The novel, human differentiating factor peptide fragment HLDF6 (Thr-Gly-Glu-Asn-His-Arg) was synthesized and purified. HLDF6 (0.1 mg/kg i.p. but not 1 mg/kg i.p.) improved not onLy long-term (24 h) memory in adult rats in the water maze behavioural paradigm but also performance in the delayed matching-to-position (DMTP) task (0.3 and 1.0 but not 0.1 mg/kg i.p). Hence, HLDF6 not only enhanced allocentric spatial learning and reference memory (water maze) but also improved temporal, spatial and working memory processes in the DMTP behavioural paradigm. Immunoreactivity blotting analysis of HLDF (the protein precursor of HLDF6) was performed and the following rank order of visual intensities from brain structures was noted: hippocampus > cerebral cortex > cerebellum > hypothalamus > striatum. Subsequently, we found that the highest absolute levels of HLDF were expressed in the hippocampus and cerebral cortex as detected by ELISA. We also demonstrated that HLDF6 enhanced [ 3H]-thymidine and [14C]-leucine incorporation into whole brain and hippocampal homogenates (maxima occurring within the range 10 -12-10-6M) suggesting that this hexapeptide promoted de novo DNA and protein biosynthesis. We discuss this data in terms of their implications for links with other integrative metabolic pathways involving immediate early gene activation which may underpin a potential application for HLDF6 in limiting memory impairments associated with neurodegenerative diseases.