Falls Induced by Optogenetic Inhibition of Basal Forebrain Cholinergic Projections after Dorsomedial Striatal Dopamine Depletion in a Dual Disruption Model of Falling Vulnerability in Parkinson Disease

Falls are a common and debilitating feature of Parkinsons Disease (PD) patients. Prefrontal acetylcholine (ACh) deficits, as well as nigrostriatal dopamine deficits, are implicated in vulnerability to falls. PD patients with loss of cortical ACh and associated cognitive dysfunction experience a higher rate of falls than PD patients without cortical ACh loss. In addition, chemogenetic inhibition of basal forebrain (BF) projections in rats increases the vulnerability to falls on a balance beam task. Here, the impact of transient optogenetic inhibitions of BF-cortical cholinergic projections was assessed in rats with dorsomedial striatal dopamine lesions during traversal of straight or zig-zag balance beams in the Michigan Complex Movement Control Task (MCMCT). Adding transient optogenetic inhibition of BF-cortical cholinergic projections in rats with striatal dopamine lesions increased falls above the level produced by striatal dopamine lesions or BF ACh inhibition alone, especially on the challenging zig-zag task. These results support the critical role of BF-cortical cholinergic circuits in alleviating vulnerability to falls in PD patients with striatal dopamine loss, suggesting that it is combined loss of BF cholinergic projections and striatal dopamine that leads to greatest vulnerability to falls and related complex movement impairments.