Newly Born Granule Cells in the Dentate Gyrus Rapidly Extend Axons into the Hippocampal CA3 Region following Experimental Brain Injury

Abstract

We investigated whether new neurons generated in the adult rat brain following lateral fluid percussion traumatic brain injury (TBI) are capable of projecting axons along the mossy fiber pathway to the CA3 region of the hippocampus. Dividing cells were labeled by intraperitoneal injection of bromodeoxyuridine (BrdU) on the day of surgery/injury, and neurons that extended axons to the CA3 region were retrogradely labeled by fluorescent tracers (FluoSpheres), stereotactically injected into the CA3 region of both the ipsi- and contralateral hippocampus at 1 or 12 days following TBI (n = 12) or sham injury (n = 12) in anaesthetized rats. Animals (n = 6 injured and n = 6 sham-injured controls per time point) were sacrificed at either 3 or 14 days post-injury. Another group of animals (n = 3) was subjected to experimental TBI and BrdU administration and sacrificed 3 days after TBI to be processed for BrdU and immunohistochemistry for polysialylated neural cell adhesion molecule (PSA-NCAM), a growth-related protein normally observed during CNS development. A fivefold bilateral increase in the number of mitotically active (BrdU+) cells was noted within the dentate gyrus when compared to uninjured controls as early as 3 days following TBI. A subgroup of dividing cells was also immunoreactive for PSA-NCAM at 3 days following TBI. By 2 weeks post-injury the number of BrdU+ cells within the dentate gyrus was increased twofold compared to the uninjured counterparts and a proportion of these newly generated cells showed cytoplasmic staining for the fluorescent tracer. These findings document rapid neurogenesis following TBI and show, for the first time, that newly generated granule neurons are capable of extending projections along the hippocampal mossy fiber pathway in the acute post-traumatic period.

Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus

“…Strikingly, increased neurogenesis has been seen concurrently with dramatic dendritic changes in the newborn population (40). Furthermore, because of the transient increase in neurogenesis we observed, it is conceivable that Notch signaling is activated in a graded manner by other potent stimulators of adult neurogenesis such as running (43), ischemia (44), and focal lesion (45). In particular, it has recently been observed that Notch signaling mediates profound postischemia responses (46), and dynamic changes in the expression pattern of Notch-related molecules suggests the involvement of Notch in the postlesion (47) and postischemia neurogenic response (42,44).…”

Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice

“…Neurogenesis by NSCs and survival of newly differentiated cells can contribute to self-repair after neuronal loss (3). The process can be stimulated in response to CNS injury (4,5) and by signaling from astroglia (6). However, neurogenesis by endogenous NSCs cannot fully compensate for the neural loss observed in CNS disorders and in aging.…”

Discovery of Novel Hippocampal Neurogenic Agents by Using an in Vivo Stable Isotope Labeling Technique

“…Imaging studies have also shown that depressed human subjects exhibit volume loss and atrophy of the hippocampus (Sheline, 2003). In addition to a role in mood disorders, increased neurogenesis may be a repair mechanism in stroke (Lichtenwalner and Parent, 2006) and traumatic brain injury (Emery et al, 2005) and may also contribute to learning and memory (Shors et al, 2001).…”