Although traumatic brain injury results in approximately 80,000 disabled persons per year, there is currently no pharmacological treatment for the head injured patient. The mechanisms by which a mechanical stimulus causes injury are extremely complex involving multiple pathways resulting in cell dysfunction or death. An understanding of these changes may suggest new therapies for brain injured patients. An in vitro device was designed and characterized which was capable of mechanically injuring cultured tissue in a manner consistent with loading conditions thought to cause non-impact, inertial brain injury in vivo. An organotypic brain slice culture preparation was chosen as the representative central nervous system tissue which maintained an in vivo morphological organization of the brain as well as the local interconnections between cell types. By m aintaining this level of complexity, the system used in this dissertation represented an in vitro model of brain trauma which faithfully reproduced the in vivo situation both mechanically as well as biologically. In vitro, mechanical injury to organotypic brain slice cultures resulted in selective alteration in the expression of a panel of genes suggesting that, after mechanical trauma, the brain mounts an active response which includes the regulation of a number of genes which may be protective or detrimental. These alterations included increases as well as decreases arguing against a generalized transcriptional impairment of injured cells. In addition, these changes occurred at different time points and returned to control levels by 48 hours post injury suggestive of an active, compensatory process. These results also demonstrated, for the first time in cultured CNS tissue, that the expression of a subset of genes was correlated with mechanical injury parameters, specifically strain and strain rate. An understanding of these molecular changes may suggest future therapeutic strategies aimed at bolstering beneficial or blunting detrimental, endogenous, post-injury responses with the ultimate goal of improving the management of the head-injured patient so as to minimize the mortality, morbidity, and cost associated with traumatic brain injury