Norepinephrine as a Memory Reset Signal: Switching the System from Retrieval to Encoding During a Spatial Memory Task can be Both Adaptive and Maladaptive

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 (NE) input from phasic locus coeruleus (LC) activation induces hippocampal plasticity resulting in the recruitment of new neurons and a disengagement from previously established representations. We hypothesize that NE 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 (DG) infusions of the {beta}-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 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 (i.e. when new information is presented e.g. 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 pre-treatment with the BAR-antagonist, propranolol (PRO). In contrast, ISO administered prior to reversal learning led to improved performance. These data support our hypothesis that NE 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. SIGNIFICANCE STATEMENTThe current work highlights the involvement of hippocampal BARs in determining the flexibility of contextual representations to promote new learning in a way that supports adaptive behavior. This work builds upon previous work showing that noradrenergic input to the hippocampus is involved in recruiting new neurons resulting in new contextual representations and may be involved in the underlying neural mechanisms that support memory updating. These data suggest targets for anxiety disorders such as PTSD, which are characterized by noradrenergic dysregulation, and may also involve impairments in memory updating mechanisms where the incorporation of new information is not effectively encoded. The further understanding of the neurobiological mechanisms involved in updating memories may provide insight into novel treatment strategies.