Norepinephrine as a spatial memory reset signal.

Contextual information is represented in the hippocampus (HPC) partially through the recruitment of distinct neuronal ensembles. It is believed that reactivation of these ensembles underlies memory retrieval processes. Recently, we showed that norepinephrine input from phasic locus coeruleus activation induces hippocampal plasticity resulting in the recruitment of new neurons and disengagement from previously established representations. We hypothesize that norepinephrine may provide a neuromodulatory mnemonic switch signaling the HPC to move from a state of retrieval to encoding in the presence of novelty, and therefore, plays a role in memory updating. Here, we tested whether bilateral dorsal dentate gyrus (dDG) infusions of the β-adrenergic receptor (BAR) agonist isoproterenol (ISO), administered prior to encoding or retrieval, would impair spatial working and reference memory by reverting, the system to encoding (thereby recruiting new neurons) potentially interfering with the retrieval of the previously established spatial ensemble. We also investigated whether dDG infusions of ISO could promote cognitive flexibility by switching the system to encoding when it is adaptive (ie, when new information is presented, eg, reversal learning). We found that intra-dDG infusions of ISO given prior to retrieval caused deficits in working and reference memory which was blocked by pretreatment with the BAR-antagonist, propranolol (PRO). In contrast, ISO administered prior to reversal learning led to improved performance. These data support our hypothesis that norepinephrine serves as a novelty signal to update HPC contextual representations via BAR activation-facilitated recruitment of new neurons. This can be both maladaptive and adaptive depending on the situation.