Microglial Nogo delays recovery following traumatic brain injury in mice

Abstract

Nogo‐A, B, and C are well described members of the reticulon family of proteins, most well known for their negative regulatory effects on central nervous system (CNS) neurite outgrowth and repair following injury. Recent research indicates a relationship between Nogo‐proteins and inflammation. Microglia, the brain's immune cells and inflammation‐competent compartment, express Nogo protein, although specific roles of the Nogo in these cells is understudied. To examine inflammation‐related effects of Nogo, we generated a microglial‐specific inducible Nogo KO (MinoKO) mouse and challenged the mouse with a controlled cortical impact (CCI) traumatic brain injury (TBI). Histological analysis shows no difference in brain lesion sizes between MinoKO‐CCI and Control‐CCI mice, although MinoKO‐CCI mice do not exhibit the levels of ipsilateral lateral ventricle enlargement as injury matched controls. Microglial Nogo‐KO results in decreased lateral ventricle enlargement, microglial and astrocyte immunoreactivity, and increased microglial morphological complexity compared to injury matched controls, suggesting decreased tissue inflammation. Behaviorally, healthy MinoKO mice do not differ from control mice, but automated tracking of movement around the home cage and stereotypic behavior, such as grooming and eating (termed cage “activation”), following CCI is significantly elevated. Asymmetrical motor function, a deficit typical of unilaterally brain lesioned rodents, was not detected in CCI injured MinoKO mice, while the phenomenon was present in CCI injured controls 1‐week post‐injury. Overall, our studies show microglial Nogo as a negative regulator of recovery following brain injury. To date, this is the first evaluation of the roles microglial specific Nogo in a rodent injury model.

Non-fibril form but not fibril form of human islet amyloid polypeptide 8–20 changes brain functions in mice

“…For instance, asymmetrical motor function was recognized 7 days post controlled cortical impact. Then, the alteration was not seen 7 days later (14 days post cortical impact) [42]. Notably, the asymmetrical motor function was not detected 7 days after controlled cortical impact in a microglia-specific inducible Nogo knockout mouse [42].…”

“…Then, the alteration was not seen 7 days later (14 days post cortical impact) [42]. Notably, the asymmetrical motor function was not detected 7 days after controlled cortical impact in a microglia-specific inducible Nogo knockout mouse [42]. The knockout mice exhibited a decrease in microglial and astrocyte immunoreactivity and an increase in microglial morphological complexity compared with injury-matched controls [42].…”

“…The knockout mice exhibited a decrease in microglial and astrocyte immunoreactivity and an increase in microglial morphological complexity compared with injury-matched controls [42]. Based on the observations, the authors suggested that the level of tissue inflammation was decreased in the knockout mice after the injury [42]. Similarly, upregulation of multiple inflammatory cytokines was observed within 1 day in rodents given spinal cord injury [43].…”

“…Notably, the asymmetrical motor function was not detected 7 days after controlled cortical impact in a microglia-specific inducible Nogo knockout mouse [42]. The knockout mice exhibited a decrease in microglial and astrocyte immunoreactivity and an increase in microglial morphological complexity compared with injury-matched controls [42]. Based on the observations, the authors suggested that the level of tissue inflammation was decreased in the knockout mice after the injury [42].…”