The molecular signaling of the unconditioned stimulus in rat pup long-term odor preference memory: support for parallel, not serial, memory models

Grimes, Matthew T. (2012) The molecular signaling of the unconditioned stimulus in rat pup long-term odor preference memory: support for parallel, not serial, memory models. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The formation of memory was originally thought to occur through learning causing the formation of early short-term memory (STM), which transitions into long-term memory (LTM) through the process of consolidation. Work in Aplysia found that memory consists of three distinct phases that are defined by their unique dependence on protein synthesis. Through altering serotonin exposure, experimenters could selectively generate a translation-independent STM, a translation-dependent intermediate-term memory (ITM), and a transcription- and translation-dependent LTM. Here we specifically examine the memory mechanisms of LTM using neonatal odor preference learning, which is a well-defined, associative mammalian learning and memory model. Within this model a single pairing of the conditioned stimulus (CS) of novel odor exposure with the unconditioned stimulus (US) of the activation of bulbar beta -adrenoceptors within rat pups causes the formation of a preference for the conditioned odor that lasts for 24 h. Previous analysis of molecular signaling found that odor preference learning increased bulbar cAMP levels and the phosphorylation of CREB. Manipulating the US of beta -adrenoceptor activation causes the alteration of cAMP signaling resulting in the formation or impairment of neonatal odor preference memory such that there is an optimal level of activation, either too little or excessive activation of the US does not produce learning. -- In the present thesis, we set out to identify the underlying molecular mechanisms that produce 24 h neonatal odor preference memory with specific focus on the US of cAMP signaling. In earlier work we had shown, using translational and transcriptional protein synthesis inhibitors, that as in Aplysia , neonatal odor preference memory includes a translation-independent STM lasting till 3 h after learning, a translation-dependent ITM occurring 5 h after learning, and a transcription- and translation-dependent LTM occurring 24 h after learning. Altering the US through decreasing beta -adrenoceptor activation causes the selective generation of ITM, demonstrating the three characteristics of invertebrate memory in mammalian memory (see Appendix). Neonatal odor preference learning causes the activation of bulbar PKA 10 min after training (Chapter 2) and the activation of bulbar ERK immediately after training (Chapter 3). The direct activation of bulbar PKA acts as a sufficient US to selectively generate ITM and LTM and extend odor preference memory to 72 h (Chapter 2). The activation of Epac is also a sufficient US for the generation of long-term neonatal odor preference memory (Chapter 3), demonstrating that cAMP can work through the PKA or Epac/ERK pathway to generate longer protein synthesis-dependent phases of neonatal odor preference memory. Inhibition of either PKA (Chapter 2) or ERK (Chapter 3) prevented the LTM of rat pup odor preference learning with a normal US, suggesting both pathways contribute synergistically to LTM. LTM can be rescued from the inhibition of either bulbar PKA (Chapter 2) or ERK (Chapter 3) through increasing (3-adrenoceptor activation to a level which normally would not produce learning. Thus higher levels of activation of either pathway alone are sufficient to produce LTM. However, the simultaneous inhibition of both kinases inhibits LTM at any level of beta -adrenoceptor activation tested. PKA (Chapter 2) and Epac (Chapter 3) activation, when given alone, as an intracellular US do not produce STM. Thus ITM and LTM occur independently of STM. In addition a high level of (3-adrenoceptor activation in the presence of either a PKA (Chapter 2) or ERK (Chapter 3) antagonist does not lead to ITM although LTM is now supported. Thus, while PKA and Epac/ERK synergistically generate normal LTM through odor preference learning, the distinct memory phases of STM, ITM and LTM can occur without the prior occurrence of the temporally earlier memory. Here we have demonstrated for the first time that PKA and/or Epac activation can act directly as an US for a long-term mammalian memory. In addition, we find that memory is likely composed of parallel intracellular processes which are quasi-independent rather than occurring as a set of serial, interdependent "consolidating" processes.

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