The document discusses the role of the hippocampus in navigation and memory, detailing the discovery of place cells and grid cells that contribute to spatial mapping in the brain. O'Keefe's research highlighted how these cells function specifically to encode location and movement within an environment, while Moser's work introduced the grid cell system providing a hexagonal mapping structure in spatial awareness. This understanding is significant for exploring neural mechanisms behind episodic memory, with implications for cognitive disorders such as Alzheimer’s disease.

1. Aditya Dayana
MBBS, 8TH semester
Positioning System in the Brain
- The Brain’s Navigational Place
and
Grid Cell System

3. Grays anatomy 40th ed pg no 347

4. Function of hippocampus as sited:
Emotional expression is organized in the hippocampus (1937)
Now widely accepted to be involved with cognitive
processes, including mnemonic functions, spatial and short-
term memory. Grays anatomy 40th Ed, Pg 345
At present they are able to find the cells involved in cognitive and
spatial function of hippocampus (21st century)

6. Case
Henry Molaison (HM)
1926-2008
Scoville,W.B., and Miller, B. (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology Neurosurgery and Psychiatry, 20, 11-21.
”After operation this young man could
no longer recognize the hospital staff nor find his way to the
bathroom, and he seemed to recall nothing of the day-to-day
events of his hospital life.”
For the next 55 years, each time he met a friend, each time
he ate a meal, each time he walked in the woods, it was as if
for the first time. Now this is called as Episodic memory

7. Place cells
John O’Keefe
• PhD in Physiological psychology, working with Ronald
Melzack at McGill University
• He started his work on behaving animals in the late
1960s.
• Discovered the place cells, when recording from
neurons in the dorsal partition of hippocampus, called
CA1, together with Dostrovsky

8. Probes into CA1 region of hippocampus(O'Keefe thought that
CA1 region will fire for all sort of stimulus and memory)
Cells are only interested in very specific type of behaviour
they were engaging in
not interested in most memory and behaviour
they are interested in where the animal was and the
environment
cells are coding for some aspect of space
Cells didn't care why the animal went there and what it did there
This looks very different from what O’Keefe studied till now, with his
colleague Dostrovsky came to a conclusion that hippocampus provide
the rest of the brain with a spatial reference map.
The hippocampus as a spatial map. Preliminary evidence from
unit activity in the freely-moving rat
O’Keefe & Dostrovsky 1971

9. COGNITIVE MAPS IN RATS
E. C. Tolman 1948
Basis of behavioural experiment on the rats running in
mazes.
The rats solved the problem by employing cognitive map.
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.
Finally determines what responses, if any, the animal will
finally release.

10. • Cognitive map can be made with Place representation cells(place
cell)but that is not just enough it need to know the place an
relationship between the places
• Flexible way of representing environment and is a very flexible way of
allowing animal to navigate
• Made many predictions like hippocampus codes for direction, distance
and speed of movement
• Deficient cause loss of place learning, navigation and exploration

11. MORRIS WATER MAZE
Test for flexible navigation of the animal from different locations to one location.

12. 2nd prediction
• Some representation about speed of movement in the hippocampus
by the place cells.
Bruce
Macnaughton
Carlo
Barnes
They are also some specialized
cell in the hippocampus tracking
for speed but they hadn’t found
many of them yet

13. Spatial cells found in hippocampus

14. Details about Place cell
• Prerequisite of O’Keefe experiment and success was the development
of appropriate recording technique
• Researchers mostly used restricted behavioural task or strict stimulus-
response protocols.
• Contrast, O’Keefe recorded the cellular activity during natural
behaviour, which allowed him to observe the unique place fields and
relate the neural activity in the place cells to represent the sense of
place.

15. Observations of single place cell in a a fixed
environment
Observations of the response of place cells in a natural field

16. Place cell differentiate between two
environments

17. Similar function is observed in humans
• Found out by an important experiment and a study
1. The Virtual Town
2. Posterior Hippocampus in larger in taxi drivers which increases with
experience
The Virtual town Posterior hippocampus in drivers (England)

18. Summary about place cells
• CA1 region of hippocampus provides “Cognitive map” which was first
described by E.C Tolman
• Mapping is provided by 2 methods
By observing environmental landmarks
Integration system which uses information about distances travelled
in particular directions.
Similar spatial system exists in human brain which provides the basis
of episodic memory.

19. Grid Cell System and
entorhinal map of space

20. May-Britt Moser and Edvard I.Moser started studying
psychology in 1980’s
• All these from development to the loss of behavior and
synaptic mechanism caught the attention of Moser's
• After working under T.Sagvolden, Anderson and
O’Keefe, Moser's moved to Trondheim and setup their
own lab (1996)
• Kavli Institute for Systems Neuroscience, Centre for
Neural Computation, Trondheim (Norway)

21. If the place cells, the product formed at the earliest stages in hippocampus then
Moser thought that we can really block the activation of place cells by simply
removing the part of hippocampus
blocked by chemical methods
DID THE HIPPOCAMPAL PALCE FIELDS DISAPPEAR

22. NO, Place cells didn’t disappear
• CA1 cells continued to express place fields after lesion of the
intrinsic hippocampal pathway, suggesting that the source of the
place signal is external ENTORHINAL CORTEX

23. • Moser's and colleagues recorded from dorsal medial entorhinal
cortex, which provides the strongest cortical input to the dorsal
hippocampus where the place cells were found.
Fyhn et al. (2004). Science 305:1258-1264
Entorhinal cells had multiple fields and the fields exhibited a regular
pattern. But what was the pattern?

24. • Entorhinal cells had spatial fields with a
periodic hexagonal structure
• The fields formed a grid that covered
the entire space available to the
animal.
• They called them grid cells
220cmwidebox
Stensola et al. Nature, 492, 72-78 (2012)
Hafting et al. (2005). Nature 436:801-806
1.Symmetry
2.Pattern is generated in the brain
itself

25. Grid cells show 3 dimensions of variations
• Phase Scale Orientation
How are these variations organized in anatomical space?

26. Grid phase (x, y-locations) is distributed: All phases are represented within a small
cell clusters
17 MICRO MTS
25 MICRO MTS
Similar to Salt and Pepper organization
PHASE

27. • Transition is not continuous but they are in four different steps called as
modules M1,M2,M3 and M4
Average scale ratio of successive modules is
constant, i.e. grid scale increases as in a geometric
progression
Mathis et al., 2012; Wei et al. 2013
Circle=cell
+ = Average
SCALE

28. Orientation is determined by the cardinal axis of the local
environment
Grid orientations peak not at 0º but at ±7.5º
Orientations shy away from both 0º and ±15º
ORIENTATION

29. Mechanism behind this 7.5 degree
• Rotation differed between the 3 grid axes…
Elliptification and axis rotation may thus be common end products of
shearing forces from the borders of the environment

30. We know that Grid cells are randomly organized
• There is a limitation in collecting the data
Electrodes pick up signals from 50-100 micrometer whereas
the soma of each stellate cell is around 20nm so each electrode take
signals of many stellate cell.
So, we cant talk about the fine topography of the grid map

31. Finding about the fine scale topography
• Optical imaging with a two photon fluorescent calcium indicator would
improve the spatial resolution beyond that of electrodes…
This can be performed on behaving animals
Imaging is difficult to perform on entorhinal cortex

32. • Animals having prisms were then injected with virus which carries
genes for fluorescent Ca indicator GcAMP-6 and the mice is made to
run in a linear virtual environment( 2D environment )

33. How is grid pattern generated???? theory
• Involves continuous attractors
localized activity is present- to stop the
spread we need to put an inhibition around
this pattern is called Mexican hat pattern
Excitatory connections

34. Origin of hexagonal pattern
• Competition between self-exciting blobs with inhibitory surrounds
may cause the network to self-organize into a hexagonal pattern, in
which distances between blobs are maximized.

35. Summary
• Grid cell form Hexagonal pattern- represents the environment.
• Arranged in step like pattern called Modules represent the anatomical
space.
• The patter of modules are preserved across the environment
• Fine scale of the grid pattern can be given by 2-photon Ca imaging
using GcAMP-6.
• Generated by continuous attractors- Mexican Hat pattern with
inhibitory ring
• Hexagonal pattern is the most stable pattern

36. Relevance into medicine
• Better understanding of neural mechanisms underlying spatial
memory
• Episodic memory is affected in several brain disorders, including
dementia and Alzheimer’s disease
• O’Keefe also showed a showed in a mouse model of Alzheimer’s
disease that the degradation of place fields correlated with the
deterioration of the animals’ spatial memory (Cacucci et al., 2008)

37. REFERENCES
• Fyhn, M., Molden, S., Witter, M.P., Moser, E.I., and Moser, M.B. (2004). Spatial representation in
the entorhinal cortex. Science 305, 1258-1264.
• Woollett K. and Maguire E.A. (2011). Acquiring "the Knowledge" of London's layout drives
structural brain changes. Current. Biology, 21(24), 2109-2114
• Hafting, T., Fyhn, M., Molden, S., Moser, M.B., and Moser, E.I. (2005). Microstructure of a spatial
map in the entorhinal cortex. Nature 436, 801-806.
• Bonnevie, T., Dunn, B., Fyhn, M., Hafting, T., Derdikman, D., Kubie, J.L., Roudi, Y., Moser, E.I., and
Moser, M.B. (2013). Grid cells require excitatory drive from the hippocampus. Nature
Neuroscience 16, 309-317.
• Fyhn, M., Hafting, T., Treves, A., Moser, M.B., and Moser, E.I. (2007). Hippocampal remapping and
grid realignment in entorhinal cortex. Nature 446, 190-194.
• O'Keefe, J. (1976). Place units in the hippocampus of the freely moving rat. Experimental
neurology 51, 78-109.
• O'Keefe, J., and Conway, D.H. (1978). Hippocampal place units in the freely moving rat: why they
fire where they fire. Experimental brain research 31, 573-590.
• O'Keefe, J., and Nadel, L. (1978). The Hippocampus as a Cognitive Map (Oxford Univeristy Press ).
• Stensola, H., Stensola, T., Solstad, T., Froland, K., Moser, M.B., and Moser, E.I. (2012). The
entorhinal grid map is discretized. Nature 492, 72-78.

38. Thank you