Transcript No Slide Title

The assessment of working memory
in rodents
Dr. Paul Dudchenko
University of Stirling
United Kingdom
outline
• how is working memory defined?
• how is working memory measured in the rodent?
• neural substrates of working memory
How is working memory defined?
Baddeley and Hitch (1974): Working memory is comprised of a
visual-spatial sketchpad, an episodic buffer, a phonological loop, all of which
are controlled by a central executive. (humans)
Honig (1978): Working memory is a representation of a cue over
a delay period in which the cue is not present, to be subsequently
used to respond. (pigeons)
Olton, Becker, and Handelman (1979): Spatial working memory,
but not reference memory, depends on the hippocampus. (rats)
Goldman-Rakic (1980s; Fuster, Kubota 1970s): Working memory
operationalised as the on-line representation of a stimulus over a
delay period in the pre-frontal cortex. (monkeys)
Dudchenko (2004): Working memory is a short term memory for an
object, stimulus, or location that is used within a testing session, but
not typically between sessions. (rats)
Neanderthals had a limited capacity
to hold and manipulate information.
Working memory may underlie ability
to imagine future events.
“On the basis of brain-imaging studies and other
research, [Daniel] Schacter and Donna Rose Addis
of the University of Aukland have concluded that
the same neural networks Are implicated in both
remembering the past and imagining the future and
that both processes probably involve something
like Baddeley’s proposed episodic buffer.
“Working memory is criticially important for
constructing simulations of future events,” Shacter
says.”
Michael Balter (2010) Did working memory spark creative culture?
Science
outline
• what is working memory?
• how is working memory measured in the rodent?
• neural substrates of working memory
• all spatial working memory tasks
• all depend on the hippocampus/medial temporal cortex
From: Hagan and Jones (2005) Predicting drug efficacy for cognitive deficits in schizophrenia
Schizophrenia Bulletin, 31(4): 830-853
How long after the determining
stimulus can an animal wait and
still react correctly? (pg. 2)
1913
Hunter observed delaydependent memory.
Rats could remember which
light had been illuminated
after a delay of up to 10s.
Hunter (1913)
However:
“The rat, when put into the release
box during the delayed reaction,
oriented immediately to the light with its
entire body, and began a series of
attacks on that side of the box in an
effort to get out.” (pg. 41)
“Mediating behaviours” during the delay between the to-be-remembered stimulus and
the response has also been observed in operant delayed non-matching to position tasks
(Dudchenko & Sarter (1992); Chudasama & Muir (1997)).
sample
delay
choice
• So, one of the intrinsic challenges in developing valid rodent
memory tasks is ensuring that delays can’t be bridged by a
behavioral response.
A simple way of testing short-term memory is the
delayed alternation task on a T-maze.
sample
choice
Start arm
Start arm
number of correct responses
Performance on the T-maze is delay-dependent
6
5
4
chance
3
2
0s
10s
1min
2min
memory delay
5min
10min
Average number correct
Working memory on the radial arm maze
Olton and Samuelson (1976)
4
3
2
chance
1
5 min
20 min 60 min 120 min 240 min
Memory delay
Bolhuis et al (1996)
From: Neuroscience exploring the brain, Bear, Connors, Pardiso (2001)
outline
• what is working memory?
• how is working memory measured in the rodent?
• neural substrates of working memory
Brain circuits implicated in neurocognitive deficits in schizophrenia
Prefrontal Cortex
Amygdala
Temporal Cortex
Striatum
VP
BFCS
Midbrain DA neurons
Raphe 5HT neurons
slide from Dr. Holly Moore
14
10
chance
6
control
hippocampus lesion
2
1
2
3
Session block
4
percent correct
Number correct
18
100
90
80
70
60
50
40
control
chance
10s
30s
medial
prefrontal
cortex
1min
memory delay
Aggleton et al. (1995) J. Neuroscience
A spatial span memory task
Odor span memory in rodents is excellent, but may not require the hippocampus.
• The hippocampus is required for remembering the order in which odors are presented
(Fortin et al. 2002).
• Humans with hippocampus damage are impaired on an odor span task (Levy et al.
2006).
Odor span: neural substrates
•Removal of basal forebrain cholinergic neurons impairs performance on this task (Turchi
and Sarter, 2000).
• Removal of cholinergic inputs to the entorhinal cortex does not impair memory for familiar
odors, but does impair memory for new ones (McGaughy et al. , 2005).
• Mice without α7 nicotinic acetylcholine receptor are impaired on the odor span task
(Young et al. 2007).
• Nicotine improves odor span memory; scopolamine and mecamylamine impair it
(Young et al. 2006; Rushforth et al. , 2010).
• Odor span also impaired in mice that over-express β-amyloid (Young et al. 2009).
Neurons in the hippocampus fire with respect to the rat’s
future destination.
no
reward
reward
no
reward
reward
Ainge et al. (2007) Journal of Neuroscience
goal 2
goal 1
goal 3
goal 4
food
if food is found on
every maze arm
(so no memory is
required)…
food
food
food
…place cells no longer encode
different maze arms
Stevenson et al. (2010) SFN abstracts
summary
• notions of working memory have developed independently
in the human and non-human literatures
• in rodents, working memory has been operationalized a
delay-dependent, short-term memory for a location, object,
or stimulus
• in rodents, spatial working memory requires the temporal
cortex and hippocampus, and neurons in the hippocampus fire
with respect to future goal locations
• as such, rodent spatial working memory tasks may reflect
the “episodic buffer” portion of Baddeley’s human working memory
model
Differential activity was also seen before the second choice point
A)
B)
first run
start
box
goal
box
second run
Dennis (1939)
food
Delay
box
food
Ladieu (1944)
Average Number Correct
Cue
No cue
6
5
4
3
chance
2
0s
10 s
1 min 2 min 5 min 10 min
Memory Delay
sample
choice
Ennaceur & Delacour (1988)
sample
100
delay
(0-6 sec)
choice
Percent correct
90
80
70
60
50
40
0
1
3
memory delay (seconds)
6
Control
Hippocampus lesion
An olfactory “span” memory task
Distribution of correct choices on the odor
span task with 12 odors
100
All animals
chance
% correct
80
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10 11
number of odors to remember (span)
left-turn trials
right-turn trials
*
*
*
40
30
20
10
0
10
Mean firing rate (Hz)
20
Modified T-maze spatial alternation task
Do place cells that fire on the
central stem of the T-maze
differentiate between leftturn and right-turn trials?
left-turn trial
right turn trial
Wood, Dudchenko, Robitsek
Eichenbaum (2000)
Neuron, 27: 623-633