Udall Catalyst Research Project: Retrosplenial Cholinergic and Attentional-Motor Integration Dysfunction

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.

Grant Number: 5P50NS123067-05
NIH Institute/Center: NIH
Principal Investigator: Omar Ahmed