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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.

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 four 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, i.e. never after Fast Blue injections, and 2) after longer WGA survival times (three 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.

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.

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.

Using the quantification of the Fos protein as an indicator of neuronal activation, we studied the involvement of the rostral thalamic nuclei and associated structures in different spatial memory tasks in two experiments. In both experiments, tasks were matched for sensorimotor factors but differed in their spatial and mnemonic demands. In Experiment 1, matched groups of rats either ran in a standard eight-arm radial maze or ran up and down just one arm of the maze while the number of runs and rewards were matched across pairs of rats. In Experiment 2, both groups were trained on the eight-arm radial maze but in different rooms. On the test day, one group was moved so that both groups now performed the same radial-maze task in the same room but for one group the extramaze cues were novel. There were significant increases in Fos in all three of the anterior thalamic nuclei (anterodorsal, anteroventral and anteromedial) as well as the adjacent nucleus reuniens and rostral reticular thalamic nucleus, in both the eight-arm versus one-arm condition (Experiment 1) and the novel room versus familiar room condition (Experiment 2). There were no significant differences in the mediodorsal thalamic nucleus in either experiment. The more spatially demanding task in each experiment also resulted in increased Fos expression in the subicular complex (postsubiculum, presubiculum and parasubiculum), as well as in the prelimbic cortex. Performing the standard radial-arm maze task also produced significant Fos increases in both rostral and caudal levels of the retrosplenial cortex when compared to rats running up and down a single arm in the same maze (Experiment 1); performing the task in a novel room did not, however, result in any further Fos increases in this region (Experiment 2). The specificity of the changes in levels of Fos was shown by a lack of any consistent difference in levels in six control sites. The present results reveal a group of anatomically related structures that work together in the intact rat brain during tasks that tax allocentric spatial working memory.

The perirhinal cortex is crucially involved in various forms of learning and memory. Decrements in neuronal responsiveness occur in the perirhinal cortex with stimulus repetition during visual recognition performance. However, very little is known concerning the underlying mechanisms of synaptic transmission and plasticity in this cortical region. In this study, we provide evidence demonstrating the presence of functional group I, II and III metabotropic glutamate receptors in the rat perirhinal cortex in vitro. Furthermore, the results demonstrate long-lasting synaptic depression in the perirhinal cortex. Extracellular synaptic responses were recorded from superficial layers of the perirhinal cortex directly below the rhinal sulcus, in response to electrical stimuli delivered in the superficial or intermediate layers to the entorhinal or temporal cortex sides of the rhinal sulcus. Evoked synaptic potentials were depressed during bath perfusion of each of the following: the broad-spectrum metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine, the group II agonist (2S,1'R,2'R,3'R)-(2',3'-dicarboxycyclopropyl)glycine and the group III agonist (S)-2-amino-4-phosphonobutanoate. Furthermore, there was a long-lasting depression of synaptic transmission following washout of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, (R,S)-3,5-dihydroxyphenylglycine or (2S,1'R,2'R,3'R)-(2',3'-dicarboxy-cyclopropyl)glycine. Activation of group III metabotropic glutamate receptors by (S)-2-amino-4-phosphonobutanoate did not result in long-lasting changes in synaptic transmission. Thus, the pharmacological activation of metabotropic glutamate receptors can produce short- or long-term changes in synaptic transmission in the perirhinal cortex. It is possible therefore, that metabotropic glutamate receptors are involved in the decrement in neuronal responsiveness associated with visual recognition in the perirhinal cortex.

To investigate substrates of recognition memory, the cellular expression of Fos protein in rat brain has been studied after groups of rats were either shown sets of novel or highly familiar objects, or were exposed to the same pattern of illumination without objects being shown. Counts of stained nuclei were made in eight brain regions, where information about novel or familiar visual stimuli is likely to be processed or stored. The counts were relatively high in occipital visual association cortex and area TE of temporal cortex, intermediate in perirhinal cortex, entorhinal cortex, anterior cingulate cortex and the diagonal band of Broca, and low in the hippocampal formation and mediodorsal nucleus of the thalamus. The number of Fos-stained cells was significantly higher for the rats shown novel objects than for those shown familiar objects in perirhinal cortex, area TE, occipital cortex and anterior cingulate cortex. Arguments are advanced that these differences in counts indicate areas involved in the processing and/or storage of information about the novelty or familiarity of visual stimuli, information important to recognition memory.

The novelty of a cue may arise from the presence of an element that has not previously been experienced or from familiar elements that have been rearranged. The present study mapped the anatomical basis of responding to this second form of novelty. For this, rats were trained on a working memory spatial task in a radial-arm maze in a cue-controlled environment. On the final test day the positions of the familiar, extra-maze cues were rearranged for half of the rats (group Novel). The spatial configuration of the cues now matched that of the control rats (group Familiar). Neuronal activation, as measured by the immediate early gene, c-fos, was then compared between the two groups. Rearrangement of visual stimuli led to significant increases in Fos-positive cells in various hippocampal subfields (rostral CA1, rostral CA3 and rostral dentate gyrus) as well as the parietal cortex and the postsubiculum. In contrast, no changes were observed in other sites including the perirhinal cortex, postrhinal cortex, lateral and medial entorhinal cortices, retrosplenial cortices, or anterior thalamic nuclei. These results highlight the selective involvement of the hippocampus for processing novel rearrangements of visual stimuli and suggest that this involvement is intrinsic as it is independent of the parahippocampal cortices. This pattern of Fos changes is the mirror image of that repeatedly found for novel individual stimuli (perirhinal increase, no hippocampal change), demonstrating that these two forms of novelty have qualitatively different neural attributes.