Paul W. Frankland*†‡ and Bruno Bontempi§*Programs in Integrative Biology and Brain and Behaviour, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8; †Department ofPhysiology and Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8; and §Laboratoire de Neurosciences
Cognitives, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5106, Université de Bordeaux 1, Avenue desFacultés, 33405 Talence, FranceStudies of brain-damaged patients
have provided remarkable insights into how our memories areorganized (1). In particular, thesestudies have established that memory consolidation is a dynamic process involving
gradual (but quite dramatic) reorganization of the circuits supporting memory
over time (2, 3). A pioneer in this field
was the French psychologist Theodule
Ribot. In the late part of the 19th century,
Ribot described how memory loss after
brain insult tended to be related to theage of the memory: the effect on more
recent memories was typically greaterthan that on older (or more remote)memories (4). Later studies establishedthat damage to the medial temporal lobe(5), and more specifically the hippocampus (1), is responsible for this typicalgraded amnesia. This Ribot gradient hassuggested that the hippocampus is only
temporarily involved in the storage andrecall of certain types of memory, andthat these functions must be subsumed byextrahippocampal structures as memories
mature (2, 6).
Hippocampal damage in experimental
animals also preferentially disrupts recent
memory. Such examples, from mice tomonkeys, suggest that time-dependent
memory reorganization is an evolutionarily conserved process for memory consolidation (3). However, differences do exist
between human and experimental animalstudies, and these differences have madeit difficult to come up with a unified
mechanistic account of memory consolidation. For example, the lengths of thegradients vary dramatically from days or
weeks (for example, in rodents) to years(in humans), suggesting that the rate ofreorganization may vary greatly acrossspecies. Second, although studies in experimental animals have begun to successfully identify extrahippocampal brain
regions that support remote memory recall, the evidence from human studies ofremote memory has been much less consistent, and it has even been suggested
that autobiographical memories may never
become truly independent of the hippocampus (7). A new functional imaging
study by Takashima et al. in this issue of
PNAS (8), however, appears to bringthese two worlds a little closer together.
Their data suggest that the rate of memory reorganization (at least for sometypes of material) may be much faster inwww.pnas.org兾cgi兾doi兾10.1073兾pnas.0510133103

humans than originally thought, occurring
over months rather than years, and they
identify the medial prefrontal cortex(mPFC) as playing a crucial role in‘‘posthippocampal’’ recall.
In the experiment (8), subjects wereasked to memorize a collection of photographs of various landscapes. In the initialstudy phase of the experiment, subjects
viewed ⬎900 of these photographs for 5.5
sec each. Recognition of these photographs was then probed during a test session conducted either the same day or 1day, 1 month, or 3 months later. Patternsof brain activation were dramatically different at the different retention delays:
whereas the confident recognition of theseprevious study items was associated withhippocampal activation at the short retention delays (1–2 days), confident recognition of these items was associated withactivation of the mPFC at the longer retention delays (1 or 3 months). Therefore,
similar to retrospective studies of braindamaged patients, these data show thatcircuits supporting this type of recognition
evolve in a time-dependent manner (albeit
on a surprisingly accelerated time scale).
There is remarkable correspondence
between these imaging data in humans
and recent cellular imaging studies inmice. In these studies, mice were initially trained in a fear conditioning or
spatial discrimination paradigm (9, 10).
Then either 1 day (recent memory test)or 1 month (remote memory test) later,
the mice were tested, and the expressionof the activity-regulated genes c-fos andzif268 induced by these tests was examined. Because the expression of thesegenes is tightly correlated with levels ofneuronal activity, they can be used to
track changes in memory organization
over time. Regardless of the type ofmemory probed, a consistent pattern
emerged: recall of the recent (day-old)memory was associated with activationof the hippocampus, whereas recall of
the month-old (remote) memory wasassociated with activation of a numberof different cortical regions (including
the mPFC). And so, just like the new
Takashima et al. (8) findings, these studies suggest that, within the space of 1
month, the circuits supporting memories
undergo major reorganization, with activity shifting from the hippocampus tothe mPFC. Although the new data in
the Takashima et al. (8) study are con-sistent with these brain-mapping studies
in mice, they also raise several newquestions.
First, why so fast? The most striking
feature of these new imaging data isthat they suggest that memory reorganization occurs at a rapid pace, with recognition of the photographs seemingly
independent of the hippocampus only 1month after the initial study phase of
the experiment. Most previous estimatesof the time course of systems consolidation are based on retrospective studiesof patients with damage to the medial
temporal lobe, including the hippocampus (1). This raises the issue of whether
retrospective neuropsychological andprospective neuroimaging approaches
give different answers to the same question. For case studies, damage is rarely
limited to the hippocampus. Therefore,
when damage extends beyond the hippocampus, longer (or even flat) gradients
may result, because sites for permanent
memory storage are also affected (11).
Although this may lead to overestimatesof the length of the gradient in someinstances, nonetheless, it is unlikely thatextrahippocampal damage alone can account for the typically longer gradientsobserved in the retrospective patientstudies.
Perhaps more important is the type ofinformation encoded and the conditionsof encoding. In retrospective studies ofbrain-damaged patients, autobiographicalmemories for the recent and remote past
have typically been examined. It is likelythat these rich detailed memories for specific events within a person’s own life are
encoded quite differently than the 960
photographs presented in a single study
session in the Takashima et al. study (8),and these encoding differences may affect
how these memories are consolidated.
The consolidation of autobiographicalmemories may involve prolonged dialogue
between the hippocampus and corticalstructures (12) to slowly integrate these
new memories into an existing knowledge
base of related experiences in the cortex(6, 12, 13). By contrast, this dialogue may
Conflict of interest statement: No conflicts declared.
See companion article on page 756.
‡To whom correspondence should be addressed. E-mail:paul.frankland@sickkids.ca.
© 2006 by The National Academy of Sciences of the USA

PNAS 兩 January 17, 2006 兩 vol. 103 兩 no. 3 兩 509 –510

COMMENTARY

Fast track to the medial prefrontal cortex

be much briefer for the large number of
rapidly presented photographs, because itis hard to imagine such material forming
richly detailed autobiographical memoriesof the kind examined in retrospective
studies (14, 15). Indeed, it would be interesting to know whether subjects would
still be able to recognize these photographs a few years later.
Second, are such dramatic changes in
network organization possible on this timescale? The imaging data in the Takashima
et al. article (8) provide evidence forlarge-scale network changes occurring
within 24 h of initial encoding; for example, there is already a significant shift
from hippocampal- to mPFC-dependent
recognition in the test session conducted
1 day after the initial study session.
What drives these rapid changes? In theTakashima et al. study (8), the subjects
were instructed to take a nap after the
initial study session. The amount of slowwave sleep during this nap positively
correlated with later recognition performance, suggesting that sleep-dependent
processes may play a key role in memory
reorganization. This is largely consistent
with the view that memory reactivation
during sleep promotes the gradual reorganization of hippocampal-cortical memory
networks (16). Also consistent with thisview, waking patterns of brain activity
associated with earlier learning are selectively replayed during subsequent sleep inhumans (17) and other species, including
rodents (18). This coordinated replay occurs in hippocampal as well hippocampalcortical and cortico-cortical networks andlikely promotes gradual stabilization ofmemory traces in the cortex. Approximately 100 known genes (and ⬇400 unidentified genes) have been shown to beup-regulated during sleep, independent ofcircadian time (19). It is likely that at least
some of these genes are involved in stabilizing changes in synaptic strength andstructure in reactivated memory circuitson the sort of time scale suggested by theTakashima et al. imaging data (8).
Third, what is the mPFC doing? The
mPFC appears to play a crucial role inremote memory recall, because pharmacological inactivation or lesions of thisregion block recall of remote memories
in mice, whether they be month-old fear
conditioning (9), spatial discrimination(10), or trace eye-blink (20) memories.
The mPFC consists of several highlyinterconnected regions, including theanterior cingulate, prelimbic, and infralimbic cortices. These regions are reciprocally connected to sensory, motor, andlimbic cortices, and they are therefore
ideally situated to integrate and synthesize information from a large number ofdifferent sources. This potential for integration has led to the hypothesis thatthe ability of the mPFC to process remote memories might mirror that of thehippocampus to process recent memories (3) (Fig. 1). Initially, the hippocampus is thought to integrate informationfrom distributed but relatively independent cortical modules that represent thevarious features of an experience andthen to rapidly fuse these various features
into a coherent memory trace (12, 21). As
memories mature, this integrative function
might be transferred to the mPFC, allowing the cortical network to function independently of the hippocampus (22).
Still, an alternative possibility is that themPFC is required for more effortful recall(23). In the Takashima et al. study (8),response latencies increased as a functionof remoteness, perhaps consistent with theidea that greater activation of the mPFCreflects the greater effort required to access a partially degraded memory trace.
However, increased latencies at thesemore remote delays could simply reflect
different temporal operating characteristics of the mPFC compared with thehippocampus. That is, mPFC-mediatedretrieval could be slower compared withhippocampal-mediated retrieval. The difficulty in distinguishing between these two
possibilities is that the age of the memory
and the amount of effort required for recall tend to be related, because as memories age, they tend to weaken. To resolvethis issue, future studies in human andexperimental animal subjects need to dissociate these two variables. For example,
this may involve creating conditions where
it is possible to contrast recall of a weak
recent memory with a strong remotememory.
These issues notwithstanding, the exciting new data presented by Takashima
et al. in this issue of PNAS (8) suggestthat a common conceptual framework
may be used to describe memory consolidation processes in both mice and humans. We have highlighted some (of themany) key questions that still need to beaddressed, but these data bring us a step
closer to coming up with a unified mechanistic understanding of these processes.

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Fig. 1. Time-dependent memory reorganization. Memory recall depends on integration of informationfrom a large number of cortical sources. The data from Takashima et al. (8) suggest that this function isinitially carried out by the hippocampus, but with time, this integrative function is taken over by the mPFC.

510 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0510133103

Frankland and Bontempi