Adult hippocampal neurogenesis: traumatic brain injury-induced dysregulation and therapeutic potentials of a novel non-invasive nano-pulsed laser treatment

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Neurogenesis, a physiological process by which new neurons are generated from neural stem cells (NSC), occurs throughout life, subverting the old dogma stating to the inability of the adult brain to replace neurons. In the adult mammalian brain, neurogenesis takes place in the subventricular zone of the lateral ventricle and in the subgranular zone (SGZ) of the hippocampus dentate gyrus. Numerous evidences in the literature demonstrate that neurogenesis decreases during aging and it is impaired in neurodegenerative diseases and after traumatic brain injury (TBI). In this work, I aimed to study TBI-induced dysregulation of neurogenesis and to assess the therapeutic potential of a highly innovative non-invasive device, combining the benefits of both near infrared laser light (808nm) and ultrasound waves, to correct neurogenesis dysfunction in the hippocampus of rats subjected to fluid percussion injury (FPI). I found that a single five minutes transcranial application of NPLT, one hour after FPI, significantly increased neuronal differentiation of DCX+ neuronal progenitor cells in the SGZ and reduced their aberrant migration into the hippocampus hilus and the dentate gyrus granular layer. Moreover, qRT-PCR analysis of laser capture microdissected (LCM) SGZ and of NSC isolated from the hippocampus of TBI rats showed that NPLT prevented injury-induced upregulation of select miRNA (miR9, miR25, miR29, miR124, miR137) known to regulate migration and differentiation of neuronal progenitor cells. Because NPLT did not prevent TBI-induced activation of microglia (amoeboid-shaped Iba1+ and CD68+) in the hippocampus DG and hilus, our results suggest that NPLT might exert its effect in part by directly modulating NSC and neural progenitor cells in the hippocampus. To further study TBI-induced dysregulation of neurogenesis, I used a rapid stretch injury device to reproduce in vitro the effect of mechanical stress, such as the one that occurs during a TBI, on cultured hippocampal NSC. Interestingly, the expression of the same miRNA upregulated by TBI in laser-captured SGZ and TBI-derived hippocampal NSC was significantly increased in NSC subjected to rapid stretch injury. Moreover, rapid stretch injury reduced NSC proliferation and reduced their neuronal and glial differentiation. Inhibition of Piezo1, a mechanoreceptor known to regulate neurogenesis, prevented stretch injury-induced miRNA upregulation, reduced proliferation and increased neuronal differentiation of hippocampal NSC. In conclusion, this work support the use of NPLT for the treatment of TBI-induced dysregulation of hippocampal neurogenesis and suggest that activation of mechanoreceptors is, at least in part, mediating TBI-induced alterations of regulatory miRNA and reduced NSC proliferation and differentiation.

TBI, Neurogenesis: Traumatic Brain Injury, miRNA, Light, Ultrasound, Optoacoustic, Hippocampus, NPLT, non-invasive therapies