Persistent CO₂ reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice

Abstract

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO2 challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity, and an impaired respiratory rate response to CO2 challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO2 brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

“…Brain metabolites are altered during sleep including acylcarnitines, hydroxylated fatty acids, phenolic compounds, and thiol‐containing metabolites 31 . Disruption of these oscillations has been observed in cerebrovascular diseases 32–34 . However, the circadian activities of glioma are still poorly understood, and circadian rhythm disruption is still controversial whether it is a cause or an effect of glioma genesis.…”

“… 31 Disruption of these oscillations has been observed in cerebrovascular diseases. 32 , 33 , 34 However, the circadian activities of glioma are still poorly understood, and circadian rhythm disruption is still controversial whether it is a cause or an effect of glioma genesis. Herein, we discussed the molecular connection between cell cycle and circadian rhythm clock, which are the major cyclic system, and focused on the external factors and internal characteristics associated with the glioma circadian clock.…”

“…31 Disruption of these oscillations has been observed in cerebrovascular diseases. [32][33][34] However, the circadian activities of glioma are still poorly understood, and circadian rhythm disruption is still controversial whether it is a cause or an effect of glioma genesis.…”