Damage to the brain triggers a host of reactive responses in neurons and glia which are seen at sites of focal injury as well as at sites that are at a distance from the injury. Although many of these responses have been studied extensively, the signals that initiate the different responses have not been fully characterized, and it is still not understood how focal injury affects neurons and glia in distant sites. The present review summarizes recent findings that suggest that physiological events that occur at the time of the injury or during the early postlesion period can play an important and variable role in modulating neuronal and glial responses to injury. We focus on the events that occur in the hippocampal formation following unilateral lesions of the entorhinal cortex - a model system that has been used extensively for studies of cellular responses following focal brain injury. This lesion destroys the cells of origin of a massive excitatory projection to the dentate gyrus and hippocampus proper. Over time, the denervated neurons in the hippocampal formation are almost completely reinnervated as a result of local sprouting of systems that survive the lesion. Thus, this model system has been useful for studying cellular responses to both denervation and reinnervation. We summarize the information that this injury triggers physiological events that can strongly modulate gene expression in neurons and glia, including episodes of spreading depression that occur at the time of the injury, seizures that occur during the early postlesion period, the loss of afferent drive which leads to decreases in postsynaptic activity, and the restoration of activity that occurs in conjunction with reinnervation. We describe recent studies which suggest that some of these physiological events occur to a variable extent in different animals, especially the episodes of spreading depression and the recurrent seizures. Thus, the spatial pattern and temporal dynamics of altered gene expression following this "model" experimental injury may vary from animal to animal. The fact that physiological events strongly modulate the reactive changes in gene expression that occur following injury has important implications for understanding the sequelae of injury, and offers new opportunities for experimental and therapeutic interventions that may improve cellular repair, regeneration, and recovery of function.