Preservation of Septo-Hippocampal Theta Oscillations via Cholinergic Protection Underlies Cognitive Recovery After Physical Exercise Post-Cardiac Arrest

BACKGROUND: Significant cognitive impairment follows cardiac arrest, yet few interventions restore memory. We previously demonstrated that physical exercise (PE) after asphyxial cardiac arrest (ACA) mitigates memory deficits and cell loss in the septal nuclei, but not in the hippocampus in rats. Given the critical role of the septum in modulating hippocampal theta oscillations, essential for memory, we hypothesize that PE preserves memory by safeguarding septal pacemaker neurons and septo-hippocampal theta activity. METHODS: Adult male and female rats underwent 8 minutes of ACA or sham surgery and were randomly assigned to 5 days of treadmill running PE or sedentary conditions. Long- and short-term memory were assessed using fear conditioning and Y-maze tests. Immunohistochemistry quantified septal cholinergic and gamma-aminobutyric acid-ergic neurons. Local field potential recordings evaluated oscillatory activity across the septo-hippocampal network. RESULTS: ACA induced persistent deficits in memory and disrupted theta oscillations throughout the septum and cornu ammonis 1 (CA1) laminae. These changes were accompanied by selective loss of cholinergic and gamma-aminobutyric acid-ergic septal neurons. PE markedly improved cognitive performance and restored theta power across the septo-hippocampal axis. Only cholinergic, not gamma-aminobutyric acid-ergic, neurons were preserved after PE. All effects were consistent across sexes. Importantly, enhancements in CA1 theta power closely tracked behavioral recovery, implying that reestablishment of cholinergic-driven network dynamics plays a central role in memory restoration. CONCLUSIONS: This study is the first to directly implicate PE-induced cholinergic neuron preservation in the reengagement of septo-hippocampal circuitry and cognitive recovery post cardiac arrest. Rather than relying on hippocampal cell survival, the observed memory improvements appear to stem from reinstated interregional theta synchrony. These findings define a novel mechanistic pathway for promoting functional recovery via targeted circuit-level rehabilitation after ischemic brain injury.