Testing 'translator' versus 'integrator' models of retrosplenial cortex function

Our ability to form and retrieve memories is dependent on an interconnected array of brain structures. One of the greatest challenges in brain sciences is to determine how and why these structures work together to support memory. One such brain structure is an area called the retrosplenial cortex, which is thought have important roles in both memory and navigation. In addition, there is growing evidence that damage to the retrosplenial cortex is found in the earliest stages of some of the commonest brain diseases that disrupt memory, e.g. Alzheimer's disease. It is, therefore, presumed that retrosplenial impairments contribute to the cognitive changes seen in these diseases. However, our understanding of retrosplenial cortex function remains very incomplete as: 1) research with humans is held back by the difficulty of isolating this particular brain region in experimental studies; and 2) research with other animals has, so far, been very limited and it has been hampered by the lack of clear theoretical frameworks. We now know that the main structural and anatomical features of the retrosplenial cortex are retained in both the rat and primate brain, and that its connections with other brain areas strongly support the notion that it is important for memory and navigation. Using the rat brain, we plan to test the predictions of two different classes of hypothesis that attempt to explain the properties of this area. Remarkably, although the retrosplenial cortex is one of the largest cortical areas in the rat brain it remains very poorly understood. The most established model is that the retrosplenial cortex is required for changing the mental viewpoint used to encode and store information. It is assumed that initial information about external events is represented by reference to the viewpoint of the recipient, e.g. in front, behind, to the right, to the left. This perspective can be called 'egocentric' or 'view-centred'. It is then supposed that over time this same information is often transformed into a viewpoint that is independent of one's own orientation, this perspective can be called 'allocentric' or 'world-centred'. Then at recollection the information may revert back to an egocentric framework. The model supposes that the retrosplenial cortex is required for these transformations. This specific model will be tested by examining the impact of retrosplenial pathology on the ability switch back and forth between these classes of information. We will also test the more general hypothesis that the retrosplenial cortex enables the switching back and forth between other different spatial codes. An alternative model of retrosplenial cortex function is that it is crucial for bringing together different forms of spatial learning to create unique, complex scenes. The research will test this 'integrator' model of retrosplenial cortex function. Two particular forms of spatial scene learning will be examined in detail. 'Structural learning' refers to learning how the individual features within a scene are spatially arranged and how they relate to each other, i.e. the organisation or 'structure' of a scene. Geometric learning refers to the use of shape information to create distinctive location or context information, e.g. defining a room by the fact that it has a long wall to the right and short wall to the left. This geometric information can then be integrated with object information placed within that context.

The functions of the retrosplenial cortex are thought to be closely linked to those of the hippocampus and the anterior thalamus. Hence, an understanding of retrosplenial cortex opens a window on both temporal lobe and diencephalic memory systems. The rat brain offers an excellent model given the wealth of knowledge about its connectivity (which closely parallels that in primate brains), the ability to make circumscribed, cytotoxic lesions of the retrosplenial cortex, and the recent development of behavioural tests that isolate key functions that might depend on this area. The proposed research will contrast two different models of retrosplenial cortex function. The first model ('translator') assumes that the retrosplenial cortex translates egocentric based information of external events into an allocentric form i.e. from a view-centred to a world-centred orientation, and vice versa. This model will be tested by measuring the ability of rats to switch back and forth, spontaneously, between these two modes of information, and also to switch back and forth when they are alternately reinforced. A more general version of this model is that the retrosplenial cortex enables the ability to switch between multiple spatial codes. The second model ('integrator') assumes that the region has emergent functions that reflect its ability to integrate different forms of spatial information. More specifically it has been proposed that retrosplenial cortex supports 'scene construction'. Attention will focus on two complementary forms of scene construction, namely structural learning and geometric learning. Structural learning (ventral visual stream) refers to how the individual features within a scene are spatially arranged, i.e. 'structured'. Geometric learning (dorsal visual stream) refers to the use of shape information to guide judgments about location, and how item information may then be integrated within distinct geometric frameworks.

The goal of the research is to advance our understanding of the functions of the retrosplenial cortex - an area thought to be vital for normal memory. For this reason, the research will add to the growing body of knowledge about how the brain supports different aspects of cognition, and the factors that optimize or degrade cognitive performance. The proposed research also has relevance for our understanding of the cognitive deteriorations that accompany some of the commonest neurological disorders that afflict humans. This relevance stems from the fact that the retrosplenial cortex is now thought to be very sensitive to Alzheimer's disease and Mild Cognitive Impairment. For example, the region centred on the retrosplenial cortex is typically the first brain area to show metabolic hypoactivity in the progression of both disorders. In addition, the retrosplenial cortex also shows abnormal activity changes in both temporal lobe and diencephalic amnesia. Despite its apparent roles in cognition, we simply do not know how important this region is for learning and memory and what are its precise functions. One of the main obstacles for studying the primate retrosplenial cortex is that it lies buried deep near the midline of the brain and has a complex three dimensional structure. A consequence is that it is extremely difficult to isolate or manipulate this region unambiguously in the primate brain using brain imaging/stimulation/recording techniques. Indeed, it is uncertain whether any descriptions exist of the cognitive changes associated with selective pathology restricted to this area in the human brain. The rat brain is free from these problems and so offers a model by which to understand how the functions of this area relate to its connections and to its physiological properties. The potential impact of research into the retrosplenial cortex is further increased by evidence that this area is unusually sensitive to the loss of its distal connections. Lesion studies in rats show that the loss of sites such as the anterior thalamic nuclei or the hippocampus results in very dramatic decreases in retrosplenial cortex activity as measured by immediate-early gene expression, even though the region shows little or no overt pathology. In some layers of the retrosplenial cortex there is a loss of 90% of the gene expression signal, even though the nerve cells appear intact. The potential significance of this hypoactivity is underlined by the recent discovery that retrosplenial cortex slices taken from rats with anterior thalamic lesions lack a form of plasticity (long-term depression) in the retrosplenial cortex. These findings not only reveal intrinsic changes in retrosplenial cortex following damage to other distal sites but strongly suggest a need to extend the functional pathology of disorders such as temporal lobe amnesia or diencephalic amnesia. In order to understand how 'hidden' pathologies in the retrosplenial cortex might contribute to cognitive deterioration it is necessary first to identify the functional properties of the region.