Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. The nestin-HSV-TK transgene has the neural progenitor-specific regulatory elements of the mouse nestin gene directing expression of a truncated/modified herpes simplex viral thymidine kinase (&delta;-HSV-TK) and an enhanced green fluorescent protein (eGFP). This allows for temporally-regulated ablation of dividing neural progenitors by systemic administration of ganciclovir (or the prodrug valganciclovir). Dividing/Proliferating cells that express HSV-TK will metabolize ganciclovir to toxic nucleotide analogues and undergo cell death. Importantly, the truncated/modified TK minigene used in these mice does not include the cryptic testes-specific promoter between the first and second ATG start codons (which was previously shown to confer leaky expression and male sterility). The phenotype of nestin-HSV-TK transgenic line 145 mice is described below. Transgene expression (&delta;-HSV-TK and eGFP) in embryonic stages was visible only in the developing neural tube. In the adult brain, transgene-expressing cells were restricted to known neurogenic areas (subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles). Overall, HSV-TK expression in this transgenic line is coincident with early hippocampal progenitors. The donating investigator reports that eGFP expression is observable by direct fluorescence, but they enhance it with antibody staining. eGFP expression is more intense in homozygotes compared to hemizygotes. Prior to ganciclovir exposure, C57BL/6 nestin-HSV-TK transgenic mice exhibit no apparent cell death and are viable with no reported gross or behavioral abnormalities. Although RT-PCR analysis revealed the expression of &delta;-HSV-TK in testes and brain in this line, both male and female mice are fertile. Transgenic mice (both hemizygotes and homozygotes) are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Systemic administration of ganciclovir (via IP pumps or with valganciclovir chow) results in efficient/robust depletion of neural progenitor cells in both the early quiescent slowly-dividing population (&gt; 60%) and the late rapidly-dividing population (&gt; 90%). In addition, ablation of progenitors is reversible - when ganciclovir is removed, remaining quiescent cells divide and repopulate the subgranular zone. These nestin-HSV-TK transgenic mice have been used to study the dynamics of early and late neural progenitors after brain injury protocol (controlled cortical impact [CCI]), with or without donepezil (an FDA-approved acetylcholine esterase inhibitor used to treat Alzheimer's disease that is minimally toxic, crosses the blood brain barrier, and acts on cholinergic neurons to specifically augment hippocampal neurogenesis).&nbsp;

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 Nestin-HSV-TK transgenic mice have the neural progenitor-specific regulatory elements of the mouse nestin gene directing expression of a truncated/modified herpes simplex viral thymidine kinase (&delta;-HSV-TK) and an enhanced green fluorescent protein (eGFP). These mice allow ganciclovir (GCV)-inducible, temporal and spatial ablation of dividing/proliferating neural progenitor cells, and may be useful in studying traumatic brain injury.

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