The assessment of working memory in rodents Dr. Paul Dudchenko University 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 which are 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 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. “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 ability to 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 schizophrenia Schizophrenia Bulletin, 31(4): all spatial working memory tasks all depend on the hippocampus/medial temporal cortex

1913 How long after the determining stimulus can an animal wait and still react correctly? (pg. 2)

Hunter (1913) Rats could remember which light had been illuminated after a delay of up to 10s. 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) Hunter observed delay- dependent memory.

sampledelaychoice “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 number of correct responses memory delay chance

Working memory on the radial arm maze Olton and Samuelson (1976) min20 min60 min120 min240 min Average number correct 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

Number correct hippocampus lesion control Session block chance memory delay percent correct 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 (Turchi and 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 no reward no reward Neurons in the hippocampus fire with respect to the rat’s future destination. Ainge et al. (2007) Journal of Neuroscience

goal 1 goal 2goal 3 goal 4

Stevenson et al. (2010) SFN abstracts food if food is found on every maze arm (so no memory is required)… …place cells no longer encode different 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

Delay box food A) B) first run second run start box goal box Dennis (1939)Ladieu (1944)

s10 s1 min2 min5 min10 min Memory Delay Average Number Correct Cue No cue chance

samplechoice Ennaceur & Delacour (1988)

sample delay (0-6 sec) choice

ControlHippocampus lesion

An olfactory “span” memory task

Distribution of correct choices on the odor span task with 12 odors number of odors to remember (span) % correct All animals chance

left-turn trials right-turn trials * * *

Modified T-maze spatial alternation task left-turn trial right turn trial Do place cells that fire on the central stem of the T-maze differentiate between left- turn and right-turn trials? Wood, Dudchenko, Robitsek, Eichenbaum (2000) Neuron, 27: