The Navigation System of the Brain 2014 Nobel Prize in Physiology Or Medicine

GENERAL ¨ ARTICLE The Navigation System of the Brain 2014 Nobel Prize in Physiology or Medicine Prasanna Venkhatesh V “It is fair to say that, in general, no problems have been exhausted; instead, men have been exhausted by the problems. Soil that appears impoverished to one researcher re- veals its fertility to another. Fresh talent approaching the analysis of a problem without prejudice will always see new possibilities – some aspect not considered by those who believe that a subject is fully understood. Our knowledge is so frag- Prasanna Venkhatesh V is currently a graduate mentary that unexpected findings appear in even the most student at the Center for fully explored topics. We must bear in mind that because Neuroscience working with science relentlessly differentiates, the minutiae of today often Aditya Murthy. He is become important principles tomorrow.” working on voluntary control of reaching and – Santiago Ramon y Cajal pointing movements. His research interests include The ability to navigate in space is one of the fundamental func- movement control, neural basis of animal behaviour, tions of the brain. It depends on the ability to have a sense of optogenetics and social position which in turn is interlinked with the sense of direction, neuroscience. distance and the knowledge of the earlier positions through which one has travelled. You depend on it for your everyday activities ranging from finding your car in a parking lot to commuting to your workplace. The 2014 Nobel Prize in Physiology or Medicine was awarded to John O’Keefe, May-Britt Moser and Edvard Moser for their discoveries of nerve cells in the brain that consti- tute a positioning system that enables one to have a sense of position and navigation (Figure 1). Edward Tolman’s Idea of Cognitive Maps Some of the early experiments on spatial learning of animals were performed by psychologist Edward C Tolman during the late 1940’s. Skinner’s behaviourist paradigm dominated psychology Keywords during that period and most psychologists focussed on functional Hippocampus, cognitive map, relations between stimulus and response, without considering the placecells,gridcells. RESONANCE ¨ May 2015 401 GENERAL ¨ ARTICLE Figure 1. Winners of 2014 Nobel Prize in Physiology or Medicine: John O’Keefe (left), May-Britt Moser (middle), Edvard Moser (right). Photocredits: O’Keefe: David Bishop/UCL; M.-B. and E. Moser: Geir Mogen/Kavli Insti- tute for Systems Neuroscience. role of internal representations. Although Tolman was firmly behaviourist in his methodology, he wanted to use behavioural methods to understand the mental processes of humans and other animals. His experiment which was conducted over several days involved three groups of rats running through a maze. For Group 1, food was kept at the end of the maze. For Group 2, no food was kept, and for Group 3, food was kept only on day 11. The Group 1 rats quickly learned to rush to the end of the maze without making many errors, while Group 2 rats wandered in the maze but did not preferentially go to the end. Rats in Group 3 essentially showed the same behaviour as Group 2 rats until food was introduced on day 11; they quickly learned to run to the end of the maze and made fewer errors like the Group 1 rats by the next day. This showed that the Group 3 rats had learned about the organisation of the maze even without the reward. Tolman reasoned that animals did not passively react to the external stimuli. Rather, they learnt facts about the world and used it as and when required. This suggested that there was some kind of ‘latent learning’, i.e., they were using the knowledge in the preceding trials to build a map and utilize it when they were motivated to do so. He concluded that spatial learning consists of building cognitive maps in the nervous system and are not mere stimulus response connections and that these maps can range 402 RESONANCE ¨May 2015 GENERAL ¨ ARTICLE from a simple narrow strip to a broader comprehensive map. This, For a long time, however, did not address where in the brain these functions may investigationswere belocalizedand howthebraincomputes suchcomplex behaviours. directed towards Tolman’s cognitive map theory faced fierce criticism from the understanding the behaviourists who believed that complex behaviours in animals underlying are achieved by chains of sensory-motor response relationships. mechanisms and the The following is an excerpt from Tolman’s paper in 1948 p.192 role of hippocampus on cognitive maps in rats and men. in the formation of memory. “We believe that in the course of learning, something like a field map of the environment gets established in the rat’s brain… The stimuli … are usually worked over ... into a tentative, cognitive- like map of the environment. And it is this tentative map, indicat- ing routes and paths and environmental relationships, which finally determines what responses, if any, the animal will finally release.” The Hippocampus and its Function During the late 1950s, the majority of the clinical studies suggested that the hippocampus (an area in the brain deep inside the temporal lobe) by and large plays a fundamental role in long-term associative memory. This idea was derived from the famous report in 1957 by William B Scoville and Brenda Milner describ- ing the results of surgical removal of the hippocampi in patient ‘H M’ in an attempt to alleviate his epileptic seizures. After the surgery, H M suffered from a severe anterograde amnesia (inability to form new episodic memories) and partial retrograde amnesia (inability to recall memories that occurred before the surgery). This report played an important role in creating the link between the hippocampus and memory. For a long time investigations were directed towards understanding the underlying mechanisms and the role of the hippocampus in the formation of memory. Several patterns of electrical activity have been recorded from the hippocampus, and they have been correlated with behavioural or psychological states. During the mid-1960s, C H Vanderwolf placed a large electrode into the RESONANCE ¨ May 2015 403 GENERAL ¨ ARTICLE hippocampus of a freely moving rat and recorded the EEG activity during a wide range of behaviours shown by the animal. He found that the theta rhythm in the EEG mostly correlated with certain behaviours of the animal like orienting, sniffing and walking or not at all, during eating, drinking, grooming, quiet sitting, and slow wave sleep. It was also known by then that rats with lesions in the hippocampus had ‘spatial problem solving’ deficits. These results indicated that there was some sort of spatial processing happening in the hippocampus. Refer to Box 1 for more on the history of hippocampal anatomy and function. Figure 2. a) Place cell in the hippocampus. b) Grid cell in Discovery of Place Cells in the Hippocampus the medial entorhinal cortex. Spike locations are repre- In the late 1960’s, single-cell neuronal recordings in awake, sented as red dots and su- unrestrained rats was a cutting-edge technology. With the help of perimposed on the animal’s the brain atlas, tiny wire electrodes were guided to specific areas trajectory in the recording of interest in the brain. When the electrode tip is close to a neuron, enclosure as black. Whereas the electrode can record the action potentials from that neuron. most place cells have a single During the experiment the action potentials were recorded along firing location, the firing fields with x, y coordinates of the rat’s location as viewed from above of a grid cell form a periodic triangular matrix tiling the with the help of a small light fixed to the rat’s head. John entire environment available O’Keefe, who was by then expert at recording neurons using this to the animal. technique in awake-behaving rats, recorded the hippocampus Reprinted from Trends Cogn neuronal activity when the animal was doing a variety of Sci., 14 (12), Derdikman D and behaviours. Any conservative neurophysiologist at that time would Moser EI, A manifold of spatial maps in the brain, 562, ¤2010, have considered this experiment radical because sensory and with permission from Elsevier. motor areas were easy and reliable targets and decoding the 404 RESONANCE ¨May 2015 GENERAL ¨ ARTICLE Box 1. History of Hippocampal Anatomy and Function The hippocampus lies deep within the medial temporal lobes of the human brain with a group of neuronal networks quite distinctly organised compared to the other areas of the brain.The Bolognese anatomist Giulio Cesare Aranzi (circa 1564) was credited for coining the name ‘hippocampus’ to this area of brain because of its remarkable appearance similar to that of a small marine fish that belongs to the genus Hippocampus. Hippocampus is the greek name for a mythical sea monster, hippos meaning ‘horse’ and kampos meaning ‘sea monster’ in ancient greek. When the hippocampus is cut in cross section, it resembles a ram’s horn. So ancient anatomists named it cornu ammonis (abbreviated as CA in modern nomenclature) which in latin literally means horn of the ram. CA (subdivided as CA1, CA2,CA3 and CA4) is one of the two interlocking gyri composing the hippocampus, the other being the dentate gyrus (DG). The unique arrangement of all the cell population into single layers had attracted the attention of many investigators of the central nervous system of the late nineteenth century. One of the pioneers to illustrate the unique organization of the hippocampus is the Italian anatomist Camilio Golgi in 1886 (Figure A, left). Santiago Ramon y Cajal in 1911 clearly illustrated the hippocampus of rodents (Figure A, right) with arrows showing his interpre- tation of the likely direction of the information flow using the staining method developed by Golgi.

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