The hippocampus—two sea horse–shaped neuronal clusters framing the midbrain—is the well-characterized seat of episodic memory that records times, places and events. Susumu Tonegawa, a professor of biology and neuroscience at the Massachusetts Institute of Technology (and 1987 Nobel laureate in Physiology or Medicine), has been for more than a decade investigating the region's role in forming memories. Working primarily with scientists at the University of Bristol in England, Tonegawa zeroed in on the hippocampus's dentate gyrus section, which he determined distinguishes between similar but different places or experiences.
The finding may pave the way for new ways to prevent or reverse deficits in episodic memory, caused by aging or neurodegenerative diseases, such as Alzheimer's.
Scientists used a sophisticated mouse model to reach their conclusions, published today in Science. Specifically, in some mice they disrupted the gene that controls receptors for the amino acid N-methyl-D-aspartic acid (NMDA) in the dentate gyrus. NMDA receptors are key players in plasticity, the cellular process of learning and memory.
The researchers then placed the mutant mice, as well as normal mice, in a chamber with a metal floor connected to an electrical source. After enough time passed for the all the mice to form memories of their new environs, scientists applied a mild shock to their feet.
The next day, the mutant and normal mice were placed in the same shock chamber and then were put in a cage that was similar but had subtle differences such as its odor and the shape of its roof and type of floor.
All of the mice, remembering the electric jolts, immediately froze when placed back in the original shock chamber. The genetically altered mice, however, had the same reaction when placed in the altered cages, while their normal compeers showed nary a trace of fear.
"The mutant animal has a problem distinguishing between chamber A and chamber B if you make them similar but different," Tonegawa says. "If you make [the] two chambers very different, even the mutant can distinguish [the variations]. But, if you start to make them more similar," the mutant will freeze, thinking it is in the shock chamber.
The researchers implanted electrodes in the heads of the mice to monitor activity in the dentate gyrus. The brain activity confirmed their varying behavior: The brain cells of normal mice remained inactive when they were placed in the shock chamber, indicating the subjects recognized their surroundings. In the slightly different chamber, their dentate gyrus neurons began sending out electrical signals, which, according to Tonegawa, suggests they were "distinguishing [between] and forming different memories." In the mutant mice there was no new pattern of cellular activity in either situation, indicating they believed the novel cage was the shock chamber.
"These two lines of evidence," Tonegawa says, "corroborate that one particular gene's intactness in this particular circuit in the hippocampus plays a crucial role in being able to form distinct memories for a similar but different experience."
He notes that the ability to distinguish between slightly different locales and experiences is a skill that can fade with time and aging. In Alzheimer's disease, he adds, many patients can still form memories, but then cannot recall similar occasions as distinct events.
"We can consider the possibility of using the molecule and the circuit as a drug development target in the future," Tonegawa says, "for reducing the aging-dependent and the pathological decline in episodic memory."