Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction.

The dopamine D2 receptor (D2R) has been used in adenoviral delivery systems and in tumor cell xenografts as an in vivo reporter gene. D2R reporter gene expression has been non-invasively, repetitively and quantitatively imaged by positron emission tomography (PET), following systemic injection of a positron-labeled ligand (3-(2'-[18F]-fluoroethyl)-spiperone; FESP) and subsequent D2R-dependent sequestration. However, dopamine binding to the D2R can modulate cyclic AMP levels. For optimal utilization of D2R as a reporter gene, it is important to uncouple ligand-binding from Gi-protein-mediated inhibition of cAMP production. Mutation of Asp80 or Ser194 produces D2Rs that still bind [3H]spiperone in transfected cells. The D2R80A mutation completely eliminates the ability of the D2R to suppress forskolin-stimulated cAMP accumulation in response to dopamine, in cells transfected with a D2R80A expression plasmid and in cells infected with replication-defective adenovirus expressing D2R80A. The D2R194A mutation substantially reduces, but does not completely eliminate, dopamine modulation of cAMP levels. Cultured cells infected with adenoviruses expressing D2R and D2R80A demonstrated equivalent [3H]spiperone binding activity. Moreover, hepatic FESP sequestration is equivalent, following intravenous injection of adenoviruses expressing D2R and D2R80A. The D2R80A mutant, which can no longer modulate cAMP levels following ligand binding, has full capability as a PET reporter gene.

Age-related differences in the use of contextual information in recognition memory: a global matching approach.

Age differences in the processing of contextual information were investigated using the Item, associated Context, and Ensemble (ICE) model (K. Murnane, M. P. Phelps, & K. Malmberg, 1999), a general global matching model of recognition memory. In two experiments, young and older adults studied words in environmental contexts and were tested in both the same and different contexts. Patterns of context effects for hit rate, false alarm rate, and d' suggest that older adults process associated context, but have difficulties integrating items and context into an ensemble. Thus, older adults appear to have a specific, rather than a general, deficit in processing contextual information. A deficiency in ensemble processing may be responsible for the prevalent finding that older adults show poorer recognition memory performance than young adults.

Context-dependent recognition memory: the ICE theory.

A solution to the problem of context-dependent recognition memory is presented in terms of the item, associated context, and ensemble (ICE) theory. It is argued that different types of context effects depend on how context information is encoded at both learning and retrieval. Matching associated context in memory and a retrieval cue produces increases in both hit and false alarm rates and may not be accompanied by a change in discrimination. Integrating item and context information in an ensemble and matching ensemble information in memory and a retrieval cue produces context-dependent discrimination. Empirical support for these predictions is presented.

When does a different environmental context make a difference in recognition? A global activation model.

The effects on recognition of changes in environmental context between learning and test are examined. A context effect occurs when memory tests that take place in an environmental context that is different from the learning context produce consistent differences in performance. A formal model of context-dependent recognition within a global activation framework is presented. The model generates the predictions that (1) context effects will be present when items are tested in a new context that was not seen during learning and (2) context effects will be absent or very small when items are tested in a context that was experienced during learning but that differs from the context in which the test item was learned. Both predictions were verified in an experiment that varied the nature of the different-context test within subjects. Implications for research concerned with context-dependent recognition are discussed.