Short-Term Exercise Ameliorates Cognitive Deficits and Upregulates the Hippocampal BDNF Pathway in Rats with Chronic Sleep Deprivation

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