Stimulus processing and control by the retrosplenial cortex

One of the greatest challenges in the brain sciences is to determine how and why different brain structures work together to support cognition. An integral part of this challenge is to understand how brain changes, e.g., through development, aging or disease, can affect cognition. The complexity of the problem, both technical and theoretical, has led researchers to study non-human brains. For this reason, research into rodent brains remains a mainstay of brain science. The retrosplenial cortex is emerging as a brain area with potentially important roles in cognition, most especially memory, though recent imaging studies also suggest an involvement in stimulus control. The main structural and anatomical properties of this area are retained across rodent and primate brains, so reinforcing the value of animal research on this area. Interest in this region is heightened by growing evidence that retrosplenial cortex abnormalities are found in the earliest stages of many of the commonest brain diseases that disrupt memory, including Alzheimer's disease, changes that presumably contribute to the loss of cognitive abilities.

Our understanding of retrosplenial cortex function remains very superficial. Research with humans is held back by the difficulty of isolating this particular brain region as it is buried deep within the primate brain. In contrast, the rat retrosplenial cortex is both relatively large and, unlike the primate retrosplenial cortex, is readily accessible as it is located on the dorsal medial surface of the rodent brain. Even so, this area remains poorly researched in rodents and that research has largely focused on spatial learning and navigation. While the retrosplenial cortex is involved in spatial processes, recent evidence points to a much broader role in cognition than hitherto suspected.

The planned research will examine the novel proposal that the rodent retrosplenial cortex works in close conjunction with frontal brain areas to enable stimulus control, including stimulus translation. This process makes it possible to switch between different representations of the same event. A sequence of clear objectives will test this model. The first objective is to examine non-spatial, as well as spatial, functions of the rodent retrosplenial cortex. The research will involve a combination of novel and established techniques. The resulting findings will open up completely new avenues of research. The second objective is guided by the fact that the retrosplenial cortex has dense, reciprocal connections with the frontal cortex of the brain. The significance of these frontal connections currently remains unknown and so we will ask the simple, but unexplored, question of how much frontal cortex function depends on its retrosplenial interactions and vice versa. By addressing these questions we will test and refine models with the potential to unite what appear to be disparate accounts of retrosplenial cortex function (the third objective).

Our understanding of retrosplenial cortex (RSC) function remains very superficial. Research with humans is held back by the difficulty of isolating this particular brain region as it is buried deep within the primate brain. In contrast, the rat RSC is both relatively large and readily accessible as it is located on the dorsal medial surface of the brain. Even so, this area remains poorly understood in rodents and that research has largely focused on spatial learning. While the RSC is involved in spatial processes, recent evidence points to a much broader role in cognition than hitherto suspected. The planned research will examine the novel proposal that the rodent RSC works in close conjunction with frontal brain areas to enable stimulus control, the translation between different representations of the same event. A sequence of clear objectives will test this model. The first objective is to examine non-spatial, as well as spatial, functions of the rodent RSC. The resulting findings will open up completely new avenues of research. The second objective is guided by the fact that the RSC has dense, reciprocal connections with the frontal cortex of the brain. The significance of these frontal connections currently remains unknown and so we will ask the simple, but unexplored, question of how much rodent frontal cortex function depends on its RSC interactions and vice versa. By addressing these questions we will test and refine models with the potential to unite seemingly disparate accounts of RSC function (the third objective). The research will involve a combination of novel and established techniques. At its core are behavioural tasks to examine stimulus integration and control. RSC activity will be examined using optical imaging and immediate-early gene (IEG) imaging. Optical imaging has never been applied to the RSC, despite area 30 being directly accessible in the rodent. Other techniques include cytotoxic RSC lesions, tract lesions, and temporary lesions.

The planned research includes a novel collaboration with Professor Sengpiel, who is a leading expert on cortical plasticity in the visual system. Consequently, the experiments bring together two different disciplines in ways that will benefit each other in novel ways.

The research will add to the growing body of knowledge about how the brain supports different aspects of cognition and, hence, the potential factors that optimise or degrade cognitive performance. One specific example is how the various pathologies in Alzheimer's disease contribute to the array of cognitive deficits in this disorder. This example is highly relevant it is now known that the retrosplenial cortex (RSC) is structurally disrupted in early Alzheimer's disease. Indeed, the RSC is the first brain area to show consistent metabolic hypoactivity in Mild Cognitive Impairment, often a prodrome for Alzheimer's disease. Such information has not only prompted us to chart early RSC activity changes in transgenic mice with diagnostic features of Alzheimer's disease (amyloid plaques) but also to consider how RSC dysfunction contributes to the early cognitive changes in these degenerative disorders. One such theme is how RSC dysfunction might affect the 'default mode network', with consequential effects upon broad areas of cognition, including memory.

Despite its apparent roles in cognition, we simply do not know the range of RSC functions. Recent white matter imaging studies at Cardiff revealed that the integrity of the cingulum at the level of the RSC correlates with performance on executive tasks, including the Stroop Test. The implication, to be tested, is that RSC activity makes an important contribution to frontal functions. If correct, then the effective extent of frontal functional activity will need to be enlarged.

The RSC has some remarkable features that have implications across wide areas of neurology (neuropathology in particular). When interpreting brain pathology there is the fundamental issue of whether 'what you see is what you get'. Starting from our discovery in Cardiff, it has repeatedly been shown that the RSC is unusually sensitive to the loss of its direct and indirect afferent connections. Lesion studies reveal that damage in sites such as the anterior thalamic nuclei, the mammillothalamic tract, or the hippocampus results in very dramatic decreases in retrosplenial cortex activity as measured by immediate-early gene expression, even though the region shows no overt pathology. In some RSC layers there is a loss of 90% of the gene expression signal, even though the nerve cells appear intact. The disconnection can be either direct (e.g. anterior thalamic lesions) or indirect (e.g. mammillothalamic tract lesions). The potential significance of this 'hidden' or 'cryptic' pathology is underlined by our discovery that RSC slices taken from rats with anterior thalamic lesions lack long-term depression. These findings not only reveal intrinsic plasticity changes in RSC following damage to other sites that cannot be detected by traditional neuropathological methods, but also suggest a need to extend the functional pathology of disorders such as temporal lobe amnesia, diencephalic amnesia, or thalamic strokes that disrupt RSC connections. However, in order to understand how 'hidden' pathologies in the RSC might contribute to cognitive deterioration it is necessary to identify first the functional properties of the region.