Memory allows us to store, retain, and retrieve information. These three processes influence and are modified by the type of information that is to be remembered, the duration of time over which it must be retained, and the way in which the brain will use the information in the future. The neural circuits underlying these processes are dynamic, reflecting the flexibility of memory itself. To delineate the neural circuitry underlying it, it is helpful to break down memory into simpler components. This categorization, however, need not lead to the assumption that memory is not a unitary phenomenon.
In an effort to explain why focal brain damage affects some aspects of memory but not others, a fundamental distinction has been made between declarative memory, which refers to the conscious memory for facts and events, and nondeclarative memory, which refers to memory for skills, habits, or other manifestations of learning that can be expressed without awareness of what was learned (Fig. e9-1). Patients with bilateral medial temporal lobe (MTL) damage show declarative memory deficits in the face of intact nondeclarative memory. For example, such a patient may learn to play the piano over time without remembering a single practice session or even recognizing the teacher who patiently works with him everyday.
Fractionation of long-term memory. (Adapted from LR Squire, SM Zola: Proc Natl Acad Sci U S A, 24: 13515, 1996.)
Within the declarative memory system, episodic and semantic memory can be distinguished. Episodic memory allows the recollection of unique personal experiences. With episodic memory, the person reexperiences the sights, sounds, smells, and other details of a specific event. Many episodic memories are kept for minutes and hours but soon discarded. Others remain for the course of a lifetime. This temporal difference in storage probably reflects different physiologic processes at work (see below). Semantic memory, in contrast, refers to knowledge about the world; generic information that is acquired across many different contexts and accessed without accompanying details of the time when the words or facts were remembered. One's vocabulary and knowledge of the associations between verbal concepts make up the bulk of semantic memory. This fractionation of declarative memory is supported by evidence that episodic and semantic memory have distinctive anatomic substrates.
In the MTL, the hippocampal formation receives processed sensory information from association areas in the frontal, parietal, and occipital lobes via the parahippocampal cortex. Given these multiple cortical neuroanatomic connections, the hippocampus is well placed to create associations between simultaneously occurring stimuli in our sensory world. Key structures involved with episodic memory include the hippocampus, entorhinal cortex, mammillary bodies, and thalamus. Alterations of episodic memory can be devastating. Overly intense or painful episodic memories can result in posttraumatic stress disorder, a devastating illness in which patients repeatedly reexperience unpleasant episodes from their lives. By contrast, loss of episodic memories, as in Alzheimer's disease (AD), will prevent the individual from learning new things about the world and will eventually strip away the old memories that constitute a life biography.
Given its anatomic placement and architecture, the hippocampus has the unique ability to bind together "what happened," "when it happened," and "where it happened." The architecture of the hippocampus includes a circular pathway of neurons from the entorhinal cortex to the dentate gyrus and CA3 and CA1 neurons of the hippocampus to the subiculum and back to the entorhinal cortex. This pathway is heavily damaged in AD. Individual elements of episodic memories are permanently stored within the same neocortical regions that are involved in initial processing and analyzing of sensory information (neocortex). Each different cortical region makes a unique contribution to the storage of a given memory, and all regions participate together in the creation of a complete memory representation. The hippocampal formation, then, is saddled with the task of binding together these different regional contributions into a coherent memory trace. The connections within the hippocampal formation and between the MTL and neocortical regions are formed more rapidly than are the connections between disparate cortical regions. Therefore, when a particular cue in the environment or the mental state of the person activates cells in the cortical regions, the MTL network that is associated with that cue is reactivated and the entire neocortical representation is strengthened. As multiple reactivations occur, the connections between the relevant neocortical regions are slowly strengthened until the memory trace no longer depends on the MTL's activity but is instead entirely represented in the cortex.
Recent work in humans and rodents has shown that the hippocampus and associated cortical structures are involved not only in the remembrance of things past but also in the imagination and/or prediction of the future. FMRI studies have shown that this region is active when people imagine the future, and patients with bilateral hippocampal damage are unable to conceive of future events. In rats, hippocampal ensembles preplay and replay event sequences even in the absence of overt behavior. These event sequences may then be recombined to form new events as a means of predicting the future. Interestingly, the hippocampal system remains active during sleep and "task-free" thought, suggesting that it is likely involved in imagination and free-form thinking.
While the MTL learns quickly and has a limited capacity for storage, the neocortex learns slowly and has a very large storage capacity. In both regions, learning occurs via Hebbian synapses, whereby "cells that fire together, wire together." With repeated activations, memories become "consolidated" in the neocortex and, therefore, independent of the MTL. This process, by which the burden of long-term (permanent) memory storage is gradually assumed by the neocortex, ensures that the MTL system is constantly available for the acquisition of new information. Recent evidence, however, points to the hippocampus as serving a critical function ...