title: Anatomical integration of newly generated dentate granule neurons following traumatic brain injury in adult rats and its association to cognitive recovery.
abstract: The hippocampus is particularly vulnerable to traumatic brain injury (TBI), the consequences of which are manifested as learning and memory deficits. Following injury, substantive spontaneous cognitive recovery occurs, suggesting that innate repair mechanisms exist in the brain. However, the underlying mechanism contributing to this is largely unknown. The existence of neural stem cells in the adult hippocampal dentate gyrus (DG) and their proliferative response following injury led us to speculate that neurogenesis may contribute to cognitive recovery following TBI. To test this, we first examined the time course of cognitive recovery following lateral fluid percussion injury in rats. Cognitive deficits were tested at 11-15, 26-30 or 56-60 days post-injury using Morris Water Maze. At 11-15 and 26-30 days post-injury, animals displayed significant cognitive deficits, which were no longer apparent at 56-60 days post-TBI, suggesting an innate cognitive recovery at 56-60 days. We next examined the proliferative response, maturational fate and integration of newly generated cells in the DG following injury. Specifically, rats received BrdU at 2-5 days post-injury followed by Fluorogold (FG) injection into the CA3 region at 56 days post-TBI. We found the majority of BrdU+ cells which survived for 10 weeks became dentate granule neurons, as assessed by NeuN and calbindin labeling, approximately 30% being labeled with FG, demonstrating their integration into the hippocampus. Additionally, some BrdU+ cells were synaptophysin-positive, suggesting they received synaptic input. Collectively, our data demonstrate the extensive anatomical integration of new born dentate granule neurons at the time when innate cognitive recovery is observed.
authors.affiliation: Department of Neurosurgery, P.O. Box 980631, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0631, USA. dsun@vcu.edu
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: McGinn
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Zhou
authors.forename: H Ben
authors.initials: HB
authors.lastname: Harvey
authors.forename: M Ross
authors.initials: MR
authors.lastname: Bullock
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Colello
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology*; D001973:Bromodeoxyuridine; D064026:Calbindins; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D003072:Cognition Disorders / Q000209:etiology* / Q000523:psychology*; D018891:Dentate Gyrus / Q000473:pathology*; D005456:Fluorescent Dyes; D008297:Male; D018782:Maze Learning; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013266:Stilbamidines; D013550:Swimming; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D064026:Calbindins; D005456:Fluorescent Dyes; D064030:S100 Calcium Binding Protein G; D013266:Stilbamidines; D016708:Synaptophysin; D001973:Bromodeoxyuridine