There is extensive evidence that aging is associated with impairments in episodic memory. Many of these changes have been ascribed to neurobiological alterations to the hippocampal network and its input pathways. A cross-species consensus is beginning to emerge suggesting that subtle synaptic and functional changes within this network may underlie the majority of age-related memory impairments. In this review, we survey convergent data from animal and human studies that have contributed significantly to our understanding of the brain-behavior relationships in this network, particularly in the aging brain. We utilize a cognitive as well as a neurobiological perspective, and synthesize data across approaches and species to reach a more detailed understanding of age-related alterations in hippocampal memory function.

Pattern separation, the ability to independently represent and store similar experiences, is a crucial facet of episodic memory. Growing evidence suggests that the hippocampus possesses unique circuitry that is computationally capable of resolving mnemonic interference by using pattern separation. In this Review, we discuss recent advances in the understanding of this process and evaluate the caveats and limitations of linking across animal and human studies. We summarize clinical and translational studies using methods that are sensitive to pattern separation impairments, an approach that stems from the fact that the hippocampus is a major site of disruption in many brain disorders. We critically evaluate the assumptions that guide fundamental and translational studies in this area. Finally, we suggest guidelines for future research and offer ways to overcome potential interpretational challenges to increase the utility of pattern separation as a construct that can further understanding of both memory processes and brain disease.

Recognizing motivationally salient information is critical to guiding behaviour. The amygdala and hippocampus are thought to support this operation, but the circuit-level mechanism of this interaction is unclear. We used direct recordings in the amygdala and hippocampus from human epilepsy patients to examine oscillatory activity during processing of fearful faces compared with neutral landscapes. We report high gamma (70–180 Hz) activation for fearful faces with earlier stimulus evoked onset in the amygdala compared with the hippocampus. Attending to fearful faces compared with neutral landscape stimuli enhances low-frequency coupling between the amygdala and the hippocampus. The interaction between the amygdala and hippocampus is largely unidirectional, with theta/alpha oscillations in the amygdala modulating hippocampal gamma activity. Granger prediction, phase slope index and phase lag analysis corroborate this directional coupling. These results demonstrate that processing emotionally salient events in humans engages an amygdala-hippocampal network, with the amygdala influencing hippocampal dynamics during fear processing.

Emotional experiences can strengthen memories so that they can be used to guide future behavior. Emotional arousal, mediated by the amygdala, is thought to modulate storage by the hippocampus, which may encode unique episodic memories via pattern separation – the process by which similar memories are stored using non-overlapping representations. While prior work has examined mnemonic interference due to similarity and emotional modulation of memory independently, examining the mechanisms by which emotion influences mnemonic interference has not been previously accomplished in humans. To this end, we developed an emotional memory task where emotional content and stimulus similarity were varied to examine the effect of emotion on fine mnemonic discrimination (a putative behavioral correlate of hippocampal pattern separation). When tested immediately after encoding, discrimination was reduced for similar emotional items compared to similar neutral items, consistent with a reduced bias towards pattern separation. After 24 h, recognition of emotional target items was preserved compared to neutral items, whereas similar emotional item discrimination was further diminished. This suggests a potential mechanism for the emotional modulation of memory with a selective remembering of gist, as well as a selective forgetting of detail, indicating an emotion-induced reduction in pattern separation. This can potentially increase the effective signal-to-noise ratio in any given situation to promote survival. Furthermore, we found that individuals with depressive symptoms hyper-discriminate negative items, which correlated with their symptom severity. This suggests that utilizing mnemonic discrimination paradigms allows us to tease apart the nuances of disorders with aberrant emotional mnemonic processing.