Insulin-like growth factor-1 overexpression increases long-term survival of posttrauma-born hippocampal neurons while inhibiting ectopic migration following traumatic brain injury

Abstract

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.

Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival: A Time Course Study in the Male Mouse Dentate Gyrus

“…Notably, proliferation in these non-neurogenic DG regions is often different in injured vs. sham rodents in both the ipsilateral and contralateral hemispheres ( Cho et al, 2015 ; Du et al, 2017 ; Neuberger et al, 2017 ). While these injury-induced changes in proliferation in non-neurogenic DG regions may reflect division of precursors of glia, not neurons ( Avendaño and Cowan, 1979 ; Dragunow et al, 1990 ; Hailer et al, 1999 ; Blümcke et al, 2001 ; Littlejohn et al, 2020 ), the impact of glia on DG structure and function stress the importance of understanding how mTBI influences these measures. Therefore, 3 dpi the ipsilateral and contralateral hilus, oGCL, and molecular layer from Sham and LFPI mice were assessed for indices of proliferation (Ki67+ and BrdU+ cell number).…”

Optimization and validation of a modified radial-arm water maze protocol using a murine model of mild closed head traumatic brain injury

“…For instance, TBI-induced deficits have been reported following a CCI using a two-day RAWM protocol [ 40 , 41 ], and three-day RAWM protocol [ 42 ]. Deficits in reversal learning in the RAWM has also been tested following a CCI [ 7 , 43 – 45 ]. TBI-induced deficits in the RAWM have also been reported following a FPI [ 46 ].…”

Tittle Exploring the Mechanism of Resveratrol on Traumatic Brain Injury by Network Pharmacology and Molecular Docking

“…MMP9 is a zinc-dependent extracellular matrix-degrading enzyme involved in angiogenesis, in ammation, and other processes. After TBI, MMP9 can aggravate brain damage by destroying the blood-brain barrier and inducing neuronal apoptosis and the in ammatory response [42] .…”