Project I develops a novel rodent model of PD gait dysfunction demonstrating how attentional impairment, caused by partial BF cholinergic neuron loss, causes pronounced abnormalities of gait by “unmasking” striatal dysfunction caused by dorsal striatal dopaminergic denervation. These rodents exhibit a high propensity for falls in situations requiring attentional supervision of complex movements and freezing-type behavior when walking through model “doorways” that is strikingly reminiscent of PD symptomatology. Using these established methods and supported by extensive additional preliminary data, Project I defines the motoric impact of loss of PPN cholinergic neurons, alone and in combination with cortical cholinergic and striatal dopaminergic loss. Project investigators employ this model to explore mechanisms of cholinergic dysfunction directly relevant to therapeutic development. Using cutting-edge technology to record cholinergic neurotransmission at millisecond resolution in awake behaving rodents we investigate the circuit mechanisms that enable cholinergic neurons to compensate for striatal dysfunction prior to their degeneration; identification of these mechanisms is critical to develop novel therapeutic approaches to mimic these effects. Our preliminary data show that administering a combination of L-DOPA and the α4β2* nAChR agonist ABT-089 appears to reduce falls and freezing, supporting the value of this model for identifying the mechanisms underlying functional improvement. The α4β2* agonist varenicline (VCN) will also be tested, and comparisons with the effects VCN administration to PD patients will advance therapeutic validation of this model.