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The Journal of Neuroscience, June 1, 2003, 23(11):4760-4765

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Early Odor Preference Learning in the Rat: Bidirectional Effects of cAMP Response Element-Binding Protein (CREB) and Mutant CREB Support a Causal Role for Phosphorylated CREB

Qi Yuan,¹ Carolyn W. Harley,² Andrea Darby-King,¹ Rachael L. Neve,³ and John H. McLean¹

¹ Division of Basic Medical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3V6, ² Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3V6, and ³ Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts 02178

Early odor preference learning in rats is associated with increases of phosphorylated CREB (pCREB) in mitral cells of the olfactory bulb. In the present study, herpes simplex virus expressing CREB (HSV-CREB) and dominant-negative mutant CREB (HSV-mCREB) have been injected into the bulb to assess a causal role for CREB and pCREB in this model. Odor paired with stroking or with the -adrenoceptor agonist isoproterenol produces odor approach 24 hr later. Isoproterenol-induced learning exhibits an inverted U curve dose-dependent learning relationship with both low and high doses failing to produce learning. pCREB increases have only been seen at the learning effective dose.

In the present study, injection of an HSV vector expressing mutant CREB into the olfactory bulb prevented learning induced by stroking. Control HSV expressing LacZ was without effect. Expression of mutant CREB shifted the dose–learning curve for isoproterenol to the right such that a higher dose was required to induce learning. Expression of CREB shifted the dose-learning curve for isoproterenol to the left, with a lower dose now producing learning. As expected from this shift, CREB overexpression interfered with learning induced by stroking.

When learning occurred, with either CREB or mutant CREB, pCREB was observed to be elevated relative to the nonlearning LacZ control groups. Unexpectedly, with odor plus stroking in the nonlearning CREB group, the level of pCREB was also higher than with odor plus stroking in LacZ controls that did learn.

The data demonstrate a causal role for CREB and pCREB in early mammalian odor preference learning, reinforcing CREB as a "universal" memory molecule. They support evidence that CREB overexpression can be deleterious and suggest the hypothesis of an optimal pCREB window for learning.

Key words: herpes simplex virus; cAMP response element-binding protein; memory; pCREB assay; olfactory conditioning; isoproterenol

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Received Nov. 26, 2002; revised Mar. 14, 2003; accepted Mar. 14, 2003.

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