Award details

Identifying the roles of the granular and dysgranular retrosplenial cortices in spatial memory

Reference	BB/D002001/1
Principal Investigator / Supervisor	Professor Seralynne Vann
Co-Investigators / Co-Supervisors	Professor John Aggleton
Institution	Cardiff University
Department	Sch of Psychology
Funding type	Research
Value (£)	278,846
Status	Completed
Type	Research Grant
Start date	21/11/2005
End date	20/12/2008
Duration	37 months

Abstract

The main aims of the proposed research are to determine whether the two principal subregions of the retrosplenial cortex, the granular and dysgranular cortices, can be functionally dissociated and whether the roles of these two subregions can be predicted on the basis of their anatomical connections. This research will be carried out using two techniques. The first is the behavioural analysis of the effects of selective neurotoxic lesions. These lesions will be made by injections of 0.9M NMDA, a technique that destroys nerve cells but spares fibres. This property is crucial as conventional lesions will cut fibres passing to both subregions and so make it impossible to differentiate the two areas. We have considerable experience of this technique and have used it in pilot studies to make selective lesions within the retrosplenial cortex. Four groups of animals will typically be tested in the lesion studies: complete retrosplenial cortex lesions, dysgranular cortex lesion, granular cortex lesions, and surgical controls. The functional effects of these lesions will then be assessed on a number of behavioural tests in the radial-arm maze, water maze and T-maze. Standard tasks in both the radial-arm maze and water maze are known to be sensitive to complete retrosplenial lesions and so provide a valuable starting point to test the effects of these more selective lesions. In addition, lesion animals will be tested on tasks that are specifically designed to examine the possible functions of the two subregions on the basis of their connectivity. For example, as the dysgranular cortex has stronger links with visual areas it would be predicted that this subregion would support more visual or allocentric-driven spatial performance. In contrast, the granular cortex has greater connections with areas implicated in head-direction and self-movement, which could support spatial performance when visual stimuli are no longer available or when path-integration is required. The second technique to be used is functional gene imaging. The protein product of two immediate-early genes, c-fos and zif268, will be identified using immunohistochemical procedures and then quantified using standard techniques that the applicants have refined. The target genes are of especial interest as they encode regulatory transcription factors and have been directly implicated in an array of learning processes. Levels of gene expression will be measured 90 mins after after learning as this is when protein production peaks. Two sets of experiments will be conducted, one in the light the other in the dark. For each experiment there are additional control groups that are matched for sensorimotor experience but differ in their spatial memory requirements. It is predicted that these two experiments will differentially involve the two main retrosplenial subregions. By using functional gene imaging it will be possible to determine whether there are qualitative or quantitative differences in the dysgranular and granular regions within the same animals. This approach also makes it possible to determine how changes in retrosplenial cortex activity accord with changes in other regions, and so determine the extent to which the retrosplenial cortex is part of an integrated circuit. Finally, this approach makes it possible to compare subregions or specific cell populations within the granular and dysgranular cortices, so providing a level of anatomical resolution that is far greater than in any previous functional study of this area.

Summary

Although the retrosplenial cortex extends over half of the length of the rodent brain, its functions remain largely unknown. The goal of the proposed research is determine how this region might contribute to memory and, in particular, to spatial memory. The focus on memory (and spatial memory) comes from one accepted fact about the retrosplenial cortex: the region is densely interconnected with other brain regions known to be important for memory (e.g. the hippocampus). Consistent with this view are reports that damage to the retrosplenial region might be sufficient to produce memory loss (amnesia) in humans. Likewise, more selective damage to the retrosplenial cortex in rats is sufficient to disrupt the learning and performance of tests of spatial memory that are sensitive to hippocampal damage. The starting point for much of the proposed research is the fact that the retrosplenial cortex is not uniform. When viewed under a microscope it is clear that the arrangement of nerve cells within the retrosplenial cortex changes, so forming two very distinct areas. These are called the granular area and the dysgranular area. Anatomical studies have also shown that these two areas not only look different but are connected to different brain regions. It can, therefore, be assumed that the granular and dysgranular areas have different functions, although this has never been tested. While the granular cortex is more closely connected with the hippocampus and other areas implicated in direction monitoring, the dysgranular area is more closely linked with visual information. Using these facts it is possible select a series of behavioural tasks that tax different aspects of spatial learning that depend either on direction monitoring or on the use of distant visual cues to locate and map space. By then testing rats in which either the granular or the dysgranular retrosplenial cortex has been removed, it is possible to test whether each area is necessary for different aspects of spatial learning and memory. These studies would provide the first experiments in which the two major subdivisions of the retrosplenial cortex have been compared using the lesion approach. Other techniques, which involve mapping the expression of particular genes, make it possible to have even more detailed comparisons of function within the retrosplenial cortex. A further issue is whether the different subregions all function as an integrated unit, so that the damage to one subdivision will disrupt other subdivisions of the retrosplenial cortex or whether the two major subdivisions have separate roles. This possibility will be tested by combining the removal of the granuluar region in just one hemisphere with the removal of the dysgranular region in just the other hemisphere. Finally, while retrosplenial function is usually considered in terms of spatial memory it is also important to assess the role, if any, of this region for nonspatial memory so a broader theory of retrosplenial function can be decided. In summary, this research will analyse how this extensive brain region supports spatial memory functions, and so provide greater understanding of the functions of connected brain regions such as the hippocampus and anterior thalamic nuclei which are also important for learning and memory.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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