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

Abstract

In this study, three lines of evidence suggest a role for a 2 -adrenoreceptors in rat pup odor-preference learning: olfactory bulb infusions of the a 2 -antagonist, yohimbine, prevents learning; the a 2 -agonist, clonidine, paired with odor, induces learning; and subthreshold clonidine paired with subthreshold b-adrenoceptor activation also recruits learning. Increased mitral cell layer pCREB occurs with clonidine-infusion, but cAMP is not increased. Similar results using a GABAa-antagonist suggest that disinhibition may support clonidine-induced learning. We suggest that norepinephrine can act through multiple bulbar adrenoceptor subtypes to induce odor learning and that cAMP-dependent, as well as cAMP-independent, signals may act as unconditioned stimuli.Odor-preference learning in the week-old rat pup occurs when a novel odor (conditioned stimulus, CS) is paired with activation of the noradrenergic locus coeruleus. The locus coeruleus is activated by the range of stimuli that can induce odor-preference learning including stroking (Sullivan and Leon 1986;McLean et al. 1993) and feeding (Johanson and Teicher 1980;Kucharski and Hall 1987;Sullivan and Hall 1988), all of which serve as unconditioned stimuli (US). Even rough maternal handling mimicked by mild shocks will engage odor-preference learning (Camp and Rudy 1988;Sullivan et al. 2000a). Odor-preference learning enables rat pups to locate the dam at a period when visual and auditory input is minimal. 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). In particular, the a 2 -adrenoceptor agonist, clonidine, has been shown to decrease granule cell excitability (Nai et al. 2010), releasing the odor-encoding mitral cells from tonic inhibition, and to promote olfactory bulb synchrony at g EEG frequencies (Pandipati et al. 2010). These studies predict a role for a 2 -adrenoceptor activation in odor-preference learning.The present experiments assess the role of bulbar a 2 -adrenoceptors in rat pup odor-preference learning.In all experiments, drugs were infused into the olfactory bulbs on postnatal day (PND) 6. Day of birth was considered PND 0. Sprague-Dawley rat pups of both sexes were used and litters were culled to 12 pups on PND 1. Dams were maintained under a 12-h reverse light/dark cycle at 22˚C in polycarbonate cages with ad l...

Early Life Trauma and Attachment: Immediate and Enduring Effects on Neurobehavioral and Stress Axis Development

“…For example, both natural and learned odors produce a similar enhancement of OB responding during the sensitive-period, which has been assessed through a variety of techniques including 2-deoxy-glucose (2-DG) uptake, c-Fos immunoreactivity (ir), CREB phosphorylation, electrophysiology, and optical imaging (205–208, 211–214). Thus, olfactory-based attachment learning in neonatal rats is associated with the acquisition of odor-specific neural changes in the OB, which can only be acquired during the sensitive-period, and are retained throughout development (111, 201, 215–218).…”

Norepinephrine Modulates Pyramidal Cell Synaptic Properties in the Anterior Piriform Cortex of Mice: Age-Dependent Effects of β-adrenoceptors

“…Several lines of evidence have suggested that neuromodulator norepinephrine (NE) is critical in early odor preference learning and it serves as a UCS signal in this model. NE is released from the locus coeruleus (LC) following tactile stimulation ( Nakamura et al, 1987 ; Nakamura and Sakaguchi, 1990 ; Rangel and Leon, 1995 ) and pharmacological blocking of either α- or β-adrenoceptors in the olfactory bulb (OB; Sullivan et al, 2000b ; Shakhawat et al, 2012 ), or the anterior piriform cortex (aPC; Morrison et al, 2013 ), prevents early odor preference learning in rat pups. Additionally, odor preference learning can be acquired when a novel odor is paired with α- or β-adrenoceptor activation ( Sullivan et al, 2000b ; Harley et al, 2006 ; Morrison et al, 2013 ).…”

α2-Adrenergic receptor activation promotes long-term potentiation at excitatory synapses in the mouse accessory olfactory bulb

“…Enhanced release of noradrenaline (NA) within the MOB plays an important role in long-term synaptic plasticity and odor learning in a variety of contexts. These include olfactory conditioning in neonatal rats (Sullivan et al 1989(Sullivan et al , 1992(Sullivan et al , 2000Harley et al 2006;Zhang et al 2010;Shakhawat et al 2012), the learning of newborn lamb odors after parturition in sheep (Pissonnier et al 1985), odor discrimination after memory formation in mice (Doucette et al 2007;Shea et al 2008;Moreno et al 2012), a specific long-term suppression of mitral cell (MC) responses to paired odors in mice (Shea et al 2008), a long-term reduction of paired-pulse inhibition in neonatal rats (Wilson and Leon 1988), long-term enhancement of synchronized γ frequency oscillations in rat MOB slices (Gire and Schoppa 2008;Pandipati et al 2010), long-term potentiation (LTP) of synaptic strength in rat MOB slices (Yuan 2009;Zhang et al 2010), and a long-term suppression of presynaptic input to MCs in mice (Eckmeier and Shea 2014).…”