1990b). For c -fos, this activation was confined to the damaged hemisphere and 
was sensitive to NMDA receptor antagonists (Herrera and Robertson 1989, 
1990a, 1990b; Dragunow et al. 1990; Traboulsee et al. 1991). There is at least 
some circumstantial evidence that damage-induced IEG activation in cerebral 
cortex is partially the result of spreading neuronal depression (Herrera and 
Robertson 1990b). 
lEGs AND CHANGES IN GENE EXPRESSION 
The impetus for studying IEG activation came from the conviction that changes 
in gene expression lay behind long-term biological change. The excitement 
associated with the discovery of IEG activation in the instances cited above 
(and many others as well) is that there is now a key for the problem of how 
neuronal activity might alter gene expression. However, there is relatively little 
direct evidence for such changes, and what evidence there is is circumstantial. 
For example, a kindling stimulus activates c -fos expression, but there is no 
direct evidence that c -fos expression is absolutely required for kindling to occur. 
Similarly, light exposure during the dark phase leads to IEG expression in the 
SCN, and in every instance studied so far, there is a relationship between IEG 
activation and the phase shift in the circadian rhythms. But this cannot be 
construed as other than circumstantial. On the positive side, there are several 
situations in which it can be said that IEG expression can lead to changes in 
gene expression. For example, the availability of mice with a transgenic c -fos 
linked to a metallothionine reporter has been used by Thoenen and colleagues 
(Hengerer et al. 1990) to demonstrate that activation of c -fos in fibroblasts in 
sciatic nerve precedes NGF synthesis. Furthermore, they were able to show 
that an AP-1 site in the first intron of the NGF promoter is necessary for NGF 
synthesis. It is interesting to note that there are eight AP-1 sites in the promoter 
region of NGF in the mouse, but only one, apparently, is essential for NGF 
synthesis. There is also a suggestion that the proenkephalin gene may be 
up-regulated via an AP-1 site present in its promoter (Sonnenberg et al. 1989). 
However, such regulation of proenkephalin is probably complex, involving 
several other control elements (Comb et al. 1988; Kobierski et al. 1991). 
Clearly, it is important to define the nature of the late-response genes. Are 
there any long-term changes that result from activation of lEGs? What are 
these changes, and how are they carried out? The other task is to show 
conclusively that the lEGs are involved (or not involved) in long- or short-term 
changes in function. 
64 
