β-adrenergic receptors modulate CA1 population coding and synaptic plasticity during cumulative spatial memory formation and updating

Hippocampal neuronal ensembles are likely to support the acquisition, stabilization and updating of spatial experience. Spatial learning is typically cumulative, but little is known about how neuronal ensembles are manifested during this process. Here, we used wide-field Ca²⁺-imaging and in vivo electrophysiology to monitor CA1 pyramidal cells and synapses, respectively, during cumulative item-place learning in adult male CBA/CaOlaHsd mice. In controls, we observed refinement in neuronal activation patterns along with reduced reactivation in response to novel item-place configuration. Synaptic plasticity responses, place cell-like properties, population burst activity, and functional connectivity were consistent with the encoding and updating of item-place memory. Noradrenaline activity via β-adrenergic receptors (β-AR) is a critical modulator of CA1 function, but its role in regulating cellular dynamics during cumulative item-place learning remains unclear. To examine this, we pharmacologically antagonized β-AR prior to the 1st item-place exposure. This led to reduced cellular recruitment, disrupted ensemble reactivation, impaired synaptic plasticity, reduced spatial tuning, dampened population bursts, and altered functional connectivity within neurons. This was accompanied by impaired spatial learning compared to controls. Our results reveal the population activity of CA1 neurons during item-place learning and show that β-AR support memory function by influencing both neuronal and network-level dynamics.