Wirtz, J.; Wang, Y.; Chaney, R.; Wirtz, L.; Drezet, Q.; Papaxanthis, C.; Quirie, A.; Meloux, A.; Lemaire, S.; Cefis, M.; Tessier, A.; Garnier, P.

Objective. Neuromuscular electrical stimulation (NMES) is increasingly used to preserve or restore muscle function in patients unable to exercise, and acute NMES improves cognitive performance and increases hippocampal mature brain-derived neurotrophic factor (BDNF). However, the consequences of repeated sessions for muscle-to-brain signaling remain poorly understood. We examined whether seven consecutive days of quadriceps NMES would reproduce this acute response. Methods. Male Wistar rats received daily 30-min quadriceps NMES or SHAM sessions under isoflurane for seven consecutive days. Blood was collected immediately after the final session and 24 h later, when muscle and hippocampal tissues were also collected. An independent cohort underwent behavioral testing. Results. Repeated NMES increased serum creatine kinase activity and quadriceps fibrillar collagen deposition without altering muscle mass, myofiber size, or degeneration-regeneration markers. These changes were accompanied by low-grade systemic inflammation and corticosterone elevation persisting 24 h after the final session. In the hippocampus, NMES increased inflammatory cytokine expression, astrocytic and microglial markers, and glucocorticoid receptor phosphorylation. Mature BDNF, TrkB phosphorylation and ERK1/2 signaling decreased, whereas proBDNF, p75NTR and JNK signaling increased; Akt and mTOR phosphorylation were unchanged. Synaptophysin, GAP43 and PSD95 also decreased. NMES increased marble burying and forced-swim immobility, without detectable changes in locomotion, recognition memory, or neuronal profile density. Conclusions. Repeated daily NMES engaged a distinct, maladaptive mode of muscle-to-brain signaling rather than reproducing the benefits reported after acute stimulation. Stimulation parameters and recovery intervals that avoid this response need to be defined before repeated NMES can be recommended as an exercise substitute.