Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls

PROJECT II: SUMMARY/ABSTRACT
Approximately two thirds of patients with Parkinson’s disease (PD) experience falls; a primary cause of
hospitalization and nursing home admission. These debilitating features of PD are resistant to dopamine
replacement therapy, emphasizing the urgent need for basic research and therapeutic development focused on
non-dopaminergic systems degenerating in PD. We previously established a rodent model of PD falls and
developed novel behavioral paradigms that reflect critical elements of PD falls. Our work identified disruptions of
the Attentional-Motor Interface (AMI) network as a major pathophysiologic substrate of impaired gait and balance
in PD. The novel Michigan Complex Motor Control Task (MCMCT) assesses falls resulting from impaired AMI
function in rats. We also demonstrated that rats with dual losses of cortical cholinergic and striatal dopamine (DL
rats), reflecting PET-based findings in PD fallers, exhibit high rates of falls on the MCMCT. As in PD fallers,
impairments in attention of DL rats predict fall rates. Treatment with an α4β2* nicotinic acetylcholine receptor
agonist, combination treatments of AChase inhibitors and a 5-HT6 receptor antagonist (idalopirdine) reduce fall
rates, indicating translational value of our system. We now propose rigorous mechanistic studies identifying
critical synaptic dysfunction within key AMI nodes. We will assess the role of basal forebrain cholinergic signaling
in falls (Aim 1), of cholinergically-driven cortico-striatal information transfer (Aim 2), and of the role of striatal
cholinergic interneurons (Aim 3). This work will directly complement the research of Projects I and III. The
proposed research is supported by extensive preliminary evidence demonstrating: 1) the impact of optogenetic
manipulations of basal forebrain cholinergic signaling on complex movement control; 2) that cues guiding
complex movements are “imported’ into the striatum via cortico-striatal glutamatergic activity; 3) that DREADD-
based inhibition or stimulation of striatal cholinergic interneuronal activity cause and prevent falls, respectively;
4) that these interneurons broadly code cues utilized to execute movements. The proposed research will identify
mechanisms of nodal and synaptic AMI dysfunctions, identify novel intervention targets, extend a valuable
preclinical model for therapy development, and substantiate falls as a useful behavioral endpoint for studying
key nodes of the AMI.

Grant Number: 5P50NS123067-05
NIH Institute/Center: NIH
Principal Investigator: Kent Berridge