H.M. became the most studied patient in the history of brain science when a 1953 operation that removed most of his hippocampus inadvertently wiped out his ability to form long-term memories. Curiously, he could still remember people and events from before the procedure. This phenomenon provided one of the earliest hints that the hippocampus was needed for newly acquired memories but later became less critical. Many labs have since examined the role of the hippocampus in memory formation and storage, including Larry Squire’s at the University of California, San Diego. Using a news events test to measure the extent of amnesia in patients with damage to the hippocampus and related medial temporal lobe structures, Squire’s group reported that memory loss correlates with the severity of brain lesions (Manns et al., 2003; Bayley et al., 2006). Importantly, the amnesia seen in those studies was time-dependent. That is, patients who had trouble remembering events occurring within the last 12 years did fine when asked to recall facts from even earlier decades. Those investigations confirmed the hippocampus’s time-limited necessity for recalling past recollections, but they did not establish whether it nevertheless remained active during memory retrieval. Nor did they reveal which other brain areas, if not the hippocampus, do support distant memories.

In the new study published in the 28 January Journal of Neuroscience, lead author Christine Smith performed a complementary experiment that answered both those questions. Rather than looking at what happens to memory when certain brain structures are harmed or missing, Smith used fMRI to measure brain activity in healthy people as they recalled answers to the same 160-item news events test given previously to the brain-damaged patients. Most other studies using fMRI to address what happens to memories over time have included just two timepoints. Squire’s study asked participants about events covering a 30-year period divided into seven distinct time periods.

According to this more detailed analysis, “the hippocampus isn’t always active,” Squire told ARF. “It diminishes its activity as memories get more remote.” The scientists observed this trend in the temporopolar cortex and amygdala as well. The pattern held for memories from within 12 years. Activity in these medial temporal regions then bottomed out, hovering at this lower level for recall of events from 13-30 years ago. In contrast, activity in the frontal, parietal, and lateral temporal lobes showed the opposite pattern—steadily increasing with the age of the memory. To control for possible confounding effects, the researchers showed that time-dependent patterns did not relate to how well participants remembered the test questions later, or to whether the memories were especially rich or connected with personal experiences.

Howard Eichenbaum, a memory expert at Boston University who was not involved with the new study, called it the “most systematic and strongest confirmation of findings that have led to further insight about the process of memory consolidation and the relation between the hippocampus and cerebral cortex.”

The new work seems to jibe with the clinical observation that Alzheimer’s patients tend to reminisce about ever-earlier memories as their disease progresses. The implication here is that those older memories remain protected during early AD, when neurodegeneration is restricted to the hippocampus, but become vulnerable by the time the destruction reaches the cortex. “In a sense, this basic research on these brain structures is really a study explaining the phenotype of AD,” Squire said. Ongoing studies in his lab are looking at patients with mild cognitive impairment (MCI), a condition that often precedes AD. Using the same tests of event recall, the team is hoping to assess patterns of memory loss and learning difficulties in people with MCI, compared to patients with hippocampal damage.

Consistent with the idea that the hippocampus becomes dispensable for fetching ever-older memories, Paul Frankland at the Hospital for Sick Children in Toronto, and colleagues, report that hippocampal lesions disrupt fear discrimination in mice that learned the behavior recently but not if they had been conditioned 42 days earlier. Their work appears in the 1 February issue of Nature Neuroscience.

A third research team, led by Fred Gage at the Salk Institute for Biological Studies in La Jolla, California, arrived at the time dependence of memories in a somewhat unexpected manner. The starting point for their study, published in the 29 January issue of Neuron, was the lingering enigma behind adult neurogenesis. The notion that mammals churn out new neurons throughout their lifetime has been around for about a decade, but there is really no consensus for what those new cells are doing, explained first author Brad Aimone, a computational neuroscience graduate student at the University of California, San Diego. Several years ago, Frankland’s group had shown that new neurons integrate into existing memory circuits in the hippocampus (see ARF related news story), and a study by Gage and colleagues suggested that the baby nerve cells might even replace older neurons in established networks (see ARF related news story).

Guided by these and other studies of adult neurogenesis, Aimone and colleagues designed a complex neural network to gain new insight into the functional significance of this phenomenon that infuses thousands of new granule cells into the dentate gyrus (DG) each month. Scientists have long theorized that the dentate gyrus is responsible for pattern separation, the process that makes memories distinctive, and that neurogenesis improves the function of this brain region.

As new neurons got incorporated into their computational model, the researchers noticed something intriguing. “When given properties based on what people had observed experimentally, we noticed that those young cells were more active within the network than mature cells,” Aimone said in an interview with ARF. What’s more, the new cells seemed to defy the pattern separation function of the surrounding mature neurons. “Instead of making the memories get encoded separately, [the young neurons] added similarity to the output memory,” Aimone said. “It wouldn't necessarily be enough to confuse a brain into thinking two things are the same when they're actually different, but it was enough to possibly show there's an association between those events.”

According to the model, though your brain distinguishes between what you ate for lunch and what you had for dinner, for instance, it places a similar time-related code on these same-day memories. By extension, “what you had for lunch last week and what you have for dinner next week are going to be encoded completely differently,” Aimone said. “You end up separating things better if they’re further apart in time.”

The model also suggests that this time-stamping feature may only occur during a critical time window. As the young cells mature, Aimone said, they gradually give up this function. This property seems consistent with other work hinting that newly generated neurons have a limited period of peak plasticity (see ARF related news story). The new study links “that biological information with something important about how you remember things—that we tend to associate together things that happened within the same time,” said Eichenbaum. Work by Tracey Shor’s group at Rutgers University in Piscataway, New Jersey, further reinforces the idea that new neurons survive if they are functionally active in memory formation. These results appear this week in PNAS (Dalla et al., 2009).

In other memory-related news, researchers led by Sander Daselaar at the University of Amsterdam, the Netherlands, report in the January issue of PLoS Biology that remembering and learning compete when both processes happen within a brief time period (Huijbers et al., 2009). And writing in this month’s Neuron, Nelson Spruston of Northwestern University, Evanston, Illinois, and colleagues provide insight into a less-studied mechanism behind cellular memory, that of non-synaptic plasticity. Like synaptic plasticity, non-synaptic plasticity is known to occur after learning and can support the formation of long-term memory. Spruston’s team discovered a new type of non-synaptic plasticity that requires synergistic activation of metabotropic glutamate receptors and muscarinic acetylcholine receptors, and that does not depend on electrical stimulation or synaptic change (Moore et al., 2009). And if this panoply of studies has sent your brain into overload, go take a nap—it may help you remember what you’ve just read (for a freely accessible essay on how memories are differentially processed during sleep and wakefulness, see Robertson, 2009).—Esther Landhuis.

References:
Smith CN and Squire LR. Medial Temporal Lobe Activity during Retrieval of Semantic Memory Is Related to the Age of the Memory. J Neurosci. 2009 Jan 28;29(4):930-938. Abstract

Wang S-H, Teixeira CM, Wheeler AL, Frankland PW. The precision of remote context memories does not require the hippocampus. Nature Neuroscience. 2009 Feb 1. Abstract

Aimone JB, Wiles J, Gage FH. Computational Influence of Adult Neurogenesis on Memory Encoding. Neuron. 2009 Jan 29. Abstract

Dalla C, Papachristos EB, Whetstone AS, Shors TJ. Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2927-32. Abstract

Huijbers W, Pennartz CM, Cabeza R, Daselaar SM. When Learning and Remembering Compete: A Functional MRI Study. PLoS Biol. 2009 Jan 13;7(1):e11. [Epub ahead of print] Abstract

Moore SJ, Cooper DC, Spruston N. Plasticity of Burst Firing Induced by Synergistic Activation of Metabotropic Glutamate and Acetylcholine Receptors. Neuron. 2009 Jan 29. Abstract