Chronic sleep deprivation (SD) severely compromises hippocampal synaptic plasticity and cognitive function, largely through the downregulation of brain-derived neurotrophic factor (BDNF). While the neuroprotective benefits of long-term exercise are well-established, the therapeutic efficacy of short-term exercise intervention initiated during established chronic SD remains poorly understood. This study investigated whether a brief, one-week treadmill exercise regimen could rescue behavioral deficits and synaptic integrity in a rat model of chronic SD. Male Wistar rats were randomized into Normal Control (NC), Sleep Deprivation (SD), and SD with Exercise (SD+Ex) groups (n = 6/group). The SD and SD+Ex groups were subjected to 30 days of continuous REM sleep deprivation. The SD+Ex group received a treadmill intervention (10 m/min, 15 min/session, 4 sessions/day) specifically from Days 14 to 20. Chronic SD induced significant cognitive rigidity and hypolocomotion ( P < 0.05), accompanied by dendritic spine loss ( P < 0.001) and profound BDNF depletion ( P < 0.0001). Critically, the one-week exercise intervention significantly improved reversal learning ( P < 0.05) and restored locomotor activity ( P < 0.01). At the molecular level, exercise attenuated spine density loss ( P < 0.05), upregulated BDNF signaling ( P < 0.05), and was associated with the concurrent recovery of NMDAR availability ( P < 0.0001) and the robust upregulation of CaMKIV ( P < 0.05), and PSD-95 ( P < 0.05) expression. In conclusion, a short-term exercise intervention effectively mitigates SD-induced cognitive and synaptic deficits. These therapeutic benefits are likely mediated by the upregulation of BDNF and the functional re-coupling of the NMDAR-CaMKIV signaling pathway. • Short-term exercise reverses cognitive deficits induced by 30-day chronic sleep deprivation • Short-term exercise restores hippocampal BDNF levels and dendritic spine density • Exercise re-couples the NMDAR-CaMKIV signaling pathway to facilitate synaptic plasticity • Therapeutic exercise intervention shows efficacy even when initiated during established chronic injury
Wen et al. (2026) studied this question.