Behavioral hyperactivity and hippocampal mitochondrial dysfunction following recurrent concussions in young mice.

Although traumatic brain injury (TBI), particularly recurrent concussions during adolescence, is strongly associated with post-traumatic hyperactivity, the role of mitochondrial dysfunction in driving this behavioral alteration remains poorly understood and insufficiently characterized. In this context, we investigated the effects of varying frequencies of recurrent concussions on exploratory behavior, hippocampal mitochondrial bioenergetics, and nitrosative stress in adolescent male Swiss mice (32 days old) subjected to a weight-drop model over 10 days and allocated to Control, 4, 7, and 10-concussion groups. Exploratory behavior was assessed using the open field test 24 h post-injury, while hippocampal mitochondrial respiration (high-resolution respirometry) and nitrosative stress markers (3-nitrotyrosine and iNOS) were evaluated 6 days after the final injury. Twenty-four hours after the final injury, behavioral hyperactivity peaked following 7 concussions. While this phenotype was attenuated after 10 recurrent concussions, exploratory alterations (increased proportion of mobile time, greater time spent in the center, and fewer immobile episodes) persisted relative to controls. Respirometry at 6 days post-injury indicated a threshold effect for mitochondrial dysfunction: although 7 concussions compromised maximal electron transfer capacity, basal and phosphorylation states were impaired only after 10 concussions, resulting in a reduction in ATP synthase activity. The severe bioenergetic failure coincided with increased hippocampal protein nitrosylation (3-NT), indicating a progressive metabolic deterioration subsequent to the early behavioral hyperactivity. Our findings suggest that early hyperactivity precedes bioenergetic failure, reflecting the sequential progression of the injury. Thus, this transient behavioral phenotype may serve as a predictive marker for subsequent mitochondrial collapse.