Research Project
10282008
CATALYST RESEARCH PROJECT: SUMMARY/ABSTRACT Many patients with Parkinson?s disease (PD) suffer from spatial disorientation ? inability to link external landmark cues to internal estimates of self-orientation. These deficits are not improved by dopamine replacement therapy (DRT). The same spatial disorientation features are found in patients with specific lesions, due to a stroke or hemorrhage, of the retrosplenial cortex (RSC), a brain region critical for encoding the combination of allocentric and egocentric navigational information. Attentional and emotional processing impairments in PD patients are accompanied by altered BOLD responses in the retrosplenial cortex. The retrosplenial cortex is densely interconnected with the secondary motor cortex, hippocampus, visual cortex, cingulate cortex and anterior thalamus (containing head orientation cells), and is therefore part of the Attentional-Motor Interface (AMI) and ideally positioned to help transform attentional and spatial information into planned actions. Furthermore, multiple basal forebrain structures send cholinergic projections to the RSC. There are pronounced increases in acetylcholine (ACh) release in the retrosplenial cortex during attentive spatial navigation. Cholinergic deficits, such as those seen in PD, are likely to severely impair the spatial orientation functions of the retrosplenial cortex. Little is known about 1) how cholinergic inputs influence the synapses, cells and circuits of the retrosplenial circuits, and 2) the impact of cholinergic dysfunction on retrosplenial-dependent spatial orientation and navigation. Our central hypothesis is that dysfunctional cholinergic systems projecting to the retrosplenial cortex will manifest in altered navigational encoding by retrosplenial circuits and spatially disoriented behaviors. In Aim 1, we will decipher the mechanisms of cholinergic control of retrosplenial cells and synapses, with preliminary data suggesting both cell-type- and synapse-specific cholinergic controls. In Aim 2, we will investigate how the loss of cholinergic inputs impairs retrosplenial encoding of space and how it impacts orientation-guided movement. The successful completion of these Aims will elucidate the contributions of the retrosplenial orientation coding circuit to the Attentional-Motor Interface, and lay the groundwork for understanding how altered perception of spatial orientation in Parkinson?s disease can directly impact motor control.
