplenial cortex and hippocampus) following anterior thalamic damage, but also indicate that these changes include decreased levels of pCREB. As pCREB is required for neuronal plasticity, partly because of its regulation of immediate early-gene expression, the present findings reinforce the concept of an 'extended hippocampal system' in which hippocampal function is dependent on distal sites such as the anterior thalamic nuclei.
[show abstract][hide abstract] ABSTRACT: Findings of pharmacological studies that have investigated the involvement of specific regions of the brain in recognition memory are reviewed. The particular emphasis of the review concerns what such studies indicate concerning the role of the perirhinal cortex in recognition memory. Most of the studies involve rats and most have investigated recognition memory for objects. Pharmacological studies provide a large body of evidence supporting the essential role of the perirhinal cortex in the acquisition, consolidation and retrieval of object recognition memory. Such studies provide increasingly detailed evidence concerning both the neurotransmitter systems and the underlying intracellular mechanisms involved in recognition memory processes. They have provided evidence in support of synaptic weakening as a major synaptic plastic process within perirhinal cortex underlying object recognition memory. They have also supplied confirmatory evidence that that there is more than one synaptic plastic process involved. The demonstrated necessity to long-term recognition memory of intracellular signalling mechanisms related to synaptic modification within perirhinal cortex establishes a central role for the region in the information storage underlying such memory. Perirhinal cortex is thereby established as an information storage site rather than solely a processing station. Pharmacological studies have also supplied new evidence concerning the detailed roles of other regions, including the hippocampus and the medial prefrontal cortex in different types of recognition memory tasks that include a spatial or temporal component. In so doing, they have also further defined the contribution of perirhinal cortex to such tasks. To date it appears that the contribution of perirhinal cortex to associative and temporal order memory reflects that in simple object recognition memory, namely that perirhinal cortex provides information concerning objects and their prior occurrence (novelty/familiarity).
[show abstract][hide abstract] ABSTRACT: Hippocampally-driven oscillatory activity at theta frequency is found in the diencephalon, but an understanding of the fundamental role of theta in the hippocampo-diencephalic circuit remains elusive. An important strategy in determining how activity modifies oscillatory properties of hippocampo-diencephalic circuitry comprises investigations of anterior thalamic responses to their main inputs: the descending dorsal fornix and the ascending mammillothalamic tract. Here, we show that the amplitude of thalamic theta spectral power selectively increases after plasticity-inducing stimulation of the dorsal fornix, but not of the mammillothalamic tract in urethane-anaesthetized young male rats. Furthermore, we show that low-frequency stimulation (LFS) significantly augments the fornix-driven theta ratio (theta over delta power, T-ratio), in parallel with depressing thalamic synaptic responses. However, the mammillothalamic synaptic response after LFS did not correlate with the slow band of theta oscillation (low T-ratio), but did correlate positively with the fast band of theta oscillation (high T-ratio). Our data demonstrate that the descending direct fornix projection is a pathway that modulates theta rhythm in the hippocampo-diencephalic circuit, resulting in dynamic augmentation of thalamic neuronal responsiveness. These findings suggest that hippocampal theta differentially affects synaptic integration in the different structures with which the hippocampus is reciprocally connected.
[show abstract][hide abstract] ABSTRACT: A mouse model of amyloid pathology was used to first examine using a cross sectional design changes in retrosplenial cortex activity in transgenic mice aged 5, 11, 17, and 23 months. Attention focused on: (1) overt amyloid labeled with β-amyloid((1-42)) and Congo Red staining, (2) metabolic function assessed by the enzyme, cytochrome oxidase, and (3) neuronal activity as assessed indirectly by the immediate-early gene (IEG), c-Fos. Changes in cytochrome oxidase and c-Fos activity were observed in the retrosplenial cortex in Tg2576 mice as early as 5 months of age, long before evidence of plaque formation. Subsequent analyses concentrating on this early dysfunction revealed at 5 months pervasive, amyloid precursor protein (APP)-derived peptide accumulation in the retrosplenial cortex and selective afferents (anterior thalamus, hippocampus), which was associated with the observed c-Fos hyporeactivity. These findings indicate that retrosplenial cortex dysfunction occurs during early stages of amyloid production in Tg2576 mice and may contribute to cognitive dysfunction.
[show abstract][hide abstract] ABSTRACT: There is growing evidence that lesions of the anterior thalamic nuclei cause long-lasting intrinsic changes to retrosplenial cortex, with the potential to alter its functional properties. The present study had two goals. The first was to identify the pattern of changes in eight markers, as measured by in-situ hydridisation, in the granular retrosplenial cortex (area Rgb) following anterior thalamic lesions. The second was to use retrograde trans-neuronal tracing methods to identify the potential repercussions of intrinsic changes within granular retrosplenial cortex. In Experiment 1, adult rats received unilateral lesions of the anterior thalamic nuclei and were perfused 4 weeks later. Of the eight markers, four (c-fos, zif268, 5ht2rc, kcnab2) showed a very similar pattern of change, with decreased levels in superficial retrosplenial cortex (lamina II) in the ipsilateral hemisphere but little or no change in deeper layers (lamina V). A fifth marker (cox6b) showed a shift in activity levels in the opposite direction to the previous four markers. Three other markers (cox6a1, CD74, ncs-1) did not appear to change activity levels after surgery. The predominant pattern of change, a decrease in superficial cortical activity, points to potential alterations in plasticity and metabolism. In Experiment 2, wheat germ agglutin (WGA) was injected into the anterior thalamic nuclei in rats given different survival times, sometimes in combination with the retrograde, fluorescent tracer, Fast Blue. Dense aggregations of retrogradely labeled cells were always found in lamina VI of granular retrosplenial cortex, but additional labeled cells in lamina II were only found: (1) in WGA cases, that is never after Fast Blue injections, and (2) after longer WGA survival times (3 days). These layer II Rgb cells are likely to have been trans-neuronally labeled, revealing a pathway from lamina II of Rgb to those deeper retrosplenial cells that project directly to the anterior thalamic nuclei.
[show abstract][hide abstract] ABSTRACT: Two forms of account have been proposed for how animals form integrated memories for patterns of stimulation: the elemental account holds that the elements that make up the pattern become directly linked to one another, whereas the configural account holds that these elements become bound together through their capacity to activate a separate, shared configural memory. The hippocampus and perirhinal cortex have been linked to both elemental and configural processes. Here, we assessed the role of the rat hippocampus and perirhinal cortex in these distinct ways of processing patterns of sensory stimulation involving auditory, visual context and temporal information. Using selective lesions and inactivation techniques we identified a specific role for the hippocampus in the retrieval of configural memories but not of those that could be encoded elementally; we also identified a role for the rat perirhinal cortex in visual contextual learning. These results, using a novel combination of behavioural assays, provide clear support for the view that patterns of stimulation can be encoded either elementally or configurally, and that disruption of hippocampal function leaves rats reliant on elemental processes.
European Journal of Neuroscience 12/2009; 30(11):2177-89. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the adult brain, the dentate gyrus continuously produces new neurons that become functionally integrated into existing neural circuits. Supporting the idea that this form of plasticity contributes to memory functions, we recently found that new neurons are recruited into neuronal networks involved in retrieval of remote spatial memory and that their activation is situation-specific . Moreover, our data revealed that the recruitment of new neurons into hippocampal networks contributes predominantly to the updating and strengthening of a previously encoded memory. Here, we examined the extent to which the population of surviving new neurons is recruited into memory networks depending on the strength of initial learning. First we evaluated whether the strength of initial spatial learning differentially affects the survival of new neurons. Two groups of mice were initially trained to find the position of the hidden platform in the water maze. Fully trained mice were submitted to a massed training procedure consisting in 24 trials over one single day. In contrast, partially trained mice underwent only 12 trials. Remote memory in these two groups was assessed 30 days later during 9 trials in the presence of the hidden platform. Mice from the partially trained group performed more poorly during remote testing than fully trained mice and exhibited no improvement over the additional trials. Then, using the birthdating marker BrdU, we examined whether memory strength influences the survival of cells born 9 days before spatial training. The extent to which the population of surviving new cells is recruited into memory networks depending on the strength of initial learning was further determined using triple BrdU/NeuN/Zif268 labeling. Structural equation modeling analyses are currently underway to help decipher the contribution of new neurons emerging from the hippocampal-cortical activation.
Frontiers in Behavioral Neuroscience Conference Abstract: 41st European Brain and Behaviour Society Meeting. 06/2009;
[show abstract][hide abstract] ABSTRACT: Four experiments examined the disruptive effects of selective lesions in limbic thalamic nuclei on retrosplenial cortex function, as characterized by striking changes in immediate-early gene activity. Major goals were to test the specificity of these retrosplenial changes, to define better their time course, and to assess the spread of retrosplenial dysfunction with time post-surgery. Experiment 1 examined the activity of two immediate-early genes (c-Fos, Zif268) in the retrosplenial cortex after unilateral anterior thalamic nuclei lesions (1, 2, or 8 weeks post-surgery). Marked immediate-early gene hypoactivity in the hemisphere ipsilateral to the thalamic lesion was consistent across these different post-surgical intervals and, hence, across different rat strains. Concurrent processing of brain tissues from rats either 4 weeks or 1 year after anterior thalamic lesions (Experiments 2 and 3) enabled direct comparisons across very different survival times. The results confirmed that over time the immediate-early gene disruption expanded from the superficial laminae to the deep laminae of granular b cortex and to the dysgranular subregion, indicative of more global disruptions to retrosplenial cortex with extended survival. Associated, subtle changes to cell morphometry (size and sphericity) were found in the retrosplenial cortex. In contrast, unilateral lesions in the adjacent laterodorsal thalamic nucleus (Experiment 4) did not significantly alter retrosplenial cortex c-Fos activity, so highlighting the anatomical specificity of the anterior thalamic lesion effects. These findings not only indicate that the impact of anterior thalamic lesions on cognition could be enhanced by retrosplenial cortex dysfunction but they also show that the effects could increase with longer post-insult survival.
[show abstract][hide abstract] ABSTRACT: The present study examines 2 factors that might moderate the object-recognition deficit seen after perirhinal cortex damage. Object recognition by normal rats was improved by extending (from 4 to 8 min) the sample period during which an object was first explored. Furthermore, there was a significant positive correlation between time spent in close exploration of the sample object and degree of successful novelty discrimination. In contrast, rats with perirhinal cortex lesions failed to benefit from increased close exploration and did not discriminate the novel object after even the longest sample period. Nevertheless, the lesions did not disrupt habituation across repeated exposure to the same object. The second factor was extent of perirhinal cortex damage. A significant correlation was found between total perirhinal cortex loss and degree of recognition impairment. Within the perirhinal cortex, only damage to the caudal perirhinal cortex correlated significantly with recognition memory deficits. This study highlights the critical importance of the perirhinal cortex within the temporal lobe for recognition memory and shows that the lesion-induced deficit occurs despite seemingly normal levels of close object exploration.
[show abstract][hide abstract] ABSTRACT: Patients who have had a colloid cyst removed from the third ventricle sometimes experience some difficulty with day-to-day memory. This study provided quantitative MR imaging volume measures of 1 structure potentially responsible for mnemonic problems, the mammillary bodies. Additional volume estimates in structures connected to the mammillary bodies sought to determine the specificity of any atrophy.
Volume estimates of the mammillary bodies were performed on 38 patients after surgical removal of colloid cysts and 20 control subjects by the application of stereologic volume-estimation techniques. For the mammillary body measures, 2 groups of MR images were assessed (0.8- and 1.0-mm section thickness) to compare the sensitivity of each imaging sequence for detecting any atrophy. Other structures associated with memory processes, such as the hippocampus and fornix, were also assessed quantitatively to determine whether there was a correlation between mammillary body damage and atrophy in connecting structures.
Our investigations established the superiority of 0.8-mm-volume scans over standard isotropic 1.0-mm-thick-volume scans for mammillary body assessments. Comparisons with 20 age-matched controls revealed that patients with colloid cysts frequently showed significant mammillary body atrophy (mean volume of colloid cysts, 0.037 cm(3) right and 0.038 cm(3) left; control subjects, 0.069 cm(3) right and 0.067 cm(3) left). In fact, every patient had a mammillary body volume below the control mean, and the majority of patients had a volume decrease of >1 SD (82% right, 74% left). Mammillary body volumes correlated with fornix volumes in the same patient group.
Our results reveal the frequent presence of mammillary body atrophy in patients with surgical removal of colloid cysts and indicate that this atrophy is partly due to a loss of temporal lobe projections in the fornix.
American Journal of Neuroradiology 01/2009; 30(4):736-43. · 3.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: The expression of two immediate-early genes (IEGs), Zif268 and c-Fos, was quantified in hippocampal subregions and related structures following spatial learning in the Morris water-maze. A critical feature was the novel control protocol alongside more standard controls, the purpose of which was to test whether hippocampal activity is set automatically when traversing an environment or whether it is dependent on reaching a specific goal using learning that requires the hippocampus (i.e. task dependent). The new control protocol (Procedural Task) made it possible to match swim time, swim distance and learning to escape from water with that of the experimental (Working Memory) group. Unlike the Working Memory group, the Procedural Task animals showed no evidence of learning the absolute platform location during the test session. While the Working Memory rats showed c-Fos increases relative to the Procedural Task controls in the frontal and parahippocampal cortices, hippocampal levels did not differ. Again, for Zif268 there was no evidence of a relative increase of hippocampal activity in the Working Memory group. In fact, hippocampal Zif268 showed evidence of a relative decrease, even though the spatial working memory task is hippocampal dependent. The study not only highlighted the shortcomings of other control procedures used in water-maze studies (free-swimming or home cage control), but also indicated that the expression of these IEGs in the hippocampus is not a direct predictor of explicit spatial location learning. Rather, the activity in combinations of regions, including prefrontal cortex, provides a stronger correlate of water-maze learning.
European Journal of Neuroscience 09/2008; 28(5):982-96. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Anterior thalamic lesions are thought to produce 'covert pathology' in retrosplenial cortex, but the causes are unknown. Microarray analyses tested the hypothesis that thalamic damage causes a chronic, hypo-function of metabolic and plasticity-related pathways (Experiment 1). Rats with unilateral, anterior thalamic lesions were exposed to a novel environment for 20 minutes, and granular retrosplenial tissue sampled from both hemispheres 30 minutes, 2h, or 8h later. Complementary statistical approaches (analyses of variance, predictive patterning and gene set enrichment analysis) revealed pervasive gene expression differences between retrosplenial cortex ipsilateral to the thalamic lesion and contralateral to the lesion. Selected gene differences were validated by QPCR, immunohistochemistry (Experiment 1), and in situ hybridisation (Experiment 2). Following thalamic lesions, the retrosplenial cortex undergoes profuse cellular transcriptome changes including lower relative levels of specific mRNAs involved in energy metabolism and neuronal plasticity. These changes in functional gene expression may be largely driven by decreases in the expression of multiple transcription factors, including brd8, c-fos, fra-2, klf5, nfix, nr4a1, smad3, smarcc2, and zfp9, with a much smaller number (nfat5, neuroD1, RXRγ) showing increases. These findings have implications for conditions such as diencephalic amnesia and Alzheimer's disease, where both anterior thalamic pathology and retrosplenial cortex hypometabolism are prominent.
[show abstract][hide abstract] ABSTRACT: A novel, appetitive, Pavlovian conditioning task was used to assess interval timing. Experiment 1 showed that normal rats could discriminate between tones of 1.5s and 0.5s duration, or between tones of 12.0 s and 3.0 s duration. Learning was demonstrated by a greater duration of magazine responding in the period before the delivery of a food reward and after cessation of the CS+ compared to the same time period after cessation of the CS-. Learning was, however, asymmetric as it was much quicker when the CS+ was the longer of the two durations (1.5s and 12.0 s, respectively). Experiment 2 assessed the impact of fornix lesions on the acquisition of one version of this task (CS+ 1.5s, CS- 0.5s). No evidence was found of a change in discrimination learning following surgery. Experiment 3 examined whether rats with either fornix or hippocampal lesions affected discriminations between 12.0 s and 3.0 s stimuli. Again, there was no evidence of a lesion-induced deficit. T-maze alternation training confirmed the effectiveness of these lesions. The results not only reveal that neither the fornix nor the hippocampus is necessary for distinguishing temporal intervals within the ranges tested but also showed how under some circumstances these lesions can leave trace conditioning intact.
Behavioural Brain Research 03/2008; 187(1):159-71. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The retrosplenial cortex is the first site that exhibits metabolic alterations in the progress of Alzheimer’s Disease (AD). This finding, however, is discordant with overt pathology localisation as earliest affected areas are the entorhinal cortex, hippocampus, and anterior thalamic nuclei. Dense connections exist between the anterior thalamic nuclei and the retrosplenial cortex. Strikingly, anterior thalamic lesions in rats result in hypo-reactivity of immediate-early genes (IEGs) in retrosplenial cortex, unaccompanied by degeneration. This effect is of potential importance to the understanding of AD and memory abilities in general.
We investigated the specificity of the retrosplenial cortex lesion-induced effect. Rats with excitotoxic lesions to sites connected to the retrosplenial cortex were placed in a novel environment, and tissue was then sampled for immunoreactivity of the IEG, c-Fos. Lesions in the anterior thalamic nuclei, hippocampus, or contralateral retrosplenial cortex produced the largest effects, followed by those in entorhinal cortex and laterodorsal thalamic nuclei. Interestingly, analyses of retrosplenial cortex laminae revealed that the effects observed did not match the pattern of innervation from the afferent regions.
Our results suggest that pathology in anterior thalamic nuclei and hippocampus has the largest impact on retrosplenial function. This is of importance to the understanding of the role of these interacting regions in cognitive function, and is of particular relevance for early dysfunction in AD. These findings also address the issue of diaschisis, and suggest caution in attributing function to a brain region. In the on-going debate about covert pathology, our study provides additional evidence for dysfunction in sites distal to a lesion.
[show abstract][hide abstract] ABSTRACT: Activity of the immediate early genes c-fos and zif268 was compared across hemispheres in rats with unilateral, excitotoxic lesions of the hippocampus (dentate gyrus and CA fields 1-4). Counts of the protein products of these genes were made shortly after rats performed a test of spatial working memory in the radial-arm maze, a task that is sensitive to bilateral lesions of the hippocampus. Unilateral hippocampal lesions produced evidence of widespread hypoactivity. Significant reductions in immediate early gene counts were observed within all three anterior thalamic nuclei, as well as the entorhinal, perirhinal, and postrhinal cortices, and much of the subicular complex. In contrast, no observable changes were detected in the anterior cingulate, infralimbic or prelimbic cortices, as well as several amygdala nuclei, even though many of these regions receive projections from the subiculum. Instead, the immediate early gene changes were closely linked to sites that are thought to be required for successful task performance, with both immediate early genes giving similar patterns of results. The findings support the notion that the anterior thalamic nuclei, hippocampus, and parahippocampal cortices form the key components of an interdependent neuronal network involved in spatial mnemonic processing.
[show abstract][hide abstract] ABSTRACT: Rats of the Dark Agouti strain were trained on delayed alternation under conditions that should encourage egocentric working memory. In two experiments a T-maze was set within a cross-maze so that different arms could be used for the sample and test runs. The maze had high opaque side-walls, and testing was conducted in low light levels so that distal visual cues might be eliminated. By rotating the maze 90 degrees between the sample and choice run and by using two identical mazes set side by side it was possible to nullify other spatial strategies. Experiments 1 and 2 showed that rats preferentially used place information, intramaze cues, and direction cues, even though only egocentric or idiothetic (nonmatch-to-turn) working memory could successfully solve every trial. Rats were able to maintain an accurate sense of location within the maze even though distal cues were not visible and the animal was moved between the sample and choice runs. Experiment 2 confirmed that another rat strain (Long-Evans) shows the same learning profiles. Both experiments indicate that rats are very poor at using either egocentric or idiothetic information to alternate, and that retention delays as short as 10 s can eliminate the use of these forms of memory.
[show abstract][hide abstract] ABSTRACT: Benzodiazepines, including lorazepam, are widely used in human medicine as anxiolytics or sedatives, and at higher doses can produce amnesia. Here we demonstrate that in rats lorazepam impairs both recognition memory and synaptic plastic processes (long-term depression and long-term potentiation). Both impairments are produced by actions in perirhinal cortex. The findings thus establish a mechanism by means of which benzodiazepines impair recognition memory. The findings also strengthen the hypotheses that the familiarity discrimination component of recognition memory is dependent on reductions in perirhinal neuronal responses when stimuli are repeated and that these response reductions are due to a plastic mechanism also used in long-term depression.
European Journal of Neuroscience 11/2004; 20(8):2214-24. · 3.75 Impact Factor