Functional and Regional Specificity of Noradrenergic Signaling for Encoding and Retrieval of Associative Recognition Memory in the Rat

Recognition of a familiar object in a novel location requires retrieval of the former object-place association and encoding of novel information. Such object-in-place (OiP) memory recruits a neural network including the hippocampus (HPC), medial prefrontal cortex (mPFC), and nucleus reuniens of the thalamus (NRe); however, the underlying cellular mechanisms are not understood. Locus ceruleus (LC) noradrenergic neurons signal novelty; thus here we focused on the contribution of LC-forebrain projections and noradrenaline (NA) receptor subtypes to OiP encoding compared with retrieval, using an arena-based OiP task in male rats. The NRe was found to receive a catecholaminergic input from LC, with the strongest innervation directed to rostral NRe. Interestingly optogenetic inactivation of the LC→NRe pathway impaired OiP retrieval but was without effect on encoding, while inactivation of the LC→HPC selectively impaired encoding. Consistent with this double dissociation, pharmacological blockade of NRe α1-adrenoreceptors selectively impaired memory retrieval, while blockade of HPC β-adrenoreceptors impaired encoding. Finally, pharmacological attenuation of noradrenergic signaling in the NRe and HPC through the infusion of the α2-adrenergic receptor agonist UK 14,304 impaired retrieval and encoding, respectively. Surprisingly, antagonism or agonism of adrenoreceptor subtypes in the mPFC had no effect on memory performance. Together these results reveal the importance of NA within the HPC and NRe for OiP, whereby selectivity of function is achieved via spatially distinct LC output projections and NA receptor subtypes consistent with a modular view of NA function. These results are also important in demonstrating the distinct neuronal mechanisms by which encoding and retrieval are achieved.