About two thirds of patients with Parkinson's disease (PD) experience falls. Falls in PD patients are a primary cause of hospitalization and nursing home admission. These debilitating features of PD are resistant to dopamine replacement therapy, emphasizing the critical need for basic research and therapeutic development focused on non-dopaminergic systems that degenerate in PD. The main goals of this research are to determine the role of cholinergic cell loss in the basal forebrain and brain stem pedunculopontine nucleus for the propensity for falls in PD. We developed a novel behavioral apparatus (?MCMCT?) that requires rats to traverse rotating surfaces. This task requires exquisite gait control, including precisely timed placement of weight-shifting steps. Furthermore, we developed a rodent model of the multisystem cholinergic-dopaminergic losses hypothesized to cause falls in PD. The available evidence suggests that dorsal striatal dopaminergic deafferentation impairs the performance of complex behavioral sequences such as gait, resulting in the manifestation of risk factors for falls. This places additional demands on the attentional control of such behaviors. Loss of cholinergic projections impairs the attentional supervision of gait and postural control, thereby contributing to the onset of levodopa-resistant abnormalities of gait and posture, and to falls. PPN cholinergic loss further dysregulates striatal circuitry, thereby increasing the severity of impairments in gait and posture and thus the propensity for falls. The proposed research will determine (1) the cognitive-motor and neuronal mechanisms that underlie falls, (2) the potential usefulness of a rationally-derived treatment approach to prevent falls, and (3) the main neuronal mechanisms mediating fall-related performance and treatment effects. These experimental goals are in accord with the ?highest priority recommendations? of the NINDS PD 2014 Research Report, which include a call for studies aimed at understanding the neural circuit mechanisms of gait and balance disorders in PD, and developing effective treatments for these L-dopa-resistant symptoms (Clinical recommendations 2 & 3; Basic recommendation 3). The proposed experiments are, to our knowledge, the ?rst to explore experimentally the interactions between abnormal basal forebrain and brainstem cholinergic and striatal dopaminergic circuits in the genesis of gait and postural defects, and falls. In addition, this research will establish falls as a useful behavioral endpoint to study cortico-striatal interactions and their modulation by brain stem ascending cholinergic projections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS091856-03
Application #
9130288
Study Section
Special Emphasis Panel (ZNS1-SRB-J)
Project Start
Project End
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
$285,102
Indirect Cost
$101,165
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bohnen, Nicolaas I; Kanel, Prabesh; Müller, Martijn L T M (2018) Molecular Imaging of the Cholinergic System in Parkinson's Disease. Int Rev Neurobiol 141:211-250
Rektor, Ivan; Bohnen, Nicolaas I; Korczyn, Amos D et al. (2018) An updated diagnostic approach to subtype definition of vascular parkinsonism - Recommendations from an expert working group. Parkinsonism Relat Disord 49:9-16
Marino, Simeone; Xu, Jiachen; Zhao, Yi et al. (2018) Controlled feature selection and compressive big data analytics: Applications to biomedical and health studies. PLoS One 13:e0202674
Albin, Roger L (2018) Tourette syndrome: a disorder of the social decision-making network. Brain 141:332-347
Rektor, Ivan; Bohnen, Nicolaas I; Korczyn, Amos D (2018) Subtype definition of vascular parkinsonism. Parkinsonism Relat Disord 52:107-108
Dinov, Ivo D; Palanimalai, Selvam; Khare, Ashwini et al. (2018) Randomization-Based Statistical Inference: A Resampling and Simulation Infrastructure. Teach Stat 40:64-73
Antoniou, Nasia; Vlachakis, Dimitrios; Memou, Anna et al. (2018) A motif within the armadillo repeat of Parkinson's-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway. Sci Rep 8:3455
Bohnen, Nicolaas I; Muller, Martijn (2018) Reader response: Odor identification as a biomarker of preclinical AD in older adults at risk. Neurology 90:343
Sarter, Martin; Phillips, Kyra B (2018) The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models. Behav Neurosci 132:1-12
Kim, Kamin; Bohnen, Nicolaas I; Müller, Martijn L T M et al. (2018) Compensatory dopaminergic-cholinergic interactions in conflict processing: Evidence from patients with Parkinson's disease. Neuroimage :

Showing the most recent 10 out of 100 publications