some of the biochemical processes whereby neurons 

 alter their responses to stimuli and the connections 

 between neurons are modified as a result of an ani- 

 mal's experience. In other words, we already under- 

 stood, in principle, what can make learning possible. 



We had gained our understanding through the 

 fortuitous choice of a research subject, the marine 

 snail Aplysia, an organism with a relatively simple 

 neurological organization. Its brain has only about 

 20,000 neurons, compared with 100 billion or so 

 in the human brain. Moreover, Aplysia neurons are 

 extremely large, some even visible to the naked 

 eye. In that simple animal, we delineated a simple 

 reflex behavior, in which fewer than one hundred 

 nerve cells take part. The reflex could be modified 

 by learning and retained in memory for several 

 weeks. In that way, we were able to pinpoint the 

 cellular and molecular mechanisms that contribute 

 to learning and memory. 



One of the rewards of any avenue of scientific in- 

 vestigation is that, as specialized and narrow as it 



0 A • 



Spatial learning in a mouse is tested on a circular tabletop rimmed with open 

 holes and one escape tunnel. When a mouse is set out in the open, under bright 

 lights, the animal searches for a hiding place. In early trials, it searches at ran- 

 dom until it finds the tunnel. In later trials it methodically checks the holes in 

 some order until the tunnel is found. Finally, the mouse learns where the tunnel 

 is in relation to the walls of the room, and makes a beeline for it. A breed of 

 mice lacking a protein for strengthening the connections between nerve cells — 

 a basis for learning — never makes the transition to the third strategy. 



may seem, it can lead to broadly useful insights. 

 Laboratory experiments or field observations that 

 may at first seem to have no practical application can 

 prove helpful or even essential in solving pressing 

 problems. Although it is too soon to say how or 

 when, the accumulating knowledge of the bio- 

 chemical mechanisms underlying learning and 



memory may one day help prevent the "normal" 

 memory loss of aging and perhaps even cure 

 Alzheimer's disease and other dreaded neurological 

 conditions associated with learning disabilities. 



Our studies of neurons in Aplysia on a biochem- 

 ical level made two things clear. First, neurons 

 can adjust their responses to stimuli in the short 

 term, either by becoming more sensitized to an im- 

 portant stimulus (such as one that is harmful) or by 

 becoming habituated to — and therefore ignoring — 

 one that is inconsequential. To make short-term ad- 

 justments, the neuron regulates the strength of its 

 connection with other neurons by chemically alter- 

 ing preexisting proteins and increasing or decreasing 

 the efficiency of preexisting synaptic connections. 



Second, neurons can adjust their responses over 

 the long term by increasing or decreasing the 

 number of contact points with other neurons. To 

 construct new points of contact, structural proteins 

 are needed; to assemble the proteins, genes that 

 serve as the blueprints for making the proteins 

 have to be turned on, or mobilized, in the nucleus 

 of the neuron. 



In the late 1980s, a number of investigators made 

 the first attempts to understand how long-term po- 

 tentiation, or enhancement, of connections between 

 neurons played a role in spatial memory. At Colum- 

 bia University, three post-doctoral fellows — Ted 

 Abel, Seth G.N. Grant, and Mark R. Mayford — and 

 I created various lines of genetically modified mice 

 that lacked one or another key protein thought to be 

 involved in long-term potentiation. We then tested 

 the animals' performance on several well-under- 

 stood spatial tasks. 



For example, we placed a mouse in the center of 

 a large, white, well-lighted circular platform, with 

 forty mouse-size holes drilled into the rim [see illus- 

 tration at left]. Mice hate being in light, open spaces, 

 but the platform is too high off the floor for a 

 mouse to escape by leaping off its edge or through a 

 hole. The only escape is through one hole that leads 

 through a tunnel to an enclosed chamber. The mice 

 do get a clue about the way out. The platform is 

 mounted in a small room, each of whose walls is 

 decorated with a different, distinctive marking. 



When a normal mouse is first exposed to this ex- 

 perimental condition, it races about in a panic, visit- 

 ing the holes at random in its search for the way out. 

 After repeated trials it adopts a serial strategy — 

 slightly more efficient than random searching, but 

 not by much — starting at one hole and methodi- 

 cally checking out each one in order until it finds 

 the right one. Neither strategy requires the mouse 

 to have an internal map of the environment stored 



NATURAL HISTORY March 2006 



