Deficient hippocampal c-fos expression results in reduced anxiety and altered response to chronic stress in female mice.

Stress response is an important neuroendocrine function. Overt or prolonged stress hormone secretion can lead to various disease states. The hippocampus plays an important role in the negative feedback onto the major player in the stress response, the hypothalamo-pituitary-adrenal axis. The transcription factor c-Fos is activated in the hippocampus following a number of stressors, including restraint stress. To determine whether c-fos modulates stress response, we previously generated mutant mice carrying a hippocampal mutation of the c-fos gene. In the current study, we found that female mutant mice display lower anxiety-like behavior than female wild-type mice in the elevated plus maze, whereas male mice are apparently normal. While both male and female mutant mice exhibit normal diurnal glucocorticoid (CORT) production and normal responses to acute restraint stress, female mutant mice habituated faster than female wild-type mice in response to chronic restraint stress. These findings suggest that hippocampal c-fos plays a role in gender-dependent response to stress.

Hippocampal expression of c-fos is not essential for spatial learning.

The formation of long-term memory is thought to involve underlying changes in synaptic strength. Many studies have focused on the mechanisms of spatial learning behavior in mammals that is critically dependent on the proper function of the hippocampus. Because of the enduring nature of long-term memory, it is thought that gene expression is involved in this process. The immediate early gene (IEG) c-fos encodes a transcription factor. The c-Fos proteins form heterodimeric proteins with the c-Jun family proteins and the resulting AP-1 transcription complex plays a key role in coupling short-term events elicited by stimuli received at the cell membrane to long-term neuroplastic changes by regulating gene expression. c-fos is induced in the hippocampus after spatial learning. Despite this knowledge, the precise role of c-fos in memory formation and the underlying mechanisms remain unknown. To start investigating the role of c-fos in learning and memory and underlying mechanisms, we evaluated spatial learning capabilities using mice carrying a hippocampal region-specific mutation of c-fos. We found that the c-fos mutant mice exhibit normal spatial learning behaviors in both the Morris water maze and the Barnes maze tests compared to control mice. Our results suggest that hippocampal c-fos expression is not essential for spatial learning.