Functional and regional specificity of noradrenergic signalling for encoding and retrieval of associative recognition memory in the rat

Tran, Stephanie, Barker, Gareth R. I., Mathiasen, Mathias L., Aggleton, John P. ORCID: https://orcid.org/0000-0002-5573-1308 and Warburton, E. Clea 2025. Functional and regional specificity of noradrenergic signalling for encoding and retrieval of associative recognition memory in the rat. The Journal of Neuroscience , e2408242025. 10.1523/JNEUROSCI.2408-24.2025

Preview

PDF - Accepted Post-Print Version Available under License Creative Commons Attribution. Download (7MB) | Preview

Abstract

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 memory (OiP) 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 coeruleus (LC) noradrenergic neurons signal novelty, thus here we focussed on the contribution of LC-forebrain projections, and noradrenaline (NA) receptor subtypes to OiP encoding compared to 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 signalling in the NRe and HPC through the infusion of the α2-adrenergic receptor agonist UK14,304 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. Noradrenaline projections from the locus coeruleus (LC) have been recognised as providing a novelty signal to the forebrain yet whether this signal is important in mediating different stages of memory is poorly understood. Our results demonstrate that associative recognition memory retrieval is selectively mediated by a direct projection from the LC to the nucleus reuniens of the thalamus (NRe) and by activation of NRe α1 and α2 -adrenoreceptors. Conversely encoding is selectively mediated by LC input to hippocampus and by hippocampal β and α2 -adrenoreceptors. These findings reveal functional and regional specificity of noradrenergic modulation of memory processing in the context of memory circuitry and thus enables the definition of clearer targets for disease-modifying therapies for patients with memory deficits. [Abstract copyright: Copyright © 2025 Tran et al.]

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Publisher:	Society for Neuroscience
ISSN:	0270-6474
Date of First Compliant Deposit:	3 June 2025
Date of Acceptance:	27 April 2025
Last Modified:	03 Jun 2025 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/178693

Actions (repository staff only)

Edit Item