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)

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5 min 20 min 60 min 120 min 240 minAve

rage

num

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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

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orre

ct

2

6

10

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18

hippocampus lesioncontrol

1 2 3 4

Session block

chance

memory delay

perc

ent c

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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)

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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

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00 11 22 33 44 55 66 77 88 99 1010 1111

number of odors to remember (span)number of odors to remember (span)

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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