PKA increases in the olfactory bulb act as unconditioned stimuli and provide evidence for parallel memory systems: Pairing odor with increased PKA creates intermediate- and long-term, but not short-term, memories

Abstract

Neonatal odor-preference memory in rat pups is a well-defined associative mammalian memory model dependent on cAMP. Previous work from this laboratory demonstrates three phases of neonatal odor-preference memory: short-term (translation-independent), intermediate-term (translation-dependent), and long-term (transcription-and translation-dependent). Here, we use neonatal odor-preference learning to explore the role of olfactory bulb PKA in these three phases of mammalian memory. PKA activity increased normally in learning animals 10 min after a single training trial. Inhibition of PKA by Rp-cAMPs blocked intermediate-term and long-term memory, with no effect on short-term memory. PKA inhibition also prevented learning-associated CREB phosphorylation, a transcription factor implicated in long-term memory. When long-term memory was rescued through increased b-adrenoceptor activation, CREB phosphorylation was restored. Intermediate-term and long-term, but not short-term odor-preference memories were generated by pairing odor with direct PKA activation using intrabulbar Sp-cAMPs, which bypasses b-adrenoceptor activation. Higher levels of SpcAMPs enhanced memory by extending normal 24-h retention to 48-72 h. These results suggest that increased bulbar PKA is necessary and sufficient for the induction of intermediate-term and long-term odor-preference memory, and suggest that PKA activation levels also modulate memory duration. However, short-term memory appears to use molecular mechanisms other than the PKA/CREB pathway. These mechanisms, which are also recruited by b-adrenoceptor activation, must operate in parallel with PKA activation.

Epac activation initiates associative odor preference memories in the rat pup

“…1A). This demonstrates that cAMP can activate Epac to generate odor preference memory and that activating bulbar Epac results in a similar pattern as activating bulbar PKA (Grimes et al 2012). One-way ANOVA (F (2,17) ¼ 8.482, P ¼ 0.0034) revealed that the Epac/ERK pathway also facilitates STM since Epac activation via 8-pCPT infusion produces 3-h memory, similar to 2 mg/kg Iso UCS (a learning control), and in contrast to the nonlearning saline control (Fig.…”

“…(A) Olfactory bulb infusion of 8-pCPT (Epac agonist) 20 min before odor exposure generates 24-h LTM even in the absence of noradrenergic activation. No inverted U-curve response occurred with different concentrations of the drug, which was also seen with the activation of another cAMP target, PKA, as the UCS (Grimes et al 2012). (B) Intrabulbar activation of Epac (5 mg 8-pCPT) is sufficient to produce 3-h STM.…”

“…Direct stimulation of b-adrenergic receptors in the olfactory bulb concomitant with novel odor is both necessary and sufficient to initiate odor preference learning (Sullivan et al 2000). Early odor preference learning depends causally on activation of the cAMP (Cui et al 2007), PKA (Grimes et al 2012), and CREB (McLean et al 1999;Yuan et al 2003) pathway, which has been implicated in multiple forms of mammalian associative learning (Lamprecht et al 1997;Silva et al 1998;Alberini 1999;Josselyn and Nguyen 2005).…”

Olfactory bulb α2-adrenoceptor activation promotes rat pup odor-preference learning via a cAMP-independent mechanism

“…Odor paired with the activation of b-adrenoceptors in the olfactory bulb is sufficient to induce odor learning, while a bulbar b-adrenoceptor antagonist prevents odorpreference learning (Sullivan et al 2000b). Thus, the olfactory bulb appears to be the critical site for the CS-US pairing, and the likely location of the odor memory.However, in addition to b-adrenoceptors, which induce odor learning via activation of the cAMP/PKA/CREB cascade (McLean et al 1999; Yuan et al 2003a,b;Cui et al 2007;Grimes et al 2012), there are bulbar a-adrenoceptors likely to be engaged by norepinephrine (NE) release. Recently, studies of a 2 -adrenoceptor activation in the olfactory bulb in vitro have revealed receptor effects that could promote odor learning (Nai et al 2010;Pandipati et al 2010).…”

“…However, in addition to b-adrenoceptors, which induce odor learning via activation of the cAMP/PKA/CREB cascade (McLean et al 1999; Yuan et al 2003a,b;Cui et al 2007;Grimes et al 2012), there are bulbar a-adrenoceptors likely to be engaged by norepinephrine (NE) release. Recently, studies of a 2 -adrenoceptor activation in the olfactory bulb in vitro have revealed receptor effects that could promote odor learning (Nai et al 2010;Pandipati et al 2010).…”