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Hippocampal Memory Markers: From Anatomy to Molecules

Adapted from a story that originally appeared on the Alzheimer Research Forum.

20 January 2012. Shrinkage of the hippocampus, which plays a key role in learning and memory, is one potential marker of Alzheimer’s disease (AD). However, poor correlation between hippocampus size and memory strength in normal, healthy people complicates matters. Could scientists have simply been measuring the wrong end of this brain region? Only the posterior hippocampus might serve as a marker of memory in young, healthy people, according to work by Jordan Poppenk at Princeton University in New Jersey and Morris Moscovitch at the University of Toronto, Canada. “The advance is that the authors subdivided the hippocampus and compared the sizes of the two ends,” said Howard Eichenbaum at Boston University. Eichenbaum was not involved in the research, which was published in the December 22 Neuron. In a separate study, Kartik Ramamoorthi, working in the lab of Yinxi Lin at Massachusetts Institute of Technology, also went hunting for memory markers, but on the molecular scale. As reported in the December 23 Science, they identified a transcription factor, called Npas4, that turns on in cells of the hippocampus only during memory processing. This is the first example of the selective induction of an immediate-early gene by contextual learning, according to the authors.

The two findings will help researchers uncover molecular and anatomical underpinnings of learning and memory. On the anatomy front, the posterior hippocampus seems particularly important. In December 2011, researchers in England reported that this region of the brain grew over the four years budding cab drivers took to learn the complex layout of London's streets. “In that study they saw that learning had an effect on the hippocampus. We wanted to look at ordinary people and ask, ‘Can this shape tell you something about their memory?’” said Poppenk.

The researchers in London observed that cabbies have smaller anterior hippocampi than normal, as though the increase in size of the posterior sides had occurred at the expense of the anterior ones. Inspired by this work and their own earlier research showing that anterior and posterior hippocampi have different activities, Poppenk and Moscovitch looked for anatomical differences between these two regions, and any association between such differences and recollection memory. Most researchers believe that recollection memory involves the hippocampus.

Poppenk scanned the brains of 18 young adults aged 21 to 34 years by magnetic resonance imaging (MRI). The authors then presented participants with lists of 80 common English proverbs (e.g., “too many cooks spoil the broth”) and 160 Asian proverbs (e.g., a single hair can hide mountains”). For half of the proverbs, participants had to rate whether each proverb would be more suitable for an adolescent or an adult. For the other half, participants had to decide whether each proverb was of good or poor quality. After a resting phase, participants were scanned once more by MRI while they were tested for their ability to remember whether each proverb had been in the age or quality list.

Poppenk and Moscovitch found that people who did better in the recall test had a larger posterior hippocampus than those with poorer memory. “There was no correlation of memory with [the size of the] total hippocampus and none with the anterior hippocampus. In fact, the anterior size seemed inversely correlated with memory,” said Poppenk. The link between hippocampus size and memory was particularly strong if size was expressed as a ratio of posterior to anterior volume. These same results held up when the researchers analyzed data collected in three earlier imaging studies, one by Poppenk and Moscovitch and two by other groups (Poppenk and Moscovitch, 2011; Skinner et al., 2010; Cohn et al., 2009). Those three studies had taken MRI measurements of hippocampi in young, healthy adults as they performed different tasks testing their recollection memory. In all four studies, they saw an association between the ratio of posterior to anterior hippocampal volume and strength of recollection memory. “We see a correlation; we cannot say whether it is causal,” said Poppenk.

Although this study did not address the connection between posterior hippocampus size and risk of dementia, it raises some intriguing questions about that relationship. “Maybe people with a larger hippocampus are less likely to get dementia, or, as many studies have suggested, perhaps building up mental skills can protect from dementia,” said Eichenbaum. The study of the London cabbies suggests that brain morphology can change in response to learning, and a number of other studies, including the ACTIVE trial that tested the long-term effects of cognitive training, also hint that cognitive skills can improve when people exercise their brain (see Willis et al., 2006 and Owen et al., 2010).

Long-term memory requires the expression of activity-regulated genes, especially immediate early genes (Guzowski et al., 2001). To get a handle on which genes play a key role in this process, Ramamoorthi and Lin trained mice in a contextual fear-conditioning paradigm, which is thought to be dependent on new gene transcription in the dorsal hippocampus (which corresponds to the posterior hippocampus in primates). In this test, mice freeze in anticipation of a mild-foot shock received during the training period. The researchers looked at the expression of genes in the dorsal hippocampus of the mice just after they had completed the training.

“We saw that Npas4 is induced specifically with learning. That was very encouraging,” said Lin. Neuronal PAS domain protein 4 (Npas4) is an activity-dependent transcription factor and a known immediate early gene. The researchers were surprised to find that Npas4 expression only rose in cells in the CA3 region of the hippocampus. “Contextual conditioning requires the CA3 region, so that told us this gene was special,” said Lin. Other immediate early genes such as c-Fos and Arc, which have been implicated in long-term memory, are not CA3 specific, according to Lin. “The specificity of Npas4 induction means that it could be an important marker for cells undergoing information processing,” said Ramamoorthi. In fact, mice genetically engineered to lack Npas4 in the CA3 region froze less than wild-type animals in the fear-conditioning test.

If and how Npas4 influences memory is unclear, but it reached its peak expression in the CA3 region in mice 30 minutes after completing contextual fear conditioning, one hour before c-Fos is turned on. “That is another indication that Npas4 is a critical factor for initiating memory programs” said Ramamoorthi. He told ARF the work is just the beginning. Having a marker for cells undergoing memory processing will allow researchers to study what other genes are turned on or off in those cells. “We want to identify the hierarchical cascade of genes regulated downstream of Npas4,” said Lin. “We want to get a better understanding of this genetic cascade after learning takes place.”—Laura Bonetta.

Poppenk J, Moscovitch MA. Hippocampal marker of recollection memory ability among healthy young adults: Contributions of posterior and anterior segments. Neuron. 2011 Dec 22; 72(6):931-7. Abstract

Ramamoorthi K, Fropf R, Belfort GM, Fitzmaurice HL, McKinney RM, Neve RL, Otto T, Lin Y. Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science. 2011 Dec 23; 334(6063):1669-75. Abstract

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