Cellular damage associated with traumatic brain injury (TBI) manifests in motor and cognitive dysfunction following injury. Experimental models of TBI reveal cell death in the granule cell layer (GCL) of the hippocampal dentate gyrus acutely after injury. Adult-born neurons residing in the neurogenic niche of the GCL, the subgranular zone, are particularly vulnerable. Injury-induced proliferation of neural progenitors in the subgranular zone supports recovery of the immature neuron population, but their development and localization may be altered, potentially affecting long-term survival. Here we show that increasing hippocampal levels of insulin-like growth factor-1 (IGF1) is sufficient to promote end-stage maturity of posttrauma-born neurons and improve cognition following TBI. Mice with conditional overexpression of astrocyte-specific IGF1 and wild-type mice received controlled cortical impact or sham injury and bromo-2′-deoxyuridine injections for 7d after injury to label proliferating cells. IGF1 overexpression increased the number of GCL neurons born acutely after trauma that survived 6 weeks to maturity (NeuN+BrdU+), and enhanced their outward migration into the GCL while significantly reducing the proportion localized ectopically to the hilus and molecular layer. IGF1 selectively affected neurons, without increasing the persistence of posttrauma-proliferated glia in the dentate gyrus. IGF1 overexpressing animals performed better during radial arm water maze reversal testing, a neurogenesis-dependent cognitive test. These findings demonstrate the ability of IGF1 to promote the long-term survival and appropriate localization of granule neurons born acutely after a TBI, and suggest these new neurons contribute to improved cognitive function.
|Journal||Acta neuropathologica communications|
|State||Published - Apr 10 2020|
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health National Institute of Neurological Disorders and Stroke (NS072302 and NS077889) and the Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT 14-12A).
© 2020 The Author(s).
- Cognitive flexibility
- Controlled cortical impact
- Dentate gyrus
- Granule cell layer
- Reversal learning
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience