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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1-SRB-J (07))
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University of Michigan Ann Arbor
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