Progressive hippocampal senescence and persistent memory deficits in traumatic brain Injury: A role of delayed testosterone

Abstract

Cellular senescence is a stable, pro-inflammatory cell cycle arrest that has been recently implicated in the persistent memory deficits experienced with repetitive mild traumatic brain injury (rmTBI). Testosterone (T) treatment immediately following traumatic brain injury (TBI) mitigates cognitive deficits and cellular dysfunction known to induce cellular senescence. However, it has yet to be elucidated whether the therapeutic window for T treatment can be extended to a subacute time post-injury. This study examined the progression of hippocampal cellular senescence after rmTBI and evaluated the effects of subacute T on persistent memory deficits and cellular senescence post-injury. Changes in senescence-associated markers in the hippocampus were quantified at 5- and 9-weeks post-injury (WPI). An age-independent progressive increase in senescence-associated gene expression was observed for Cdkn2a, Cdkn1a, and p53 protein levels, along with a decrease in Sirt1 gene expression. Acute and persistent cognitive deficits were observed in the rmTBI rats as compared to sham rats. Serum T levels were significantly decreased at 4 WPI. Testosterone administration at 5 WPI ameliorated these persistent memory deficits. Moreover, subacute T treatment reduced rmTBI-induced levels of Cdkn2a 4 weeks post-treatment. This study indicates that rmTBI results in a progressive cellular senescence pathology that may contribute to the underlying mechanisms of persistent cognitive symptoms. Therapeutically targeting cellular senescence within this extended temporal window holds implications for patients dealing with the chronic cognitive ramifications of rmTBI.