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.

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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

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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

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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. The early anatomical studies of the hippocampus were important during the nineteenth century controversy between the neuron doctrine (by Ramon y Cajal) and the reticular theory (by Golgi). Golgi used his observations of the hippocampal formation to support his arguments for the reticular theory. During the ninteenth century and the early twentieth century, the hippocampus was believed to have several functions like olfactory, emotion and attentional control. The idea that the hippocampal formation is intimately associated with memory came into existence mainly due to the observations made on the patient ‘H M’ by William Scoville and Brenda Milner in 1957. Figure A. (Left) Golgi's schematic drawing summarizing the structure of the hippocampus which was published in the book, Golgi, C. Sulla fina anatomia degli organi centrali del sistema nervoso (On the Fine Structure of the Central Organs of the Nervous System). Milan,Ulrico Hoepli, 1886. Courtesy: Wikipedia. (Right) The famous drawing of the hippocampus by Santiago Ramon y Cajal was published in his book, Cajal SR. Histologie du système nerveux de l’homme & des vertébré (Histology of the nervous system of humans and vertebrates), Paris, Maloine, 1909–1911. Courtesy: https://archive.org (Identifier: histologiedusyst01ram), Wikipedia. 1. Chapter 2, P Andersen, R Morris, D Amaral, T Bliss, J O’Keefe, The hippocampus book, Oxford University Press, Oxford, 2006. 2. C Golgi, M Bentivogli, L Swanson, On the fine structure of the pes hippocampi major, Brain Res. Bull., Vol.54, pp.461–483, Translated from Golgi C, 1886. 3. Prasanna Venkhatesh V, Santiago Ramon y Cajal: The Father of Neuroscience, Resonance, Vol.15, pp.968– 976, 2010.

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Place cells fire neuronal data and correlating it with the behaviour from areas when the animal is deep inside the brain was like finding a needle in a hay stack. moving in a However, this approach proved quite fruitful for John O’Keefe specific location in and his student Dostrovsky in 1971, because they discovered the environment, neurons in the rat hippocampus that showed activity correlated to which corresponds the rat’s location within its environment. They called these neu- to the place field of rons ‘place cells’ (Figure 2a). that particular Place cells fire when the animal is moving in a specific location in neuron. the environment, which corresponds to the place field of that particular neuron. These place cells were first found in the pyramidal cell layer of area CA1 of the hippocampus. Later, other groups showed that area CA3 of the hippocampus also has place cells. With extensive research, he concluded the following in his 1976 paper. Place cells firing in a part of the animal’s environment is not because of something the animal does there or because of its motivation for going to that place. Rather, they appear to be a cognitive process, signalling the animal’s position within an environment irrespective of its behaviour and motivational state or the reward properties of that place. The discovery of place cells by John O’Keefe in the hippocampus created a new surge of interest in the field in spite of the skepticism from a few investigators [18].

The Influential Book by O’Keefe and Nadel

O’Keefe and Lynn Nadel authored an influential book called the The Hippocampus as a Cognitive Map in 1978, delineating the theoretical foundation for the hippocampal function and the importance of the relationship between place cells and cognitive map theory. According to the cognitive map theory, there must be an abstract representation of the environment in the brain and the map may be used by the animal to calculate efficient paths. The theoryputforthbyO’KeefeandNadelwasinfluencedbyEdward Tolman’s theory about ‘cognitive maps’ in rats.

There was, however, a fundamental conceptual difference between Tolman’s original formulation of cognitive maps and the cognitive map theory formulated in the book. In rodents, Tolman

406 RESONANCE ¨May 2015 GENERAL ¨ ARTICLE linked the cognitive maps to spatial information; in humans, he Experimental results associated cognitive maps more to events and emotions without showed that place referring to a spatial framework. On the other hand, O’Keefe and cells do not respond Nadel’s cognitive maps ascribed increased importance to spatial to particular stimuli framework in all animals and also asserted that the hippocampus but will continue to is the core of a neural memory system providing an objective indicate the animal’s spatial framework within which the items and events of an position as long as organism’s experience are located and interrelated. That is to say, subsets of spatial the hippocampus not only provides a spatial map but also pro- cues are available. vides a platform for embedding context-dependent memory.

The figures in the book and in the early papers were marginally convincing, and there was no quantitative analysis. Only in the mid 1980’s, computer-based data acquisition produced a convincing presentation of the robust phenomenon of place cells. Several studies have tried to identify the cues which are respon- sible for the selective firing of neurons in the place field. It was clear that the notion of place constructed by the place cells was at least in part due to the cues available to the animal at that location. Experimental results showed that place cells do not respond to particular stimuli but will continue to indicate the animal’s position as long as subsets of spatial cues are available. Also, locations in the environment were not mapped onto the hippocampus in any orderly topographic manner. O’Keefe and Nadel envi- sioned that if all the place cells are connected appropriately, it would form a spatial map of the environment.

Place-Cell Remapping

A couple of papers by Bob Muller and colleagues in 1987 left little room for the place-cell skeptics who criticised the spatially correlated activity of these cells as being confounded by spatially correlated cues. The main evidence they showed in their articles was that, minimization of local sensory cues did not diminish spatial specificity of neurons. In fact, this drove the field to such an extreme, that most of the experiments were conducted in cue- poor environments long after the convincing demonstration of representation of ‘space’ by ‘place cells’ and not anything sensory.

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These two papers also answered the following questions: How are different environments represented in the hippocampus? When an animal goes from one environment to a second environment, how will the spatial maps respond? Are there rules and regulari- ties? These papers also contained the discovery that place-cell maps are completely different in two environments: a phenomenon later called ‘remapping’. They found that, if a place cell has firing fields in two environments, knowing the location of the firing field in the first environment will not predict the location of the firing field in the second environment. Changing the shape of an enclosure invariably induces full remapping. To be brief, the 1 Theta rhythm is an oscillatory pattern in electroencephalo- hippocampal map of space is sensitive to non-spatial factors and graphy (EEG) signals recorded understanding these factors will be essential in decoding the either from inside the brain or relationship between hippocampal maps and memory. from electrodes glued to the scalp. Two types of theta rhythm Head Direction Cells and Boundary Cells have been described. The ‘hippocampal theta rhythm’ is a In order to maintain the spatial orientation and to guide naviga- strong oscillation that can be tion, an animal must have knowledge of its location, displacement observed in the hippocampus and other brain structures. ‘Cor- or distance and direction from that location. By now, we know tical theta rhythms’ are low-fre- thatplacecellscouldbeusedtoidentifyfamiliarenvironmental quency components of scalp locations. Also, there was a speculation that the oscillations of the EEG, usually recorded from hu- theta rhythm1 of the LFP2 (local field potentials) that occurred mans. Cortical theta rhythms observed in human scalp EEG during running could measure the distance. The missing piece in are a different phenomenon, with the puzzle is that if the hippocampal system were to guide no clear relationship to the hip- navigation, it needed a sense of direction, which was predicted by pocampus. In human EEG stud- O’Keefe and Nadel in their 1978 book. In 1984, Jim Ranck ies,thetermthetareferstofre- quency components in the 4–7 reported that cells in the post-subiculum of the rat brain dis- Hz range, and the hippocampal charges whenever the animal’s head points to a specific direction, theta refers to a cycle of 6–8Hz independent of their location or behaviour, thus providing a range. compass signal. Head direction cells are found in many brain 2 The local field potential (LFP) regions like the anterior thalamic nuclei, post and parasubiculum refers to the electric potential in and also in the entorhinal cortex. Two papers in 1990 from Jim the extracellular space around Ranck’s group studied in detail the properties of the head direc- neurons. The LFP is a widely available signal in many record- tion (HD) cells. They found that HD cells are strongly modulated ing configurations, ranging from by environmental cues such as visual landmarks. single-electrode recordings to multi-electrode arrays. The vestibular system and the self movement cues play a critical

408 RESONANCE ¨May 2015 GENERAL ¨ ARTICLE role in the generation of head direction signals. HD cells provide a continuous signal that an animal will use to guide its navigation and maintain orientation. Neil Burgess and O’Keefe in 1996 demonstrated that the boundaries of an environment can elicit modulation in the location-specific firing of place cells. They stretched/compressed the walls of the chamber and correspond- ingly the place fields remapped. Burgess and colleagues formulated a ‘boundary vector cell’ model that not only explained the existing data but successfully predicted how cells would respond to new manipulations. It is remarkable that the model predicted the existence of boundary related cells and almost 10 years after the prediction, boundary cells were discovered in a number of brain regions.

Hippocampal Circuitry and the Entorhinal Cortex

The neuronal antecedents to the place cells were not understood clearly. The obvious line of investigation was whether the map is located within the hippocampus or it is constructed elsewhere and merely transferred to the hippocampus. Anatomically entorhinal cortex is the major source of cortical input to the hippocampal place cells. This is substantiated by the findings that entorhinal damage causes serious deficits in spatial problem-solving tasks as hippocampal lesions do.

Important insights about the role of the entorhinal cortex as a major input to the place cells came from lesion studies on the dentate gyrus (DG) as reported in McNaughton et al, 1989. They found that the place cells fired sharply even after a major lesion in dentate gyrus, while the connections of the CA3 and the entorhinal cortex were still intact. Clear evidence came from the Moser group (led by Edward Moser and May-Britt Moser) in 2002; they showed that even when the connections of the CA3 and the CA1 were disrupted, CA1 still exhibited spatial firing. This negated the possibility that the internal hippocampal circuitry was involved in the computation of the spatial signals. This study suggested that, the likely input to the CA1 place cells in the dorsal hippocampus is from the entorhinal cortex. The connectivity of

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Figure 3. Anatomy of hippocampal formation and parahippocampal region. a) Shows the right hemisphere of a rat brain, with a focus on the hippocampal formation and the parahippocampal region. The borders and the extent of individual subregions are colour-coded. b) The current standard connectivity model of the hippocampal formation and parahippocampal region. presubiculum (PrS), parasubiculum (PaS), dentate gyrus (DG), lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC). Reprinted by permission from Macmillan Publishers Ltd: Nature Review Neuroscience, doi:10.1038/nrn3766, 2014. [22]

the hippocampal formation (DG, CA1, CA3 and subiculum) and the parahippocampal areas (PrS, PaS, LEC and MEC) can be found in Figure 3.

The first study about the spatial activity in the entorhinal cortex was reported by Quirk et al, in 1992. They found that neurons in

410 RESONANCE ¨May 2015 GENERAL ¨ ARTICLE the medial entorhinal cortex that project to intermediate hippoc- The most striking ampus displayed weak spatial modulation compared to that of the and remarkable hippocampal cells. Anatomically, the entorhinal cortex contains observation in that two major subdivisions – the medial and the lateral. By the late study was the 90’s it became clear that the medial entorhinal cortex (MEC) spatial regularity (a shows a dorsal-to-ventral organization in which the most dorsal tessellated parts project exclusively to the dorsal hippocampus and the most pattern) of the ventral parts only to the ventral hippocampus. Thelateral entorhinal neuronal firing cortex (LEC) shows a medial-to-lateral organization of projec- tions to the hippocampus. Until 2004, most of the recordings of spatial cells in the entorhinal cortex were from intermediate or ventral parts of either LEC or MEC. These studies were not ideal because, the ventral region projects primarily to the ventral hippocampus, where place fields are large, and exhibit minimal spatial variation in small environments. The cells from the most dorsal parts of the entorhinal cortex, which provide the connections to the dorsal hippocampus where place cells were discovered, were not investigated. With the help of the neuroanatomist, Menno Witter, the Mosers in 2004 recorded from the dorso-caudal region of the medial entorhinal cortex. They found that superficial layers showed discrete firing fields (only the cell layers II and III of the dorso-caudal medial entorhinal cortex (dMEC)) of the animal’s current location as that of the place cells with each cell having multiple firing fields. This study confirmed the hypothesis that the spatial information is processed upstream of the hippocampus.

Discovery of Grid Cells in the Entorhinal Cortex

The Moser group noticed that the fields in the 2004 recordings from the dMEC followed a regular organization with optimal distance between them. In order to have a better understanding of the spatial organization of the firing fields, the same cells were subsequently recorded in larger environments, including boxes with surface areas that were more than three times larger than those of previous studies.

In 2005, the Mosers published a paper that provided a detailed description of the spatial properties of the dMEC. The most

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Figure 4. Parameters that striking and remarkable observation in that study was the spatial define grid cells. Cartoons of regularity (a tessellated pattern) of the neuronal firing in the layer firing patterns of pair grid cells II of the dMEC while the rat was walking in the enclosure (Figure shown in green and blue. Spatial phase is the position 2b). The firing fields of the neurons in the layer II of dMEC of the gird vertices in the x–y formed a beautiful grid like structure of tessellating equilateral plane. (Left panel) Black and triangles; in other words the firing locations form the vertices of a red crosses represent the hexagonal grid, representing the entire space traversed by the animal. phases of two different grid The basic unit of the tessellated spatial firing pattern is called a grid cells. (Middle panel) Spacing and the cells that elicit such a firing pattern are called ‘grid cells’. The in the grids is the distance between any vertex of the grid characteristic features of the grids are the spatial phase, spacing of the and the six adjacent vertices grid and their orientation (Figure 4). The temporal and spatial auto intheratemaporinthe correlation analysis suggested that the recurring peaks in the autocorrelogram. (Right auto-correlograms did not reflect artefacts in the analytical proce- panel) Orientation of the grid dures. vertices is defined by the lines that intersect the grid verti- Properties of Grid Cells ces indicated in black and red. The questions that immediately arose are the following: how is Reprinted by permission from the grid cell population organized anatomically? Is the same Macmillan Publishers Ltd: Na- pattern of spatial firing seen in all layers? What are the factors ture Review Neuroscience, doi:10.1038/nrn3766, ¤2014 that determine the spacing, orientation and the size of the field? [22]. The Moser group found that the spacing and the field size increased from the dorsal to the ventral part of the dMEC. A key question that pops up is, how much of external cues contribute to the locations of the discharge by grid cells, and also whether the cues are necessary to maintain the grid structure. Repeated tests in the same environment showed that the vertices of the grids are located at identical positions.

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However, when the landmarks are rotated, the grids rotate. Visual cue deprivation studies showed that the grid was maintained even in darkness and the grid space remains the same. Then the question is – what determines the phase and orientation of the grid cells? Although configuration of the environment may not be essential for producing a grid pattern, what seem to be the essential determinant of the phase and orientation are the landmarks.

There are two conclusions which are derived from these results; 3 The vestibular senses (the sen- sations of body rotation and of first, the external cues exert a significant influence over the phase gravitation and movement) arise and orientation. Second, from the visual deprivation studies, the intheinnerear;thesenseor- authors concluded that self motion (vestibular-kinesthetic)3 is the gans are the hair cells that send only likely source of maintained discharge in the grid cells in out signals over the auditory nerve. Movement of the body’s moving animals. Also, the invariance of the firing pattern for muscles, tendons, and joints is change in direction and velocity explains that the changes in also monitored by mechanore- velocity and heading must be integrated over time to enable a ceptors in these structures and constant representation of spatial relationship between positions this process is called kinesthe- sis. which is called ‘path integration’4 [10,22]. 4 Path integration is the process Latest Findings of summing up information about direction and distance travelled, I am listing here some of the interesting recent findings in the grid in order to keep track of one’s cell and place cell literature. The readers can look into the recent relative position. Path integration is hypothesized to be the reviews for more information. [19–23] basis for the formation of the ‘place code’ the hippocampus 1. In 2011, Deshmukh and Knierim discovered that the Lateral uses to encode spatial memo- Entorhinal Cortex (LEC) represents both spatial and non-spatial ries. ‘Dead reckoning,’ tradition- information. They found that some LEC neurons fire at the ally used by seafarers uses a location of the objects in the environment as well as showing that combination of path integration (compass direction and speed LEC has ‘place cells’ in the presence of objects. This is an measured in ‘knots’) and taking important contribution because LEC and MEC may be providing a fix on actual position when complementary spatial information to the hippocampus – MEC ‘landmarks’ are available. This provides path integration derived space while LEC provides is akin to the emerging pattern of MEC representing path inte- sensory derived space (as well as object related information). gration derived space while LEC representing landmark derived 2. Eichenbaum’s group, in 2011, reported that cells in the space. hippocampal formation code for time and they called these ‘time cells’.

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Acknowledgements 3. Recent work has shown that within a single animal, grid cells can be clustered into 4 or 5 modules, such that grid scale increases I would like to thank in a discrete fashion between one module to the other. The other Sachin Deshmukh and interesting finding is the fact that, when the grid spacing in each Kousik Sarathy for the module is defined by the dimensions of a fitted ellipse, the ratio critical comments and for grows in leaps of ~2. The geometric progression defined by this the discussions. I also ac- constant scale factor has been suggested to be optimal for repre- knowledge Divija Rao, senting environments at high spatial resolution. Namrata Iyer and Ranjani Seshadri for their helpful 4. There are several computational models that try to understand inputs. the relationship between the grid cells, head direction cells, border cells and place cells.

5. The grid and place cell systems are found in many mammalian species including humans. Recently researchers have found place- like cells in hippocampus and grid cells in the entorhinal cortex of other mammalian systems like non-human primates, bats and humans by directly recording from these areas. The fact that there exists a similarity in most mammals, in the hippocampal-entorhinal structure (with navigational capacity) suggests that the place cell- grid cell system is robust, functional and conserved in vertebrate evolution.

Concluding Remarks

The discovery of place cells and grid cells by John O’Keefe, Edvard Moser and May-Britt Moser has clearly revolutionised our understanding of the cognitive functions of the brain, espe- cially the spatial navigation. These findings open a lot of avenues for future research in both memory and spatial navigation, since the link between the two are yet to be understood.