Lipoxygenases are nonheme, iron-containing enzymes that catalyze the oxygenation of cer- tain polyunsaturated fatty acids, such as lipids and lipoproteins. 15-Lipoxygenase has been implicated in the pathogenesis of several dis- eases, including atherosclerosis (15), asthma (16), cancer (17), and glomerulonephritis (18). The biological functions of murine or human 15-LO have not yet been determined with cer- tainty. Nevertheless, there is accumulating evi- dence to suggest a potential mechanism by which overexpression of 12/15-LO could exert a negative effect on skeletal development. Plu- ripotent marrow stromal cells can differentiate into one of several mature forms including adi- pocytes and osteoblasts, a process regulated by both protein and lipid factors. In many instanc- es, lipid regulation of differentiation is mediat- ed through PPAR-dependent signaling path- ways. Linoleate is the most abundant fatty acid in low density lipoprotein (LDL) and is thought to be the largest reservoir of 12/15-LO sub- strate. Oxidized LDLs serve as PPAR ligands (19) and have been shown to activate CD36 expression (20). Furthermore, oxidized lipids inhibit osteoblastic differentiation from preosteoblasts in vitro (21, 22) and bone formation in vivo (23). In addition, 5- lipoxygenase metabolites of arachidonic acid inhibit bone formation in vitro (24) and 5-LO– deficient mice exhibit increased cortical thickness (25); however, no BMD QTL has been identified on chromosome 6 where Alox5 resides. The identification of Alox15 as a suscep- tibility gene for peak BMD in mice may have relevance to human osteoporosis. An autoso- mal genome screen for spinal BMD in 17 extended pedigrees found linkage to a chro- mosomal region (17p13.1) containing the genes encoding human 12-LO and 15-LO (26). In addition, an association between a single-nucleotide polymorphism of PPAR and BMD was identified in postmenopausal women (27). Further studies in both animal models and human populations will be re- quired to gain a deeper understanding of the role the 12/15-LO pathway plays in processes leading to peak bone mass attainment. If 12/ 15-LO is confirmed to contribute to human osteoporosis risk, inhibitors of the enzyme may merit investigation as a treatment for osteoporosis. Such inhibitors have already been developed for other indications (14). References and Notes 1. M. Peacock, C. H. Turner, M. J. Econs, T. Foroud, Endocr. Rev. 23, 303 (2002). 2. Q. Y. Huang, R. R. Recker, H. W. Deng, Osteoporos. Int. 14, 701 (2003). 3. T. F. Mackay, Annu. Rev. Genet. 35, 303 (2001). 4. R. F. Klein et al., J. Bone Miner. Res. 16, 1953 (2001). 5. Materials and methods are available as supporting material on Science Online. 6. J. T. Huang et al., Nature 400, 378 (1999). 7. H. Kuhn, M. Walther, R. J. Kuban, Prostaglandins Other Lipid Mediat. 68-69, 263 (2002). 8. O. Nosjean, J. A. Boutin, Cell. Signal. 14, 573 (2002). 9. B. Lecka-Czernik et al., Endocrinology 143, 2376 (2002). 10. E. Khan, Y. Abu-Am, J. Lab. Clin. Med. 142, 29 (2003). 11. D. Sun, C. D. Funk, J. Biol. Chem. 271, 24055 (1996). 12. D. B. Lewis et al., Proc. Natl. Acad. Sci. U.S.A. 90, 11618 (1993). 13. S. M. Sendobry et al., Br. J. Pharmacol. 120, 1199 (1997). 14. J. A. Cornicelli, B. K. Trivedi, Curr. Pharm. Des. 5, 11 (1999). 15. D. Harats et al., Arterioscler. Thromb. Vasc. Biol. 20, 2100 (2000). 16. V. R. Shannon, P. Chanez, J. Bousquet, M. J. Holtzman, Am. Rev. Respir. Dis. 147, 1024 (1993). 17. I. Shureiqi et al., J. Natl. Cancer Inst. 92, 1136 (2000). 18. A. Montero, K. F. Badr, Exp. Nephrol. 8, 14 (2000). 19. M. Inoue et al., Arterioscler. Thromb. Vasc. Biol. 21, 560 (2001). 20. J. Feng et al., J. Lipid Res. 41, 688 (2000). 21. F. Parhami et al., Arterioscler. Thromb. Vasc. Biol. 17, 680 (1997). 22. Y. Tintut, F. Parhami, V. Le, G. Karsenty, L. L. Demer, J. Biol. Chem. 274, 28875 (1999). 23. J. J. Turek et al., J. Nutr. Biochem. 14, 24 (2003). 24. K. Traianedes, M. R. Dallas, I. R. Garrett, G. R. Mundy, L. F. Bonewald, Endocrinology 139, 3178 (1998). 25. L. F. Bonewald et al., Adv. Exp. Med. Biol. 433, 299 (1997). 26. M. Devoto et al., Eur. J. Hum. Genet. 6, 151 (1998). 27. S. Ogawa et al., Biochem. Biophys. Res. Commun. 260, 122 (1999). 28. K. F. Manly, J. M. Olson, Mamm. Genome 10, 327 (1999). 29. We thank V. K. Chambers, D. Dinulescu, J. Guo, B. Hansen, J. Kansagor, D. A. Olson, B. Orwoll, B. Skinner, R. J. Turner, and K. A. Vartanian for technical assist- ance. This work was supported by funds from the Northwest Health Foundation, Veterans Affairs Med- ical Research Service and the NIH (AR44659 awarded to R.F.K. and HG02322 awarded to G.P.). Supporting Online Material www.sciencemag.org/cgi/content/full/303/5655/229/ DC1 Materials and Methods Figs. S1 and S2 References and Notes 2 September 2003; accepted 21 November 2003 Neural Systems Underlying the Suppression of Unwanted Memories Michael C. Anderson, 1* Kevin N. Ochsner, 2 Brice Kuhl, 1 Jeffrey Cooper, 2 Elaine Robertson, 2 Susan W. Gabrieli, 2 Gary H. Glover, 3 John D. E. Gabrieli 2 Over a century ago, Freud proposed that unwanted memories can be excluded from awareness, a process called repression. It is unknown, however, how repression occurs in the brain. We used functional magnetic resonance imaging to identify the neural systems involved in keeping unwanted memories out of awareness. Controlling unwanted memories was associated with increased dorsolateral prefrontal activation, reduced hippocampal activation, and im- paired retention of those memories. Both prefrontal cortical and right hip- pocampal activations predicted the magnitude of forgetting. These results confirm the existence of an active forgetting process and establish a neuro- biological model for guiding inquiry into motivated forgetting. Stopping retrieval of an unwanted memory im- pairs its later retention (1), and this provides a psychological model for the voluntary form of repression (suppression) proposed by Freud (2, 3). Two brain regions that may play important roles in the neurobiological mechanism of memory suppression are the hippocampus and lateral prefrontal cortex. The hippocampus is essential for declarative memory formation (4 ), and increased hippocampal activation is associ- ated with successful memory formation (5, 6 ) and the subjective experience of recollecting a recent event (7 ). Memory suppression requires people to override or stop the retrieval process. Lateral prefrontal cortex is involved in stop- ping prepotent motor responses (8–11), switching task sets (12, 13), and overcoming interference in a range of cognitive tasks (14–17 ). It may be hypothesized, therefore, that people suppress unwanted memories by recruiting lateral prefrontal cortex to disen- gage hippocampal processing. We adapted the think/no-think paradigm developed to study the suppression of un- wanted memories (1) for use in an event- related functional magnetic resonance imag- ing (fMRI) design (Fig. 1A) (18). Subjects learned word pairs (e.g., Ordeal Roach) and then performed a think/no-think task while being scanned. On each trial, subjects were presented with one member of a pair (e.g., Ordeal) and asked either to recall and think about the associated response (e.g., Roach) (Respond condition) or to prevent the associ- ated word from entering consciousness at all (Suppression condition) for the entire four seconds that the stimulus was presented. 1 Department of Psychology, University of Oregon, Eugene, OR 97403, USA. 2 Department of Psychology, 3 Department of Radiology, Stanford University, Stan- ford, CA 94305, USA. *To whom correspondence should be addressed. E- mail: mcanders@darkwing.uoregon.edu R EPORTS 9 JANUARY 2004 VOL 303 SCIENCE www.sciencemag.org 232