the assessment of working memory in rodents dr. paul dudchenko university of stirling united kingdom
TRANSCRIPT
The assessment of working memory in rodents
Dr. Paul DudchenkoUniversity of Stirling
United Kingdom
outline
• how is working memory defined?
• neural substrates of working memory
• how is working memory measured in the rodent?
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)
Baddeley and Hitch (1974): Working memory is comprised of a visual-spatial sketchpad, an episodic buffer, a phonological loop, all of whichare controlled by a central executive. (humans)
Olton, Becker, and Handelman (1979): Spatial working memory, but not reference memory, depends on the hippocampus. (rats)
How is working memory defined?
Goldman-Rakic (1980s; Fuster, Kubota 1970s): Working memoryoperationalised as the on-line representation of a stimulus over adelay period in the pre-frontal cortex. (monkeys)
Dudchenko (2004): Working memory is a short term memory for anobject, 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.
“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
Working memory may underlie abilityto imagine future events.
outline
• what is working memory?
• how is working memory measured in the rodent?
• neural substrates of working memory
From: Hagan and Jones (2005) Predicting drug efficacy for cognitive deficits in schizophreniaSchizophrenia Bulletin, 31(4): 830-853
• all spatial working memory tasks
• all depend on the hippocampus/medial temporal cortex
1913
How long after the determining stimulus can an animal wait andstill react correctly? (pg. 2)
Hunter (1913)
Rats could remember whichlight had been illuminatedafter a delay of up to 10s.
However:“The rat, when put into the releasebox during the delayed reaction, oriented immediately to the light with itsentire body, and began a series ofattacks on that side of the box in aneffort to get out.” (pg. 41)
Hunter observed delay-dependent memory.
sample delay choice
“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)).
• So, one of the intrinsic challenges in developing valid rodent memory tasks is ensuring that delays can’t be bridged by a behavioral response.
sample
Start arm
choice
Start arm
delay
A simple way of testing short-term memory is the delayed alternation task on a T-maze.
Performance on the T-maze is delay-dependent
num
ber o
f cor
rect
resp
onse
s
memory delay
chance
Working memory on the radial arm mazeOlton and Samuelson (1976)
1
2
3
4
5 min 20 min 60 min 120 min 240 minAve
rage
num
ber
corr
ect
Memory delay
chance
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
Striatum VP
Amygdala
Midbrain DA neurons
Temporal Cortex
BFCS
Raphe 5HT neurons
slide from Dr. Holly Moore
Num
ber c
orre
ct
2
6
10
14
18
hippocampus lesioncontrol
1 2 3 4
Session block
chance
memory delay
perc
ent c
orre
ct
chance
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).
•Removal of basal forebrain cholinergic neurons impairs performance on this task (Turchiand Sarter, 2000).
Odor span: neural substrates
• 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).
• Nicotine improves odor span memory; scopolamine and mecamylamine impair it (Young et al. 2006; Rushforth et al. , 2010).
• Mice without α7 nicotinic acetylcholine receptor are impaired on the odor span task (Young et al. 2007).
• Odor span also impaired in mice that over-express β-amyloid (Young et al. 2009).
reward
reward
noreward
noreward
Neurons in the hippocampus fire with respect to the rat’sfuture destination.
Ainge et al. (2007) Journal of Neuroscience
goal 1
goal 2 goal 3
goal 4
Stevenson et al. (2010) SFN abstracts
food
food food
food
if food is found onevery maze arm (so no memory isrequired)…
…place cells no longer encodedifferent maze arms
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
Delayboxfood food
A) B)first run
second run
startbox
goalbox
Dennis (1939) Ladieu (1944)
2
3
4
5
6
0 s 10 s 1 min 2 min 5 min 10 min
Memory Delay
Ave
rage
Num
ber
Cor
rect Cue
No cue
chance
sample choice
Ennaceur & Delacour (1988)
sample
delay (0-6 sec)
choice
Control Hippocampus lesion
An olfactory “span” memory task
Distribution of correct choices on the odorDistribution of correct choices on the odorspan task with 12 odorsspan task with 12 odors
00
2020
4040
6060
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100100
00 11 22 33 44 55 66 77 88 99 1010 1111
number of odors to remember (span)number of odors to remember (span)
% c
orr
ec
t%
co
rre
ct
All animalsAll animals
chancechance
left-turn trialsleft-turn trials right-turn trialsright-turn trials
40 30 20 10 0 10 20
Mean firing rate (Hz)
***
Modified T-maze spatial alternation taskModified T-maze spatial alternation task
left-turn trialleft-turn trial
right turn trialright turn trial
Do place cells that fire on the Do place cells that fire on the central stem of the T-maze central stem of the T-maze differentiate between left-differentiate between left-turn and right-turn trials?turn and right-turn trials?
Wood, Dudchenko, Robitsek,Eichenbaum (2000)Neuron, 27: 623-633