Alterations in glucocorticoid inducible RNAs in the limbic system of learned helpless rats

Glucocorticoids (GC) have an important effect on mood in humans and influence learned helplessness, an escape avoidance paradigm that is considered one of the best animal models of depression. A strong genetic component underlies the development of learned helplessness as shown by the emergence of a line of highly vulnerable rats (LH strain) through selective inbreeding. In addition, hormonal factors play a role. Adrenalectomy (adx) for example is known to increase the vulnerability to acquire learned helplessness, an effect that is reversed by glucocorticoids (GC). Since GC function primarily by modulating gene expression, hormone mediated alterations in mRNAs expressed in the brain may be important in the development of an adequate escape avoidance response. Conversely, we postulate that the deficit in escape avoidance behavior exhibited by the LH strain may be associated with an alteration in GC-mediated gene expression in the brain. To test this hypothesis, we analyzed GC-responsive mRNAs that are expressed in the hippocampus. Control Sprague-Dawley (SD) rats showed consistent alterations in mRNAs that are modulated by GC, such as type II GC receptor (GR) and metallothionein-1 (MT-1). Under our experimental conditions, both GR and MT-1 mRNA are significantly increased in the hippocampus of hormone-treated SD rats. An increase in hypothalamic GR mRNA was also observed. However, under the same experimental conditions, LH rats showed more selective hormone induced changes since GC had no effect on hypothalamic and hippocampal GR mRNA whereas a significant increase in MT-1 mRNA was observed. The data support the hypothesis that the increased vulnerability exhibited by LH rats is correlated with alterations in GC-mediated gene expression in limbic structures.