Abstract
Traumatic brain injury (TBI) increases hippocampal neurogenesis, which may contribute to cognitive recovery after injury. However, it is unknown whether TBI-induced adult-born neurons mature normally and functionally integrate into the hippocampal network. We assessed the generation, morphology, and synaptic integration of new hippocampal neurons after a controlled cortical impact (CCI) injury model of TBI. To label TBI-induced newborn neurons, we used 2-month-old POMC-EGFP mice, which transiently and specifically express EGFP in immature hippocampal neurons, and doublecortin-CreERT2 transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, to permanently pulse-label a cohort of adult-born hippocampal neurons. TBI increased the generation, outward migration, and dendritic complexity of neurons born during post-traumatic neurogenesis. Cells born after TBI had profound alterations in their dendritic structure, with increased dendritic branching proximal to the soma and widely splayed dendritic branches. These changes were apparent during early dendritic outgrowth and persisted as these cells matured. Whole-cell recordings from neurons generated during post-traumatic neurogenesis demonstrate that they are excitable and functionally integrate into the hippocampal circuit. However, despite their dramatic morphologic abnormalities, we found no differences in the rate of their electrophysiological maturation, or their overall degree of synaptic integration when compared to age-matched adult-born cells from sham mice. Our results suggest that cells born after TBI participate in information processing, and receive an apparently normal balance of excitatory and inhibitory inputs. However, TBI-induced changes in their anatomic localization and dendritic projection patterns could result in maladaptive network properties.
Highlights
In mammals, the generation of adult-born hippocampal neurons persists into late adulthood and is influenced by multiple environmental contingencies, such as learning (Gould et al, 1999), exposure to enriched environments (Kempermann et al, 1997), and exercise
Because adult-born hippocampal neurons are important for learning and memory (Shors et al, 2001; Dupret et al, 2008; Sahay et al, 2011), post-traumatic hippocampal neurogenesis may compensate for functional deficits resulting from injury and contribute to cognitive recovery
It is well established that injuries such as traumatic brain injury (TBI) can increase neurogenesis in the dentate gyrus
Summary
The generation of adult-born hippocampal neurons persists into late adulthood (van Praag et al, 2005; Zhao et al, 2008; Spalding et al, 2013) and is influenced by multiple environmental contingencies, such as learning (Gould et al, 1999), exposure to enriched environments (Kempermann et al, 1997), and exercise (van Praag et al, 1999). Because adult-born hippocampal neurons are important for learning and memory (Shors et al, 2001; Dupret et al, 2008; Sahay et al, 2011), post-traumatic hippocampal neurogenesis may compensate for functional deficits resulting from injury and contribute to cognitive recovery. The axons of granule cells born after TBI project to hippocampal region CA3 (Sun et al, 2007), it remains unknown whether these outputs are functional and, more importantly, whether these cells receive afferent input. Because mature granule cells in the dentate gyrus can be hyperexcitable after TBI (Santhakumar et al, 2000; Gupta et al, 2012), it is possible that cells born after TBI develop similar changes during their maturation
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