Making memory : noradrenergic and serotonergic interaction leading to cAMP response element binding protein activation via cAMP mediated 2nd messenger signalling in neonate rat odor preference learning

Yuan, Qi (2002) Making memory : noradrenergic and serotonergic interaction leading to cAMP response element binding protein activation via cAMP mediated 2nd messenger signalling in neonate rat odor preference learning. Doctoral (PhD) thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (46MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

Abstract

Early odor preference learning offers a unique paradigm for the study of natural mammalian learning. Week-old rat pups form an approach response to an odor that is paired with a tactile stimulus such as stroking. In this associative conditioning paradigm, norepinephrine (NE) input to the olfactory bulb from the locus coeruleus serves as the unconditioned stimulus (UCS) while olfactory nerve stimulation by odor input serves as the conditioned stimulus (CS). β-adrenoceptors are critically implicated in NE-mediated UCS effects. The β-adrenoceptor agonist, isoproterenol, can substitute for stroking to induce early odor preference learning. Activation of β-adrenoceptors in the olfactory bulb is both necessary and sufficient to induce early odor preference learning. The effects of isoproterenol exhibit an inverted-U curve; while a moderate dose of isoproterenol is effective in inducing odor preference learning when paired with an odor, both higher, or lower doses of isoproterenol fail to induce learning. Serotonin (5-HT) depletion shifts the isoproterenol UCS curve to the right. In an earlier model for odor preference learning, Sullivan and Wilson proposed that early odor preference learning results from the NE disinhibition of mitral cells from granule cells via β-adrenoceptors. This strengthens the mitral to granule cell synapses and increases mitral cell inhibition during memory retrieval. -- In the present thesis, I propose a new model for early odor preference learning. I suggest that a cAMP cascade activated by the NE UCS, likely via β₁-adrenoceptors, directly modulates the olfactory nerve to mitral cell connections and results in CREB transcriptional activation in the mitral cell which underpins long-term memory formation. The new model is based on the following evidence: effective CS and UCS pairing enhances phosphorylated CREB (pCREB) expression in mitral cells of the olfactory bulb and potentiates the olfactory nerve evoked field potentials of mitral cells (Chapter 2). Odor preference learning produces long-lasting increases in blood flow at the level of the olfactory nerve to mitral cell synapses which are observed during memory retrieval, and which support the hypothesis of a stronger odor input signal during memory. This is demonstrated by intrinsic optical imaging showing an enhanced response at the level of glomeruli 24 hrs after odor conditioning (Chapter 3). β₁-adrenoceptors and 5-HT₂A receptors co-localize in mitral/tufted cells. 5-HT depletion decreases NE-induced elevations of cAMP in mitral cells. 5-HT appears to promote NE-induced learning through convergence on the cAMP cascade in mitral cells (Chapter 4). CREB plays a causal role in early odor preference learning. Manipulations of CREB levels by a viral vector injection directly into the olfactory bulb change the likelihood of learning and this is reflected in alterations in pCREB (Chapter 5).

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