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The Journal of Neuroscience, February 1, 2006, 26(5):1407-1417; doi:10.1523/JNEUROSCI.3463-05.2006

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Behavioral/Systems/Cognitive
The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

Björn H. Schott,^1,3 Constanze I. Seidenbecher,³ Daniela B. Fenker,¹ Corinna J. Lauer,¹ Nico Bunzeck,¹ Hans-Gert Bernstein,² Wolfgang Tischmeyer,³ Eckart D. Gundelfinger,³ Hans-Jochen Heinze,^1,4 and Emrah Düzel^1,5

¹Department of Neurology II and Center for Advanced Imaging and ²Department of Psychiatry, University Hospital of Magdeburg, 39120 Magdeburg, Germany, ³Departments of Neurochemistry and Molecular Biology and ⁴Behavioral Neurology, Leibniz-Institute for Neurobiology, 39118 Magdeburg, Germany, and ⁵Institute for Cognitive Neuroscience, and National Hospital for Neurology and Neurosurgery, University College London, London WC1N 3AR, United Kingdom

Correspondence should be addressed to Björn H. Schott, Klinik für Neurologie II, Otto von Guericke Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Email: bschott{at}neuro2.med.uni-magdeburg.de

Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance.

Key words: dopamine transporter; catechol-O-methyl transferase; polymorphism; dopamine; midbrain; episodic memory; fMRI

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Received May 13, 2005; revised Dec. 13, 2005; accepted Dec. 13, 2005.

Correspondence should be addressed to Björn H. Schott, Klinik für Neurologie II, Otto von Guericke Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Email: bschott{at}neuro2.med.uni-magdeburg.de

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