Cognitive neurobiology: Studies on the brain mechanisms of declarative memory

(selected recent papers on each topic are provided after each paragraph)

The research in my laboratory concerns the neurobiological bases of memory. We are particularly interested in how the brain mediates a higher form of memory called declarative or explicit memory. Declarative memory involves memory for everyday facts and events that can be brought to conscious recollection. While it would obviously be very useful to understand how the brain mediates this kind of memory, it is difficult to create valid animal models of "episodic memory" and "conscious recall" so that brain processes active during such memory be studied with biological tools. So far we have identified structures of the cerebral cortex and other structures, particularly the hippocampal region, that play key roles in this kind of memory.

Our research efforts are now focused in two directions of study. One direction involves psychological testing of animals with experimental damage to specific cortical or hippocampal areas. These studies inform us about what aspects of memory rely on particular brain areas. This work is guided by neuroananatomical work that allows us to model the flow of information through the brain, and has given us a good behavioral model of declarative memory in animals. An example of this work is our recent study of how memory breaks down after experimental damage to the hippocampus in rats. The hippocampus is critical to declarative memory in humans. This kind of memory involves associations among items or events that can be accessed flexibly to guide memory expression in various and even novel situation. In animals, there has been controversy about whether the hippocampus is specialized for spatial memory or whether it mediates a general memory function, as it does in humans. To address this issue we trained normal rats and rats with hippocampal damage on a variety of tasks that involve episodic memory and involve the creation of memory networks that are accessible by many routes of expression. Normal rats demonstrate rather amazing capacities for learning and making inferences from memory that indicate they have the capacity to form episodic memories and can express their memory in ways consistent with conscious recollection. Rats with damage to the hippocampus fail to show these capacities, indicating that declarative processing depends specifically on the hippocampus in animals as it does in humans. In aging, rats also selectively lose the capacity for episodic memory. These findings support our goal to identify the functional circuits that support fundamental features of declarative memory using animal models.

Fortin, N.J., Wright, S.P. & Eichenbaum, H. (2004) Recollection-like memory retrieval in rats is dependent on the hippocampus. Nature 431:188-191. PDF

Sauvage MM, Fortin NJ, Owens CB, Yonelinas AP and Eichenbaum H (2008) Recognition memory: Opposite effects of hippocampal damage on recollection and familiarity. Nature Neuroscience 11:16-18. PDF

Robitsek, R.J., Fortin, N.J., Koh, M.T., Gallagher, M., and Eichenbaum, H. (2008) Cognitive aging: A common decline of episodic recollection and spatial memory in rats. Journal of Neuroscience 28: 8945-8954. PDF

Farovik, A., Dupont, L.M., Arce, M., and Eichenbaum, H. (2008) Medial prefrontal cortex supports recollection, but not familiarity, in the rat. Journal of Neuroscience 28:13428-13434. PMC2680425 PDF

The other major direction of our research involves electrophysiological recordings of single neurons and neuronal ensembles in these same brain regions while animals perform memory tasks. These studies have allowed us a window on the brain that tells us how information is processed and stored in different areas. The results of this work confirm our working hypothesis that the cerebral cortex encodes highly specific facts and events, whereas the hippocampus mediates the organization of these representations into a memory network that supports the properties of declarative memory. Our findings support a novel, anatomically-guided hypothesis regarding the mechanisms by which different regions of the medial temporal lobe may interact to support the phenomenology of recollection and familiarity: During encoding, information about stimuli to be remembered, processed by the perirhinal and lateral entorhinal areas, and information about their context, processed by parahippocampal and medial entorhinal areas, converges in the hippocampus. When a previously encountered stimulus is processed, perirhinal and lateral entorhinal areas can signal its match to a pre-existing item representation, observed as suppressed activation. This match signal can be propagated back to neocortical areas, which may be sufficient to generate the sense of familiarity without participation of the hippocampus. Additionally, processing of the stimulus may drive the recovery of object-context associations in the hippocampus that, via back projections, reactivate a representation of the contextual associations in parahippocampal and medial entorhinal areas. These areas, in turn, project back to neocortical areas that processed the context in which the item was previously encountered, thereby eliciting the subjective experience of recollection.

Manns, J.R., Howard, M., and Eichenbaum, H. (2007) Gradual changes in hippocampal activity support remembering the order of events. Neuron 56: 530-540. PDF

Lipton, P.A., White, J., and Eichenbaum, H. (2007) Disambiguation of overlapping experiences by neurons the medial entorhinal cortex. Journal of Neuroscience 27:5787-5795. PDF

Komorowski, R.W., Manns, J.R., and Eichenbaum, H. (2009) Robust conjunctive item-place coding by hippocampal neurons parallels learning what happens. Journal of Neuroscience 29:9918-9929. PDF

Eichenbaum, H., Yonelinas A.R., and Ranganath, C. (2007) The medial temporal lobe and recognition memory. Annual Review of Neuroscience 20:123-152. PDF

In addition, recollection seems to involve three major types of associations, associations between specific items of interest and the context in which they were experienced, associations between events that occur in sequence to compose a unique episode, and associations between memories to compose a network of memories that supports the use of memories in novel situations. Each of these capacities depends on the hippocampus and critical features of each of these kinds of associations are represented by hippocampal neurons.

Wood, E., Dudchenko, P., Robitsek, J.R. & Eichenbaum, H. (2000) Hippocampal neurons encode information about different types of memory episodes occurring in the same location. Neuron 27:623-633. PDF

Fortin, N.J., Agster, K.L. & Eichenbaum, H. (2002) Critical role of the hippocampus in memory for sequences of events. Nature Neuroscience 5:458-462. PDF

Ergorul, C. & Eichenbaum, H. (2004) The hippocampus and memory for "What", "When", and "Where". Learning and Memory 11:397-405. PDF

Ross, R.S. and Eichenbaum, H. (2006) Dynamics of Hippocampal and Cortical Activation during Consolidation of a nonspatial memory. Journal of Neuroscience 26: 4852-4859. PDF

Eichenbaum, H. (2004) Hippocampus: Cognitive processes and neural representations that underlie declarative memory. Neuron 44:109-120. PDF

In considering the overall neurobiological approach to memory, it is important to note that declarative memory is only one of multiple memory systems in the brain. The idea that there are multiple memory systems in the brain has a long and interesting history. Early views, based on philosophical considerations and introspection suggested distinctions between recollective memory, habit formation, and the adoption of preferences and aversions to arbitrary stimuli. Early experimental work focused on controversies over which of these is the fundamental mechanism that underlies memory. A reconciliation of these divergent views has emerged from recent studies in the cognitive neuroscience of memory showing that these different forms of memory can be selectively disrupted by damage to distinct brain regions. This research, and parallel characterizations of neural activity in different brain areas, has shown that the three major forms of long term memory are supported by distinct brain systems. These include (1) a cortical-hippocampal circuit that mediates declarative memory, our capacity to recollect facts and events, (2) motor memory subsystems involving on a cortical-neostriatal circuit that mediates habit formation and a brainstem-cerebellar circuit that mediates sensori-motor adaptations, and (3) a circuit involving subcortical and cortical pathways through the amygdala that mediates the attachment of affective status and emotional responses to previously neutral stimuli. These systems can operate in parallel and can interact competitively or cooperatively. In addition to these systems, there is also a broad cortical network that supports both the details of permanent knowledge and cognitive operations that support short term working memory. My work on declarative memory is viewed from the perspective of interactions with each of these other memory systems.

Berke, J.D., Breck, J.T, and Eichenbaum, H. (2009) Striatal versus hippocampal representations during win-stay maze performance. Journal of Neurophysiology 101:1575-1587. PDF

Eichenbaum, H. & N.J. Cohen (2001) From Conditioning to Conscious Recollection: Memory Systems of the Brain. Oxford University Press.

Eichenbaum, H. (2002) The Cognitive Neuroscience of Memory: An Introduction. Oxford University Press.