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 Parkinson's 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) neurons in rats increases the vulnerability to falls on a balance beam task. Here, the impact of transient optogenetic inhibition specifically of BF cholinergic neurons was assessed in rats with dorsomedial striatal dopamine lesions during traversal of straight or zig-zag balance beams using the Michigan Complex Movement Control Task (MCMCT). Adding transient optogenetic inhibition of BF cholinergic neurons with striatal dopamine lesions elevated 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 activity and striatal dopamine that leads to greatest vulnerability to falls and related complex movement impairments.