in its brain. Finally, the mouse learns to recognize 

 which marked wall is aligned with the target hole, 

 and then it makes a beeline for that hole. Most mice 

 soon learn to use that spatial strategy. 



In one of our special breeds of mice, we had in- 

 hibited a gene that encodes a protein — protein ki- 

 nase A. The protein is important for long-term 

 potentiation because it mobilizes genes that, in 

 turn, code for the structure proteins required for 

 building new synaptic connections. Inhibiting the 

 kinase A gene compromised the strengthening of 

 synapses in a pathway in the hippocampus. The 

 mutant mice never learned to use the markings on 

 the wall as a guide to the escape hole; they kept 

 searching for it with the simpler but inefficient 

 strategies, in trial after trial. 



In later work — in collaboration with the neuro- 

 biologist Robert U. Muller of the State University 

 of New York Downstate Medical Center in Brook- 

 lyn and his student Alexander Rotenberg — Ted 

 Abel, my student Naveen T. Agnihotri, and I dis- 

 covered that both protein kinase A and the synthe- 

 sis of structural proteins are needed for a spatial map 

 to become "fixed" over the long term — so that, for 

 instance, a mouse recalls the same map every time it 

 re-enters a particular space. 



In his initial formulation, O'Keete regarded a cog- 

 nitive map as merely a kind of a navigational tool, 

 comparable to a compass. Such an internal represen- 

 tation ot space would enable an animal to move effi- 

 ciently in the environment by recognizing directions 

 and landmarks, but it would not endow the animal 

 with any long-term memory ot the space. In con- 

 trast, our experiments showed that the hippocampus 

 may also serve as a memory store for past responses 

 in encountering those landmarks — thus enabling a 

 normal mouse on the platform to appreciate the 

 value of the spatial landmarks in locating the re- 

 ward — the escape hole. In this sense it endows an 

 animal with an explicit memory of its space. 



My colleagues and I were intrigued by the fact 

 that, despite certain similarities, people's ex- 

 plicit memory of space differs in substantial ways 

 from their implicit memory. For example, hotel 

 guests may remember to proceed to the nearest 

 stairwell if they hear the fire alarm (implicit mem- 

 ory), without remembering that they must pass fif- 

 teen rooms before reaching the stairwell (an explicit 

 memory they would possess only if they had con- 

 sciously counted the doors). Thus, explicit memory 

 requires selective attention for encoding and recall. 

 To examine the relation between neural activity and 

 explicit memory, we decided to study attention. 

 Selective attention is widely recognized as a 



H Experimental setup 



Positions visited by mouse 



Mouse introduced into enclosure 



PI Baseline attention 



Day 1 Day 2 Day 5 



H Maximum attention 



Mouse learns to run over to the goal 

 in order to turn off lights and noise. 



How attention contributes to the formation and stability 

 of spatial memory was studied by the author and his co- 

 workers in laboratory mice. In the experimental setup (a), 

 a probe detects the firing of a "place cell" in the hip- 

 pocampus of a mouse's brain, while a camera records the 

 mouse's position as it moves about in the enclosure. 

 Visual cues enable the mouse to orient itself within the 



enclosure. At first the neuron being monitored may fire at random places, but 

 soon it tends to fire only when the mouse visits a certain part of the enclo- 

 sure. In the diagrams, the colors in the key (above left) indicate the probed 

 cell's rate of firing; areas crossed by the mouse where the cell did not fire are 

 yellow. Data are displayed from three recording sessions for two mice, one 

 simply allowed to explore the empty enclosure (b), the other subjected to 

 noise and bright lights in an identical enclosure (c). In both experiments, the 

 mouse was given thirty minutes on day one to become familiar with the en- 

 closure; it then spent three hours in its home cage before being returned to 

 the enclosure for a thirty-minute recording session. It was then retested for 

 thirty minutes on day two and day five. At a baseline level of attention (b), 

 the firing pattern has shifted by day two and dispersed by day five. In the 

 mouse forced to pay maximum attention to its location (c), the neuron fired 

 only when the mouse visited a highly localized area of the enclosure. This 

 precise mapping was retained for several days. 



March 2006 NATURAI HISTORY 



