Fig. 2.

SNpc hemi-lesioning produced motor deficits across several domains, which recovered via DREADD-CNO stimulation of remaining PPN cholinergic neurons. (A) During accelerating rotarod testing of the lesioned rats, latency to first fall increased from 33.5 ± 16.5 s (CNO OFF) to 53 ± 28.2 s (CNO ON) (**p = 0.002). Sham-lesioned rodents displayed consistent, nonimpaired performance regardless of CNO-induced stimulation or not. (B) At CNO OFF, evaluation during the PIT revealed reduced average stepping distance because of PPN cholinergic and SNpc DAergic lesioning compared with sham control rats (***p < 0.001). Lesioned rats showed significant functional recovery during CNO ON (***p < 0.001). (C, D) The results of vertical cylinder “wall placement” and “wall exploration,” respectively. SNpc and PPN hemi-lesioning produced significant under-use of the contralateral forelimbs, with subsequent amelioration in performance during CNO ON. (C) **p = 0.007; (D) *p < 0.05). (E) For lesioned rats, dramatic loss of function at CNO OFF followed by recovery at CNO ON was particularly evident in the VEFP test, in which responses to vibrissae stimulation were terminated in all lesioned animals, but mean response rate recovered near-completely during CNO ON (****p < 0.0001). (F) In the OF arena, lesioned rats tended to freeze and/or display reduced motion, but recovered in this aspect during CNO ON (***p < 0.001). (G) For the same testing paradigm, the lesioned rats covered significantly less distance over the 10-min test period at CNO OFF compared with CNO ON (*p = 0.02) and also compared with sham control rats at CNO OFF (***p = 0.0003). Error bars depict SEM throughout. Lactacystin-lesioned: CNO ON n = 12, CNO OFF n = 12; sham-lesioned: CNO ON n = 10, CNO OFF n = 10