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L46. SPATIAL NAVIGATION

BioNB424

Nov. 16, 2011

Rattus norvegicus

CA1

neuron

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Rattus norvegicus

What do we know about the ecology of rats?

Cosmopolitan

Human settlements

Nocturnal

Diet

L =

W=

Origin

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Rattus belongs to Rodentia Rodentia Rodents: mice, rats, hamsters, squirrels, gophers, porcupines, beavers, etc.

Wild Rattus live in burrows

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Calhoun (1963) kept rats in a semi-natural enclosure. Norway rats dug

underground tunnels and chambers.

f. food

n. nest

e. entrance

e e e

e

e e e

e

e

e

e

e e

e

n

n n

f

f

f

Calhoun, 1963 J.B. Calhoun, The Ecology and Sociology of the Norway Rat. U.S. Public Health Service Publication No.

1008, (1963).

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Rats were used in early behavioral studies

Psychology testing.

Model of human behavior

Easy

Maze running

Edward Tolman (1886-1959).

(focus on behavior)

Maze learning

‘cognitive map’

‘Latent learning’

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Radial Arm Maze

David Olton

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Radial Arm Maze

food reward

at end of each

arm

Observe path taken

to find food pellets,

depending on cues

available in different

arms of maze.

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Olton Radial Arm Maze

Typical track of rat in radial arm

maze.

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Hippocampus

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Evidence that Hippocampus is involved in

spatial memory

Human patient, H.M. (studied by Brenda Milner and surgeon William

Scoville (1950’s).

Scoville Henry Molaison Brenda Milner

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Lesion in H.M.

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2 3

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Popular thriller film, MEMENTO depicts human

with memory loss after hippocampal lesion

(caused by bullet wound)

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dentate gyrus

granule cells

CA3

CA1 cells

ENTORHINAL CORTEX

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Cajal’s circuit diagram of

Hippocampus

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Hippocampal Formation

Trisynaptic pathway:

(1) fibers enter

Hippocampus from

perforant pathway

(which originates in the

entorhinal cortex) to

terminate on Granule

cells.

2) Mossy fiberts

connect the dentate to

CA3 neurons.

3) Schaffer collaterals

of the CA3 connect to

CA1 pyramidal cells. -

-Commissural

connections which

pass through Fimbria

to synapse on CA1

cells.

Carew (2000)

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2) Lesions to

Hippocampus impairs

spatial learning in

rodents

Olton, 1977 (from Carew, 2000)

mean

correct

responses

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3) Behavior in Morris Water Maze

Rat in Morris water maze swims in

cloudy water, submerged platform is

hidden from view.

Platform is fixed in position relative to

external visual cues.

Testing: probe trials test for swimming

quadrants with no platform after

training with platform.

http://www.sciam.com/article.cfm?articleID=000DA854-8ACE-1CBD-B4A8809EC588EEDF&sc=I100322

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…shows deficit after hippocampal lesion

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4) Imaging of Human Brain shows involvement of right

Hippocampus During Spatial Memory Tasks

Human subject watching film

about vehicle driving from point A

to point B in Irish town.

Control: film of cars moving past

non-moving point in space

(activity difference shown as

colored area).

Human taxi driver mentally

recalling route around city of

London.

Right hippocampus activity only.

From Maguire (1996).

Image show area of increased

blood flow measured by FMRI

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Hippocampal volume of London TaxiDrivers is slightly larger than

control subjects (non-taxidriver)

Elanor Maguire et al (2000)

Volume of posterior hippocampus increases with

time on job (as Taxidriver).

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The Rodent (Rat) Hippocampus

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Rodent Hippocampus

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Hippocampal Formation

Carew (2000)

Dentate Gyrus

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Place Cells in the Hippocampus

Discovered in 1971 by

John O’Keefe and John

Dostrovsky. Recording

from single cells in

hippocampus while freely

moving rat move around in

a closed space.

Spike recordings from CA1

cell.

Where was the rat when

the cell fired?

Muller, Kubie, Ranck (1987)

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Place Cells in the Hippocampus

white cue card (photo) provides cue of

location.

Not odor.

--Rotate card, response field changes.

No change in firing pattern when lights

are off. the lights are off and cue card

is not visible.

Rat is capable of “dead reckoning”

using idoeothetic (internally-generated)

cues (such as acceleration, gravity,

distance walked, etc.)

experiments of Muller, Kubie, Ranck, (1987)

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Properties of Place Cells

Place cells are the CA1 Pyramidal neurons

that serve as the output cells for the

hippocampus.

Place cells are sometimes broadly

responsive, sometimes focused point in

space, sometime more than one place.

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Place cells are stable over time

Recording of a single place cell over a

19 day period.

On each day indicated, the rat was

placed in the same circular arena to

record spikes from the same large

pyramidal neuron (implanted

electrode).

Eric Hargreaves

Robert Muller Lab

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Properties of Place Cells

Position of place cells is influenced by visual cues, and by vestibular

cues.

According to O’Keefe and Nadel (1978). The hippocampus, with its

place cells, is the site for the cognitive map (although there is no

evidence that the place cells are mapped in any way).

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Place cells can fire in anticipation of a turn in a given maze.

prior to a left turn

trial, cell fires very

little

Prior to right turn

trial, vigorous

firing.

Rat is trained to

turn left, and

then turn right

on successive

runs through

maze.

From experiments of Howard

Eichenbaum.

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Head direction cells

Navigation requires both a ‘map’

of space and a compass to tell

direction.

Head direction specific cells

discovered James Ranck (1984) in

postsubiciculum.

Cells fire when head is in fixed

direction, both in standard and in

novel environments.

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Synaptic plasticity in the Hippocampus

Stimulation at any one of the three

excitatory connections shows plasticity

(Bliss and Lømo, 1973)

Brief, high frequency burst causes

increased EPSP. Can last for hours.

Long Term Potentiation (LTP).

Stimulation of Schaffer collaterals, record

from CA1 neuron in the hippocampus.

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LTP Characteristics

Stimulation of just a few

fibers does not generate an

LTP. Instead, different inputs

must cooperate to get the

effect.

Here, just a weak input is

given shocks. No LTP.

Similar stimulation of strong

input gives LTP.

Specificity: Stong stimulation at one

site produces LTP there, but there

is no LTP at a different site. The

effect is plasticity at the post

synaptic site.

If a weak input arrives at the

same time as a strong input,

there will be association

between the two. LTP will be

produced at the weak input.

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LTP mediated by NMDA type Glutamate Receptor

The NMDA

receptor binds to

glutamate,

opens a channel

for Calcium ions.

In the absence

of cell

depolarization,

Mg++ ions plug

up the NMDA

receptor, not

much of a

response

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NMDA Receptor Allows Coincidence Detection in Post-

Synaptic Neuron

When the cell is

depolarized (say,

by activating a

second pathway,

which may also

involve a

glutamate

receptor), the

Mg++ pops out of

the pore.

Extra Ca++ .

stronger

response; bigger

EPSP.

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NMDA: Double-Gated

Requires synaptic transmitter (glutamate).

Requires simultaneous depolarization of

terminal.

LTP: an example of a synapse that shows

Hebbian Learning

(if a pre-synaptic fiber was active when a post synaptic cell fired,

the synapse should be strengthened).

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LTP’s role in spatial learning can be established by

specific inhibitors of NMDA receptors

• AP5 is NMDA blocker. What is

the spatial learning in AP5

mice?

• chronic AP5 infusion causes

failure to learn on Morris water

maze

• Results of water maze learning

trials comparing normal to AP5

treated mice. 8 days of

training, results of test trial on

9th

day.

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Transgenic + Knockout Mice

Now possible to knock out a gene for a

specific receptor, in a specific part of

brain.

Combine transgenic mouse (insert new

gene) with gene knockout that control

expression in specific cell types.

Expression of a modified NMDA receptor in

CA1 neurons in mouse.

Tonegawa et al

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Mutant has defect in the LTP behavior in the

Schaffer collateral pathway in the

Hippocampus. (Input to CA1 cells)

In the Morris water maze, mutant mice do not learn the position of the platform

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Recording from Place Cells in Virtual Reality

Environment Permits Intracellular Recording

Harvey, C. D., Collman,

F., Dombeck, D. A. and

Tank, D. W. (2009).

Intracellular dynamics of

hippocampal place cells

during virtual navigation.

Nature 461, 941-946.

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Harvey, C. D., Collman, F., Dombeck, D. A. and Tank, D. W. (2009). Intracellular dynamics of hippocampal place cells

during virtual navigation. Nature 461, 941-946.

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Harvey, C. D., Collman, F., Dombeck, D. A. and Tank, D. W. (2009).

Intracellular dynamics of hippocampal place cells during virtual navigation. Nature 461,

941-946.

rewards obtained in

session 4

session 10

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Nature (2009)

Video link

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Evidence for

“place cell”

responses in

VR.

extracellular

recording

ISI histogram

3 place cells in

3 mice.

spikes vs.

theta waves in

hippocampus

phase

precession

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Summary:

Spatial navigation requires the ability to recall

landmarks, and to rely upon internal (ideothetic)

cues about movement and direction.

Spatial learning has been studied in mazes in the

laboratory.

Lesions in the hippocampus produce spatial learning

deficits.

The hippocampus appears active during spatial

learning tasks.

The hippocampus is enlarged in certain individuals

that perform demanding spatial tasks.

Place cells appear to respond to specific places in

environment.

Head direction cells respond to particular directions

of head in the environment.

Cells in hippocampus give plastic responses to

electrical stimulation. Basis is NMDA receptor.

Blockade or genetic modification of NMDA receptor

impairs spatial memory, even when restricted to CA1

cells of Hippocampus.

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Hippocampal formation

Cell bodies of CA1 neurons

CA2 neurons

CA3 neurons CA1

neuron