MOSER, Edvard and May-Britt, GRID CELLS, Trondheim, April 10 2013

This is an endowed  Eric Shooter = ES lecture.
ES discovered neurotrophins at Stanford.
This is at 4PM Wednesday April 10, 2013 in Berg Hall in LKS Center at Stanford.

Intro by Lisa Giacomo  (who studied with them) : Asst Prof at Stanford: PhD 2008 from BU .
Mosers worked with John O'Keffe  (place cell discoverer).

Lisa pronounces  May-Britt as  MY-Britt.

They work in Trondheim, Norway. (in the far north).
Kavli Institute;

**************************** First Talk by May-Britt MOSER ***********************

title:  Grid Cells and the Neural Map of Space: Part I.

How do we know where we are?
She has been lost:  it's scary.

How does the brain compute position?
What are the elements and how do they interact?

EC  Tolman in Calif  ... studied spatial behavior.
He suggested that spatial knowledge is map-like:  1930 to 1950.

Patient HM =  Henry Molaison. (famous pt. who had surg. excision of medial temporal lobes)

medial temporal lobe structures importance. including HC = hippocampus.

this led to work of John O'Keefe at UCL = Univ Col. London;

in 1971 he recorded from single units from HC of freely moving animal.  (rabbit and/or rat)

she shows  a video clip
of Laura Colgin 2005 at U Texas.

of  rat with  head mounted electrodes roving in a cage.

one particular HC cell fires heavily when rat is in the northeast corner (and not otherwise);

each cell has a different  place where it fires.
(and you can predict where the animal is by observing which cells are firing)

2002:  CA1 cells continue to express place fields even after lesion of the intrinsic HC pathway.

(so, is it possible that the signals themselves originated in the EC = entorhinal cortex)

(this is in rats)

Mosers record from the dorsolateral nucleus of the EC.

she shows a clip:

this cell looks v different from a place cell.
(they video record a white dot (mounted on the rat's head) every time one of these grid cells fires.)

the task of the rat was looking for chocolates in its cage.

2005:  GRID CELLS form a grid:  if you connect their centers you get  a triangular grid.

but is this only in rats  (and only in Trondheim?? she jokes)

No!:  Lisa Giocomo replicates this work at Stanford. (so, it is not just in Trondheim)

in monkeys?  YES!  Killan, Jutras and Buffalo in Nature 2012;

2006:  Grid cells coexist with head-direction cells
(An inner compass: Ranck: 1985)

Sargolini  2006  Science 312: 758 to 762;

(head direction cells only fire when head is oriented in one direction:
she comments: this is great for demos for journalists!)

...And border cells  that fire specifically along local borders:  2008

Solstad 2008 in Science;

you can also introduce an extra wall (mid experiment) and the cell detects it.

Now,  what is the source of these computations?
eg  can place fields be constructed from grid cell firing patterns?

in 2006  that was our model...
we just assumed a linear sum:  with a convergence of grid cells to form place cells.

But are grid cells the only spatial input to place cells?

Stanford is heaven for molecular bio! (as she introduces her optogenetics work)

Optogenetic ID of HC-projecting cells in medial EC..

1)  we infused  AAV virus into HC,,, etc,''both HC and EC are red 
 (both were infected by injection into HC) and
both are labeled red. (by retrograde infection)
see Zhang 2013 in Science.

we found a  photoresponsive grid cell..(turn on the fiber optic light and the grid cell fires)

constant short-latency firing suggests that GRID CELLS DO project to the HC;

also found a photoresponsive border cell;

a " candle response"

head direction cells also project to HC.

all these cells have a latency of about 10 ms or so.

but... were these cells activated by the light or synaptically from some other region?

they tested the alveus... (much longer latency)
with alveus it is 15 to 20 ms  (rather than <10 ms)

how about backfiring  (antidromic firing)

we confirm that all cells from MEC stimulate HC  (MEC = medial EC)

does the HC have instrinsic mechanisms for gating selected partial inputs?

HC  receives input from a broad spectrum of medial EC cells types.

this may be more dynamic than our initial (static) model..

Summary:

grid cells, head direciton cells and border cells  and place clls are
the main compoents in Tolman's cognitive map...

Place cells are probably generated by convergence of signals from these.

Acknow and collabs:  many collabs/ large lab
and many funders:  Kavli;  NTNU,  Euro Commis.

Jennifer R asks Q: are there places where head direction cells are gated in?
(I missed her answer)

Q  are these cells environment dependent?  ie do they change in different spatial environments?

A  you can apply grid cells to any new environment;

Q (David Prince)  do maps change with age of the rat  (over time)
A : rats live for 2 years;  we  have recorded these over one year and they are
completely stable!!!

*************************  EDVARD MOSER begins his talk *********************

PART 2: (these talks are consecutive; this talk immediately follows the one above by May-Britt)

how are the grid cells organized among themselves? is there just one map or many?

Functional organiz of grid cells:

big finding:  these grids  come at different size scales:

cell 1:  eg  30 cms (from center to center of a grid cell)
but he shows some cells with 80 cm  (intercell distance);

the scale of grid cells increases topographically along the dorso-ventral axis of the medial EC. (Entorhinal Cortex)

but is this anatomy continuous or modular?

ie  is the anatomic change continuous or step-like...

really need to record many grid cells to determine this...
 the record number of cells from one rat is 186 cells ...

tangential approach of recording:  successively record large numbers of grid cells
(by slowly advancing an electrode tangentially  )

it IS a STEP-LIKE CHANGE...  ie, the grids are discretely arranged!

Edvard shows  that as you move ventralward the grid size increases!  (in a step-like fashion)

see Stensola et al in Nature 2012...

so, these are discrete steps... but do they differ in other ways?

do they differ on other grid properties?

the main result:  each scale has a unique head orientation tuning...

so, orientation and scale change together;

the small scale cells have several different orientations...

how many grid modules are there? (answer is 4, maybe 5)

using k-means clustering, he shows that there were 4 discrete modules
in one partic rat in which 176 cells were recorded.

the smallest grid was about 50 cm and the biggest was about 120 cm  (center to center);

grid modules change only along the dorsoventral axis  (is they are horizontal bands)
(but there is a lot of overlap btwn modules)

the bigger scale modules are ventralward.

how rigid is the grid map?

he compares  16 rats..

all animals have discrete modules  but they are each different
(so that if you do a group average , it obscures this discreteness)

but the scale ratio of successive moduels is constant!  (and the avg ratio is  1.421  !!)
ie  areas are  doubled  as you go from one scale to the next  (1.421 = sqrt of 2)

are grid modules functionally discrete?  (or do they interact)

The SQUEEZE experiment = expt;

Yes.  modules do respond independently to geometric transformation of the (cage/ maze/ enviro)
eg  by squeezing it to change it from a square to a rectangle...

bottom line:  small module and big module  operate independently;

what could be the advantage of a modular organization of grid cells?

he speculates:  different combinations could form a large combo of codes for the HC
to use for eg  global remapping as you go from say the bedroom to the bathroom;

is there functional topography in other EC cell types?

grid cells coexist with head-direction cells...

Lisa Giocomo showed that EC head direciton cells also exhibit dorso-ventral topography..

dorsalmost  cells  are v sharply tuned  ( v direction specific)  but this
almost disappears witht the ventralmost cells.

same effect was shown in mice as in rats...

is the head direction gradient discrete or continuous?  this is early work
but it appears to be continuous  (discrete effect is not detectable so far)

Mechanism of the grip pattern : what is it? 
(this section of the talk is complex and speculative)
how could grid cells form?

see Fuhs and Touretzky J Neurosci 2006

Network modules for grid cells have 2 components: (so the initial proposal goes)

1)  cells with similar fields mutually excit each other  surrounded by a ring
of inhibition  (a Mexican hat distrib);

multiple blobs then would form by competitive interaction in which the distance btwn interacting blobs is maximized.

component 2) (in this proposal)

activity is then translated (in space)  in proportion to the animal's speed and direction.

But  ... a major problem for this fine theory:  (Mexican hat theoretical proposal does not actually seem to exist);
all connections that they actually found were inhibitory  ...
 there were NO excitatory connections btwn stellate cells
(and they looked at 600 connections)

so, back to the drawing board...

they tested a computat model with a hexagonal grid connected only by all-or-none inhibition...

but you need an external source of excitation (since all the cells are mutually inhibitory)

we used muscimol to silence the HC... then the grid cells disappear;

Acknowledgement and collabs:  large lab;

Barabara T: Q  what's more important  locomotion or vision?
A: both;  must have access to velocity info; but
vision is obviously important for maintaining stability (eg with visual cues)

Q:  is there a correspondence btwn  grid cell size and the mouse's spatial ability...
(missed answer)

Q:  role of learning and role of task?
A  :  if you divide up the maze into different regions then you get separate maps for each region (but these are stable over time)

Jay McC Q:  consider patient HM;  he could do well in his own home but not in novel areas..
so, , Jay surmises, perhaps HC is important in learning but not so much in navigation...

A:  certain tasks  (eg in Larry Squire's expts)  may be capable of being done by other systems 
 (rather than just EC navigation system);  prob. have backup systems  that do not involve EC cortex.