By Emilie Reas, PLOS Neuroscience Community Editor
At a recent dinner party, the memories flood your mind as you reminisce with an old friend. A woman approaches and your friend introduces you: “I’d like you to meet my wife, Margaret.” Your attention shifts from the past to this present moment, as you focus on making a new association between “Margaret” and the tall, dark-haired woman before you.
As during a dinner party with old friends and new acquaintances, the dynamically shifting stimulus landscape around us may trigger the retrieval of old memories or the formation of novel ones, often in overlap or rapid succession. What’s more, memory does not simply involve compartmentalized processes of the birth or reactivation of memories in isolation. Rather, successful execution of these processes also relies on support from non-mnemonic processing, such as evaluating a recalled memory or paying attention to new information. Although there is some overlap in the brain regions involved in laying down new memories and recovering old ones, the complex coordination of the many sub-processes of encoding and retrieval naturally requires cross-talk across distinct neural systems.
The brain’s medial temporal lobe is commonly considered the seat of memory – with the hippocampus lying at its heart – as encoding and retrieval rely critically on these regions. However, just as memory involves the coordination of many cognitive functions, so does it require the coordination of widespread brain networks. Both small-scale circuits across hippocampal subregions, and long-range brain systems, work together to integrate sensory information, control attention and filter relevant details in support of memory. A recent study from Katherine Duncan, Alexa Tompary, and Lila Davachi at NYU demonstrated just how the hippocampus shifts its communication with the surrounding brain to support its remarkable ability to rapidly switch between memory processes.
The researchers conducted fMRI while participants performed alternating blocks during which they encoded pairs of objects and then recalled those object pairs. A day later, participants returned for an unscanned long-term memory test, in which they reported whether they recognized the objects, and rated how confidently they recalled the pairs. This delayed memory test was used to measure how well the object associations had been encoded the day prior.
A standard analysis confirmed that across all hippocampal subregions (CA1, DG/CA3, subiculum) activity increased for both successful encoding and retrieval. Notably, the retrieval effect was strongest in DG/CA3, in line with past studies suggesting that this region might function as an auto-associative network that serves to reactivate stored memory traces. Now, we’ve long known that the hippocampus is engaged during these processes; but less certain is how the region interacts with the surrounding brain.
The researchers focused on hippocampal subregion CA1, an important hub along the bidirectional cortex-hippocampus highway, as it both receives input from the medial temporal lobe (via the dentate gyrus and CA3), and also provides output back to the cortex. Connectivity between DG/CA3 and CA1 was stronger during the retrieval than the encoding block, whereas connectivity with CA1 didn’t differ between memory blocks for any of the other medial temporal lobe or midbrain regions they investigated (Figure 1). Thus, not only was DG/CA3 highly activated, but it was also more strongly connected with its downstream hippocampal target, during retrieval.
But how might memory-specific communication across regions subserve the brain’s changing cognitive goals? To test whether connectivity patterns in fact support memory success, the researchers correlated functional connectivity measures with encoding and retrieval performance. Supporting their prior findings, CA1-DG/CA3 connectivity correlated with immediate retrieval accuracy, but not with long-term memory (i.e., day 2 retrieval) (Figure 2, left). Conversely, connectivity between CA1 and the ventral tegmentum correlated with long-term memory, but not immediate retrieval accuracy (Figure 2, right). As Davachi explains, “This suggests that whatever this signal represents, it is explaining long-term – not short-term – memory, which arguably suggests that across subject variability in CA1-ventral tegmentum connectivity is related to the consolidation of memories, not just their initial encoding.”
Notably, these connectivity patterns emerged when examining activity across each encoding or retrieval block, but disappeared when isolating the trial-evoked responses. It therefore seems possible that these increases in connectivity strength may not directly support isolated moments of memory formation or reactivation, but instead, auxiliary processes that evolve gradually over time. However, Davachi cautions “These null effects do not necessarily imply that there are not important trial-evoked changes in connectivity, but rather, that the trial-evoked data are simply swamped with the incoming perceptual and task signals.”
While the role of DG/CA3 and its connectivity to CA1 in associative retrieval has been well documented, the encoding-specific link between CA1 and the ventral tegmentum is less expected. Regions such as the medial temporal lobe and the prefrontal cortex are traditionally considered the major players in memory encoding; yet, recent research has hinted at a more important role for the ventral tegmentum than previously thought. Furthermore, this finding aligns well with animal studies showing that input to CA1 from the ventral tegmentum is required for synaptic plasticity, and that long-term potentiation – key to long-term memory formation – is dopamine-dependent. But as Davachi emphasizes, “You can never know if the BOLD response is related to long-term potentiation. All we show is that the coordinated activation between the ventral tegmentum and CA1 is related to successful encoding (and not retrieval) but what this represents is unclear.” Indeed, the ventral tegmentum is involved in a host of other, non-memory functions as well, such as novelty detection and motivation, both of which would be critical for the encoding task used here – or when making a new acquaintance at a dinner party. What remains to be determined is how, if at all, hippocampal connectivity with the ventral tegmentum supports memory consolidation, or rather, these adjunct processes that might be important for establishing new memories.
Although this study demonstrated unique hippocampal interactions during encoding and retrieval, it can’t speak to the direction of information flow. For instance, since the hippocampal-ventral tegmentum connection is reciprocal, signaling could feasibly proceed in either direction. Furthermore, their findings don’t show that encoding and retrieval are exclusively associated with CA1-ventral tegmentum and CA1-DG/CA3 connectivity, respectively – only that the strength of these interactions differs depending on the memory manipulation.
While further studies, especially those which more directly measure neural activity, will help clarify questions concerning directionality and causality, these findings build significantly upon our knowledge of human memory. In particular, Duncan and colleagues’ techniques enable the assessment of communication with and across hippocampal subregions while directly evaluating memory, which has been challenging in animals. Their findings not only raise several important questions for follow-up, but critically, also bridge the gap between human and animal studies to help unify our understanding of the brain systems supporting encoding and retrieval.
Any views expressed are those of the author, and do not necessarily reflect those of PLOS.
Duncan K, Tompary A and Davachi L (2014). Associative encoding and retrieval are predicted by functional connectivity in distinct hippocampal area CA1 pathways. J Neurosci 34(34): 11188-98. doi: 10.1523/jneurosci.0521-14.2014
Murty VP and Adcock RA (2014). Enriched encoding: Reward motivation organizes cortical networks for hippocampal detection of unexpected events. Cereb Cortex 24(8):2160-8. doi: 10.1093/cercor/bht063
Treves A and Rolls ET (2004). Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network. Hippocampus 2(2):189-99. doi: 10.1002/hipo.450020209
Emilie Reas received her PhD in Neuroscience from UC San Diego, where she used fMRI to study memory. As a postdoc at UCSD, she currently studies how the brain changes with aging and disease. In addition to her tweets for @PLOSNeuro she is @etreas.