Thyroid hormones play critical roles in brain functions. The underlying mechanisms remain unknown but classical regulation of gene expression through binding to nuclear thyroid hormone receptors has been widely implicated. Evidence has also accumulated suggesting that thyroid hormone can exert effects through non-classical mechanisms involving activation of signal transduction pathways. Whether thyroid hormone can activate signal transduction pathways in the brain is not fully understood. In this study, we administrated 3,5,3′-triiodo-L-thyronine (T3) into rat dorsal hippocampus and determined the phosphorylation of Akt and its downstream targets, mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6k) and the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) signaling molecules. T3 caused specific rapid and persistent activation of phosphatidylinositol 3-kinase (PI3K)/Akt-mTOR signaling pathway, which was mediated by thyroid hormone receptors. Furthermore, the rapid action of T3 did not require protein or RNA synthesis, whereas, the persistent action of T3 was translational and transcriptional activities-dependent. These findings indicated that activation of PI3K/Akt-mTOR signaling pathway provides a new molecular mechanism for thyroid hormone actions in the hippocampus and this new mechanism may contribute to some effects of thyroid hormones in the central nervous system.